AU705083B2 - Multi-functional hematopoietic receptor agonists - Google Patents

Description

wn 07/ 109a5 DP/'1" T/nU 1 1 1 m MULTI-FUNCTIONAL HEMATOPOIETIC RECEPTOR AGONISTS The present application claims priority under 35 USC §119(e) of United States provisional application Serial No.

60/004,834 filed October 05, 1995.

Field of the Invention The present invention relates to multi-functional hematopoietic receptor agonists.

Background of the Invention Colony stimulating factors (CSFs) which stimulate the differentiation and/or proliferation of bone marrow cells have generated much interest because of their therapeutic potential for restoring depressed levels of hematopoietic stem cell-derived cells. CSFs in both human and murine systems have been identified and distinguished according to their activities. For example, granulocyte-CSF (G-CSF) and macrophage-CSF (M-CSF) stimulate the in vitro formation of neutrophilic granulocyte and macrophage colonies, respectively, while GM-CSF and interleukin-3 (IL-3) have broader activities and stimulate the formation of both macrophage, neutrophilic and eosinophilic granulocyte colonies. IL-3 also stimulates the formation of mast, megakaryocyte and pure and mixed erythroid colonies.

U.S. 4,877,729 and U.S. 4,959,455 disclose human IL-3 and gibbon IL-3 cDNAs and the protein sequences for which they code. The hIL-3 disclosed has serine rather than proline at position 8 in the protein sequence.

International Patent Application (PCT) WO 88/00598 discloses gibbon- and human-like IL-3. The hIL-3 contains a Ser 8 Pro 8 replacement. Suggestions are made to replace Cys by Ser, thereby breaking the disulfide bridge, and to replace one or more amino acids at the glycosylation sites.

WO 97/12985 PC"rT/T TC c" 2 V I0 U.S. 4,810,643 discloses the DNA sequence encoding human G-CSF.

WO 91/02754 discloses a fusion protein comprised of GM- CSF and IL-3 which has increased biological activity compared to GM-CSF or IL-3 alone. Also disclosed are nonglycosylated IL-3 and GM-CSF analog proteins as components of the multi-functional hematopoietic receptor agonist.

WO 92/04455 discloses fusion proteins composed of IL-3 fused to a lymphokine selected from the group consisting of IL-3, IL-6, IL-7, IL-9, IL-11, EPO and G-CSF.

WO 95/21197 and WO 95/21254 disclose fusion proteins capable of broad multi-functional hematopoietic properties.

GB 2,285,446 relates to the c-mpl ligand (thrombopoietin) and various forms of thrombopoietin which are shown to influence the replication, differentiation and maturation of megakaryocytes and megakaryocytes progenitors which may be used for the treatment of thrombocytopenia.

EP 675,201 Al relates to the c-mpl ligand (Megakaryocyte growth and development factor (MGDF), allelic variations of c-mpl ligand and c-mpl ligand attached to water soluble polymers such as polyethylene glycol.

WO 95/21920 provides the murine and human c-mpl ligand and polypeptide fragments thereof. The proteins are useful for in vivo and ex vivo therapy for stimulating platelet production.

Rearrangement of Protein Sequences In evolution, rearrangements of DNA sequences serve an important role in generating a diversity of protein structure and function. Gene duplication and exon shuffling provide an important mechanism to rapidly generate diversity and thereby provide organisms with a competitive advantage, especially since the basal mutation rate is low (Doolittle, WO 97/12985 PCT/ TSQA /I 7P A Protein Science 1:191-200, 1992).

The development of recombinant DNA methods has made it possible to study the effects of sequence transposition on protein folding, structure and function. The approach used in creating new sequences resembles that of naturally occurring pairs of proteins that are related by linear reorganization of their amino acid sequences (Cunningham, et al., Proc. Natl. Acad. Sci. U.S.A. 76:3218-3222, 1979; Teather Erfle, J. Bacteriol. 172: 3837-3841, 1990; Schimming et al., Eur. J. Biochem. 204: 13-19, 1992; Yamiuchi and Minamikawa, FEBS Lett. 260:127-130, 1991; MacGregor et al., FEBS Lett. 378:263-266). The first in vitro application of this type of rearrangement to proteins was described by Goldenberg and Creighton Mol. Biol.

165:407-413, 1983). A new N-terminus is selected at an internal site (breakpoint) of the original sequence, the new sequence having the same order of amino acids as the original from the breakpoint until it reaches an amino acid that is at or near the original C-terminus. At this point the new sequence is joined, either directly or through an additional portion of sequence (linker), to an amino acid that is at or near the original N-terminus, and the new sequence continues with the same sequence as the original until it reaches a point that is at or near the amino acid that was N-terminal to the breakpoint site of the original sequence, this residue forming the new C-terminus of the chain.

This approach has been applied to proteins which range in size from 58 to 462 amino acids (Goldenberg Creighton, J. Mol. Biol. 165:407-413, 1983; Li Coffino, Mol. Cell.

Biol. 13:2377-2383, 1993). The proteins examined have represented a broad range of structural classes, including proteins that contain predominantly a-helix (interleukin-4; Kreitman et al., Cytokine 7:311-318, 1995), P-sheet (interleukin-1; Horlick et al., Protein Eng. 5:427-431, WO 97/12985 PCT/US96/1 5774 4 1992), or mixtures of the two (yeast phosphoribosyl anthranilate isomerase; Luger et al., Science 243:206-210, 1989). Broad categories of protein function are represented in these sequence reorganization studies: Enzymes T4 lysozyme dihydrofolate reductase ribonuclease T1 Bacillus P-glucanse Zhang et al., Biochemistry 32:12311-12318, 1993; Zhang et al., Nature Struct. Biol. 1:434-438 (1995) Buchwalder et al., Biochemistry 31:1621-1630, 1994; Protasova et al., Prot. Eng. 7:1373-1377, 1995) Mullins et al., J. Am. Chem. Soc.

116:5529-5533, 1994; Garrett et al., Protein Science 5:204-211, 1996) Hahn et al., Proc. Natl. Acad. Sci.

U.S.A. 91:10417-10421, 1994) Yang Schachman, Proc. Natl. Acad.

Sci. U.S.A. 90:11980-11984, 1993) Luger et al., Science 243:206-210 (1989; Luger et al., Prot. Eng.

3:249-258, 1990) Lin et al., Protein Science 4:159- 166, 1995) Vignais et al., Protein Science 4:994-1000, 1995) aspartate transcarbamoylase phosphoribosyl anthranilate isomerase pepsin/pepsinogen glyceraldehyde-3phosphate dehydro- WO 97/12985 WO 9712985PCT/US96/15774 genase orni thine decarboxylase yeast phosphoglycerate dehydrogenase Li Coffino, Mol. Cell. Biol.

13:2377-2383, 1993) Ritco-Vonsovici et al., Biochemistry 34:16543-16551, 1995) Enzyme Inhibitor basic pancreatic trypsin inhibitor Cytokines interleukin-f3 interleukin-4 Goldenberg Creighton, J. Mol.

Biol. 165:407-413, 19873-) Horlick et al., Protein .Eng. 5:427- 431, 1992) Kreitman et al., Cytokine 7:311- 318, 1995) Tyrosine Kinase Recognition Domain a-spectrin SH3 domain Viguera, et al., T.

M01. Biol. 247:670-681, 1995) Transmembrane Protein omp A Koebnik Kramer, J. Mol. Biol.

250:617-626, 1995) Chimeric Protein WO 97/12985 PCT/US96/1 5774 6 interleukin-4- Kreitman et al., Proc. Natl. Acad.

Pseudomonas Sci. U.S.A. 91:6889-6893, 1994).

exotoxin The results of these studies have been highly variable.

In many cases substantially lower activity, solubility or thermodynamic stability were observed coli dihydrofolate reductase, aspartate transcarbamoylase, phosphoribosyl anthranilate isomerase, glyceraldehyde-3-phosphate dehydrogenase, ornithine decarboxylase, omp A, yeast phosphoglycerate dehydrogenase). In other cases, the sequence rearranged protein appeared to have many nearly identical properties as its natural counterpart (basic pancreatic trypsin inhibitor, T4 lysozyme, ribonuclease T1 Bacillus P-glucanase, interleukin-l1, a-spectrin SH3 domain, pepsinogen, interleukin-4). In exceptional cases, an unexpected improvement over some properties of the natural sequence was observed, the solubility and refolding rate for rearranged a-spectrin SH3 domain sequences, and the receptor affinity and anti-tumor activity of transposed interleukin-4-Pseudomonas exotoxin fusion molecule (Kreitman et al., Proc. Natl. Acad. Sci. U.S.A. 91:6889-6893, 1994; Kreitman et al., Cancer Res. 55:3357-3363, 1995).

The primary motivation for these types of studies has been to study the role of short-range and long-range interactions in protein folding and stability. Sequence rearrangements of this type convert a subset of interactions that are long-range in the original sequence into shortrange interactions in the new sequence, and vice versa. The fact that many of these sequence rearrangements are able to attain a conformation with at least some activity is persuasive evidence that protein folding occurs by multiple folding pathways (Viguera, et al., J. Mol. Biol. 247:670- 681, 1995). In the case of the SH3 domain of a-spectrin, choosing new termini at locations that corresponded to 3- WO 97/12985 PCT/US9/1 5774 7 hairpin turns resulted in proteins with slightly less stability, but which were nevertheless able to fold.

The positions of the internal breakpoints used in the studies cited here are found exclusively on the surface of proteins, and are distributed throughout the linear sequence without any obvious bias towards the ends or the middle (the variation in the relative distance from the original N-terminus to the breakpoint is ca. 10 to 80% of the total sequence length). The linkers connecting the original N- and C-termini in these studies have ranged from 0 to 9 residues. In one case (Yang Schachman, Proc. Natl.

Acad. Sci. U.S.A. 90:11980-11984, 1993), a portion of sequence has been deleted from the original- C-terminal segment, and the connection made from the truncated Cterminus to the original N-terminus. Flexible hydrophilic residues such as Gly and Ser are frequently used in the linkers. Viguera, et al.(J. Mol. Biol. 247:670-681, 1995) compared joining the original N- and C- termini with 3- or 4-residue linkers; the 3-residue linker was less thermodynamically stable. Protasova et al. (Protein Eng.

7:1373-1377, 1994) used 3- or 5-residue linkers in connecting the original N-termini of E. coli dihydrofolate reductase; only the 3-residue linker produced protein in good yield.

WO 97/12985 PCT/US96/15774 8 Summary of the Invention Novel hematopoietic proteins of this invention are represented by the formulas: R1-L1-R2, R2-L1-R1, R1-R2, or R2-R1 wherein R1 and R2 are independently selected from the group consisting of; A polypeptide comprising; a modified human G-CSF amino acid sequence of the formula: 1 Xaa Leu Ala Xaa Ala Xaa Leu Xaa Gin Gin Gly Xaa Leu Xaa Glu Pro Leu Gin Thr 120 Gln Gly 150 Gly Xaa Xaa Leu Xaa Leu Ser Ala Leu Met Ala Val Gly Pro Xaa Xaa Gin Glu Xaa Val Ser Ser Gin Leu Leu Glu Gin Xaa Glu Xaa Met Pro Leu Val Ala Glu Xaa Xaa Xaa His Gly Asp Xaa Ala Ala Ser Ser Gin Val Leu Xaa Xaa Gly Pro Ser Ser Gly Ile Ser 110 Val Ala Gly Met 140 Phe Ala Ser Xaa Leu Xaa Ala His Xaa Leu Pro Asp Ala Ser Leu Pro Lys Thr Ser Ala Phe Glu Phe Pro Ala Gin Gin Ser Xaa Gin Tyr Lys Xaa Gly Leu Xaa Leu Tyr 100 Leu Gly Ala Xaa 130 Ala Leu Xaa Gin 160 Xaa Phe Xaa Gly Leu Ile Leu Gin Pro Thr Gin Xaa Leu Xaa Gly Xaa Xaa Pro Trp Ala Gly Gly Leu Thr Leu Ile Trp Pro Thr Xaa Ala Xaa Xaa WO 97/12985 PCT/US96/15774 9 170 Leu Xaa Xaa Leu Ala Gin Pro (SEQ ID NO:1) Ser Tyr Arg Val wherein Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa position position position position position position position position position position position position position position position 1 is Thr, Ser, Arg, Tyr or Gly; 2 is Pro or Leu; 3 is Leu, Arg, Tyr or Ser; 13 is Phe, Ser, His, Thr or Pro; 16 is Lys, Pro, Ser, Thr or His; 17 is Cys, Ser, Gly, Ala, Ile, Tyr or Arg; 18 is Leu, Thr, Pro, His, Ile or Cys; 22 is Arg, Tyr, Ser, Thr or Ala; 24 is Ile, Pro, Tyr or Leu; 27 is Asp, or Gly; 30 is Ala, Ile, Leu or Gly; 34 is Lys or Ser; 36 is Cys or Ser; 42 is Cys or Ser; 43 is His, Thr, Gly, Val, Lys, Trp, Ala, Arg, Cys, or Leu; Xaa at position 44 is Pro, Gly, Arg, Asp, Val, Ala, His, Trp, Gin, or Thr; Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa at position at position at position at position at position at position at position at position at position at position at position at position at position at position at position at position at position at position at position at position at position at position at position 104 108 115 120 123 144 146 147 156 159 162 163 169 170 Glu, Arg, Phe, Arg, Ile or Ala; Leu or Thr; Leu, Phe, Arg or Ser; Leu, Ile, His, Pro or Tyr; Leu or His; Cys or Ser; Gin, Lys, Leu or Cys; Gin, Pro, Leu, Arg or Ser; Cys or Ser; 3 Asp, Gly or Val; s Leu, Ala, Val, Arg, Trp, Gin or Gly; 3 Thr, His, Leu or Ala; 3 Gin, Gly, Arg, Lys or His 3 Glu, Arg, Phe or Thr 3 Phe, His, Arg, Pro, Leu, Gin or Glu; 3 Arg or Gin; s Arg or Gin; s His, Gly or Ser; 3 Ser, Arg, Thr, Tyr, Val or Gly; s Glu, Leu, Gly or Trp; s Val, Gly, Arg or Ala; s Arg, Ser, Leu, Arg or Cys; s His, Arg or Ser; wherein optionally 1-11 amino acids from the N-terminus and from the C-terminus can be deleted; and WO 97/12985 PCT/IS96/1 n TA wherein the N-terminus is joined to the C-terminus directly or through a linker capable of joining the N-terminus to the C-terminus and having new C- and N-termini at amino acids; 38-39 39-40 40-41 41-42 42-43 43-44 45-46 48-49 49-50 52-53 53-54 54-55 55-56 56-57 57-58 58-59 59-60 60-61 61-62 62-63 63-64 64-65 65-66 66-67 67-68 68-69 69-70 70-71 71-72 91-92 92-93 93-94 94-95 95-96 96-97 97-98 98-99 99-100 123-124 124-125 125--126 126-127 128-129 128-129 129-130 130-131 131-132 132-133 133-134 134-135 135-136 136-137 137-138 138-139 139-140 140-141 141-142 or 142-143; (II) A polypeptide comprising; a modified hIL-3 amino acid sequence of the formula: Ala Pro Met Thr Gln Thr Thr Ser Leu Lys Thr Ser Trp Val Asn Cys Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Asn Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 55 WO 97/12985 WO 9712985PCTIUS96/1 5774 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa .0 Xaa Phe Xaa Xaa Xaa Xaa Xaa Xaa 110 Gin 125 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa xaa xaa xaa xaa Xaa 70 Xaa 85 Xaa 100 Xaa 115 L eu 130 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 105 Xaa 120 Ala Ile Xaa Xaa Xaa Gin Thr Thr Leu Ser Phe (SEQ ID NO:2); wherein Xaa at position 17 Xaa at position 18 is Asn, Xaa at position 19 is Met, Xaa at position 20 is Ile, Xaa at position 21 is Asp, Thr, Ser or Val; Xaa at position 22 is Giu, Leu, Val or Gly; Xaa at position 23 is Ile, Leu, Ser, or Arg; Xaa at position 24 is Ile, Xaa at position 25 is Thr, Xaa at position 26 is His, Xaa at position 27 is Leu, Xaa at position 28 is Lys, Xaa at position 29 is Gin, Xaa at position 30 it Pro, Xaa at position 31 is Pro, Xaa at position 32 is Leu, is Ser, Lys, Gly, Asp, Met, Gin, or Arg; His, Leu, Ile, Phe, Arg, or Gin; Phe, Ile, Arg, Gly, Ala, or Cys; Cys, Gin, Giu, Arg, Pro, or Ala; Phe, Lys, Arg, Ala, Gly, Giu, Gin, Asn, Trp, Pro, Ser, Ala, His, Asp, Asn, Gin, Val, Ala, Gly, Trp, Lys, Phe, Gly, His, Thr, Gly, Arg, Asn, His, Asp, Val, Val, Gly, Phe, Arg, Leu, Leu, Thr, Giy, Arg, Arg, Gin, Giy, Thr, Gin, Pro, Gly, Ala, Gin, Ser, Arg, Arg, Ser, Gly, Arg, Asp, Arg, Asn, Phe, or Leu; Pro, or Ala; Ala, or Trp; or Ala; Pro, Val or Trp; or Val; Gin, Ser, Leu, or Lys; Leu, or Gin; Gly, Ala, or GiU; WO 97/12985 12 Xaa at position 33 is Pro, Leu, Gin, Ala, Xaa at position 34 is Leu, Val, Gly, Ser, Arg, Ala, Phe, Ile or Met; Xaa at position 35 is Leu, Ala, Gly, Asn, Xaa at position 36 is Asp, Leu, or Val; Xaa at position 37 is Phe, Ser, Pro, Trp, Xaa at position 38 is Asn, or Ala; PCT/US96/15774 Thr, or Glu; Lys, Glu, Gin, Thr, Pro, Gin, or Val; or Ile; Xaa at position 40 is Leu, Trp, or Arg; Xaa at position 41 is Asn, Cys, Arg, Leu, His, Met, Xaa at position 42 is Gly, Asp, Ser, Cys, Asn, Lys, Val, Glu, Phe, Tyr, Ile, Met or Ala; Xaa at position 43 is Glu, Asn, Tyr, Leu, Phe, Asp, Gin, Arg, Thr, Gly or Ser; Xaa at position 44 is Asp, Ser, Leu, Arg, Lys, Thr, Glu, Asn, Gin, Ala or Pro; Xaa at position 45 is Gin, Pro, Phe, Val, Met, Leu, Trp, Asp, Asn, Arg, Ser, Ala, Ile, Glu or His; Xaa at position 46 is Asp, Phe, Ser, Thr, Cys, Glu, Lys, His, Ala, Tyr, Ile, Val or Gly; Xaa at position 47 is Ile, Gly, Val, Ser, Arg, Pro, Xaa at position 48 is Leu, Ser, Cys, Arg, Ile, His, Lys, Thr, Ala, Met, Val or Asn; Xaa at position 49 is Met, Arg, Ala, Gly, Pro, Asn, Xaa at position 50 is Glu, Leu, Thr, Asp, Tyr, Lys, Ala, Ile, Val, His, Phe, Met or Gin; Xaa at position 51 is Asn, Arg, Met, Pro, Ser, Thr, Xaa at position 52 is Asn, His, Arg, Leu, Gly, Ser, Xaa at position 53 is Leu, Thr, Ala, Gly, Glu, Pro, Xaa at position 54 is Arg, Asp, Ile, Ser, Val, Thr, Lys, His, Ala or Leu; Xaa at position 55 is Arg, Thr, Val, Ser, Leu, or Gl1 Xaa at position 56 is Pro, Gly, Cys, Ser, Gin, Glu, Thr, Ala, Tyr, Phe, Leu, Val or Lys; Xaa at position 57 is Asn or Gly; Xaa at position 58 is Leu, Ser, Asp, Arg, Gin, Val, or Pro; Thr, Leu, Ala, Cys, Met, Trp, Thr, Lys, Asn, Gin, or His; Phe, Glu, His, or Asp; Asn, Ser, or His; or Thr; Lys, Ser, or Met; Gln, Asn,

Y;

Arg, His, or Cys; WO 97/12985 13 Xaa at position 59 is Glu Tyr, His, Leu, Pro, or Arg; PCT/US96/15774 Xaa at position 60 Xaa at position 61 Xaa at position 62 Xaa at position 63 Xaa at position 64 Xaa at position 65 Xaa at position 66 Xaa at position 67 Xaa at position 68 Xaa at position 69 Xaa at position 70 Xaa at position 71 Trp, or Asn; Xaa at position 72 Xaa at position 73 Xaa at position 74 Xaa at position 75 Gin, or Leu; Xaa at position 76 Xaa at position 77 Xaa at position 78 Xaa at position 79 Xaa at position 80 Xaa at position 81 Xaa at position 82 is Ala, Ser, is Phe, is Asn, is Arg, is Ala, is Val, is Lys, is Ser, is Leu, is Gin, is Asn, is Ala, is Ser, is Ala, Asn, His, Tyr, Asn, Thr, Ile, Ala, Val, Ala, Leu, Met, Glu, Glu, Pro, Tyr, Glu, Pro, Val, Arg, Trp, Lys, Pro, Ser, Pro, His, Arg, Val, Phe, Val, Trp, Ser, Pro, Thr, Val, Trp, Leu, Pro, Met, Ala, Asp, Leu, Asn, or Thr; Lys, Arg, or Ser; Pro, Thr, Asp, or Ile; Ser, His, Pro, or Val; or Lys; Leu, Phe, or Ser; Asn, Glu, or Ser; Gly, Asn, Ile, Pro, or His; Ile, Phe, Thr, or His; Glu, Arg, Trp, Gly, or Leu; Pro, or Ala; Arg, Glu, -Thr, Gin, His, Asn, Arg, or Asp; Ser, Gly, Thr, or Arg; is Ile, Met, Thr, Pro, Arg, Gly, Ala; is Glu, Lys, Gly, Asp, Pro, Trp, Arg, Ser, is Ser, Val, is Ile, Ser, is Leu, Ala, is Lys, Thr, is Asn, Trp, is Leu, Gin, is Leu, Gin, His, Thr, Ser, Ala, Tyr, Xaa at position 83 is Pro, Ala, Xaa at position 84 is Cys, Glu, Xaa at position 85 is Leu, Asn, Xaa at position 86 is Pro, Cys, Xaa at position 87 is Leu, Ser, Xaa at position 88 is Ala, Lys, Xaa at position 89 is Thr, Asp, Xaa at position 90 is Ala, Pro, Ala, Asn, Trp, Glu, Pro, Gly, or Asp; Arg, Thr, or Leu; Ser, Glu, Phe, Gly, or Arg; Asn, Met, Arg, Ile, Gly, or Asp; Val, Gly, Thr, Leu, Glu, or Arg; Gly, Ala, Trp, Arg, Val, or Lys; Lys, Trp, Arg, Asp, Glu, Asn, Phe, Ile, Met or Val; Thr, Trp, Arg, or Met; Gly, Arg, Met, or Val; Val, or Gin; Arg, Ala, or Lys; Trp, or Gly; Arg, Val, or Trp; Cys, Leu, Val, Glu, His, Asn, or Ser; Ser, Thr, Gly, Asp, Ile, or Met; WO 97/12985 PCT/USTQ96/15 A 14 J 4 Xaa at position 91 is Ala, Pro, Ser, Thr, Phe, Leu, Asp, or His; Xaa at position 92 is Pro, Phe, Arg, Ser, Lys, His, Ala, Gly, Ile or Leu; Xaa at position 93 is Thr, Asp, Ser, Asn, Pro, Ala, Leu, or Arg; Xaa at position 94 is Arg, Ile, Ser, Glu, Leu, Val, Gin, Lys, His, Ala, or Pro; Xaa at position 95 is His, Gin, Pro, Arg, Val, Leu, Gly, Thr, Asn, Lys, Ser, Ala, Trp, Phe, Ile, or Tyr; Xaa at position 96 is Pro, Lys, Tyr, Gly, Ile, or Thr; Xaa at position 97 is Ile, Val, Lys, Ala, or Asn; Xaa at position 98 is His, Ile, Asn, Leu, Asp, Ala, Thr, Glu, Gin, Ser, Phe, Met, Val, Lys, Arg, Tyr or Pro; Xaa at position 99 is Ile, Leu, Arg, Asp, Val, Pro,-Gln, Gly, Ser, Phe, or His; Xaa at position 100 is Lys, Tyr, Leu, His, Arg, Ile, Ser, Gin, or Pro; Xaa at position 101 is Asp, Pro, Met, Lys, His, Thr, Val, Tyr, Glu, Asn, Ser, Ala, Gly, Ile, Leu, or Gin; Xaa at position 102 is Gly, Leu, Glu, Xaa at position 103 is Asp, or Ser; Xaa at position 104 is Trp, Val, Cys, Gin, Lys, Ala, Phe, or Gly; Xaa at position 105 is Asn, Pro, Ala, Leu, Lys, Ile, Asp, or His; Xaa at position 106 is Glu, Ser, Ala, Xaa at position 108 is Arg, Lys, Asp, Ala or Pro; Xaa at position 109 is Arg, Thr, Pro, Xaa at position 110 is Lys, Ala, Asn, Ser, or Trp; Xaa at position 111 is Leu, Ile, Arg, Xaa at position 112 is Thr, Val, Gin, Xaa at position 113 is Phe, Ser, Cys, Lys, Leu, Ile, Val or Asn; Xaa at position 114 is Tyr, Cys, His, Xaa at position 115 is Leu, Asn, Val, Lys, Ser, Tyr, or Pro; Tyr, Thr, Met, Pro, Leu, Phe, Ser, Trp, Gin, Tyr, Lys, Leu, Glu, Thr, Asp, Tyr, His, Ser, Pro, Thr, Thr, Tyr, Leu, Ile, Ile, Leu, Arg, Gly, Gin, Ser, Gin, Ser, Tyr, or Pro; His, Ser, or Gly; His, Glu, or Phe; Asp, or Met; Glu, His, Gly, Trp, Trp, Arg, Arg, Ala, or Leu; His, Thr, WO 97/12985 PCT/IUS96f/1 774 Trp, or Met; Xaa at position 116 is Lys, Leu, Pro, Thr, Met, Asp, Val, Glu, Arg, Trp, Ser, Asn, His, Ala, Tyr, Phe, Gin, or Ile; Xaa at position 117 is Thr, Ser, Asn, Ile, Trp, Lys, or Pro; Xaa at position 118 is Leu, Ser, Pro, Ala, Glu, Cys, Asp, or Tyr; Xaa at position 119 is Glu, Ser, Lys, Pro, Leu, Thr, Tyr, or Arg; Xaa at position 120 is Asn, Ala, Pro, Leu, His, Val, or Gln; Xaa at position 121 is Ala, Ser, Ile, Asn, Pro, Lys, Asp, or Gly; Xaa at position 122 is Gin, Ser, Met, Trp, Arg, Phe, Pro, His, Ile, Tyr, or Cys; Xaa at position 123 is Ala, Met, Glu, His, Ser, Pro, Tyr, or Leu; wherein optionally from 1 to 14 amino acids-can be deleted from the N-terminus and/or from 1 to 15 amino acids can be deleted from the C-terminus; and wherein from 0 to 44 of the amino acids designated by Xaa are different from the corresponding amino acids of native (1-133) human interleukin-3; and wherein the N-terminus is joined to the C-terminus directly or through a linker (L2) capable of joining the N-terminus to the C-terminus and having new C- and N-termini at amino acids; 26-27 49-50 83-84 27-28 50-51 84-85 28-29 51-52 85-86 29-30 52-53 86-87 30-31 53-54 87-88 31-32 54-55 88-89 32-33 64-65 89-90 33-34 65-66 90-91 34-35 66-67 91-92 35-36 67-68 92-93 36-37 68-69 97-98 37-38 69-70 98-99 38-39 70-71 99-100 39-40 71-72 100-101 40-41 72-73 101-102 41-42 82-83 102-103 or 103-104; WO 97/12985 WO 9712985PCTIUS96/1 5774 or (III) A polypeptide comprising; a modified human c-mpl ligand amino acid sequence of the formula: SerProAlaProProAlaCysAspLeuArgValLeuSerLysLeuLe-uArg~sp~ er Hi~leHL~rr~ue~nysr~ua~sr~ur~rr ValLeuLeuProAlaValAspPheSerLeuGlyGluTrpLysThrGl1ietGluGlu 45 50 ThrLysAlaGlnAspIleLeuGlyAlaValThrLeuLeuLeuGluGlyValMetAla AlaArgGlyGlnLeuGlyProThrCysLeuSerSerLeuLeuGlyGlnLeuSerGly GlnValArgLeuLeuLeuGlyAlaLeuGlnSerLeuL euGlyThrGlnXaaXaaXaa 100 105 110 xaaGlyArgThrThrAlaHisLysAspProAsnAlal lePheLeuSerPheGinHis 115 120 125 130 LeuLeuArgclyLysValArgPheLeuMetLeuValGlyGlyS erThrLeuCysVal 135 140 145 150 ArgArgAlaProProThrThrAlaValProSerArgThrSerLeuValLeuThrLeu 155 160 165 170 AsnGluLeuProAsnArgThrS erG lyLeuLeuGluThrAsnPheThrAlaSerAla 175 180 185 190 WO 97/12985 WO 9712985PCTIUS96/1 5774 17 ArgThrThrGlySerGiyLeuLeuLysTrpGlnGlnGlyPheArgAlaLy 51 lePro 195 200 205 GiyLeuLeuAsnGlnThrSerArgSerLeuAspGlnIeProGyTyrLeuAsfl~rg 210 215 220 225 IleHisGluLeuLeUAsnGiyThrArgGiyLeuPheProclyProSerArgArgThr 230 235 240 245 LeuGlyAlaProAsplleSerSerGiyThrSerAspThrGiySerLeuProProAsn 250 255 260 265 LeuGlnProGlyTyrSerProSerProThrHisProProThrGlyGlnTyrThrbeu 270 275 280 285 PheProLeuPro ProThrLeuProThrProValValG inLeuHi sProL euLeuPro 290 295 300 AspPro SerAiaProThrProThrProThrS erProL euLeuAsnThrS erTyrThr 305 310 315 320 HisSerGinAsnLeuSerGineluGiy (SEQ ID NO:3) 325 330 332 153 wherein; Xaa at position 112 is deleted or Leu, Ala, Val, Ile, Pro, Phe, Trp, or Met; Xaa at position 113 is deleted or Pro, Phe, Ala, Val, Leu, Ile, Trp, or Met; Xaa at position 114 is deleted or Pro, Phe, Ala, Val, Leu, Ile, Trp, or Met; Xaa at position 115 is deleted or Gin, Gly, Ser, Thr, Tyr, or Asn;.and WO 97/12985 PCT/US96/15 774 18 wherein the N-terminus is joined to the C-terminus directly or through a linker (L2) capable of joining the N-terminus to the C-terminus and having new C- and N-termini at amino acids; 26-27 51-52 108-109- 27-28 52-53 109-110 28-29 53-54 110-111 29-30 54-55 111-112 30-31 55-56 112-113 32-33 56-57 113-114 33-34 57-58 114-115 34-35 58-59 115-116 36-37 59-60 116-117 37-38 78-79 117-118 38-39 79-80 118-119 40-41 80-81 119-120 41-42 81-82 120-121 42-43 82-83 121-122 43-44 83-84 122-123 44-45 84-85 123-124 46-47 85-86 124-125 47-48 86-87 125-126 48-49 87-88 126-127 50-51 88-89 or 127-128; or (IV) A polypeptide comprising; a modified hIL-3 amino acid sequence of the formula: Ala Pro Met Thr Gln Thr Thr Ser Leu Lys Thr Ser Trp Val Asn 1 5 10 Cys Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 25 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Asn Xaa Xaa Xaa Xaa Xaa Xaa 40 WO 97/12985 WO 9712985PCT[US96/15774 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Phe Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 110 Gin Gin Thr 125 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 55 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 70 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 85 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 100 105 Xaa Xaa Xaa Xaa Xaar Xaa Xaa Xaa Xaa 115 120 Thr Leu Ser Leu Ala Ile Phe 130 (SEQ ID NO:2) wherein Xaa at position 17 Xaa at position 18 is Asn, Xaa at position 19 is Met, Xaa at position 20 is Ile, Xaa at position 21 is Asp, Thr, Ser or Val,- Xaa at position 22 is Giu, Leu, Val or Gly; Xaa at position 23 is Ile, Leu, Ser, or Arg; Xaa at position 24 is Ile, Xaa at position 25 is Thr, Xaa at position 26 is His, Xaa at position 27 is Leu, Xaa at position 28 is Lys, Xaa at position 29 is Gin, Xaa at position 30 is Pro, is Ser, Lys, Giy, Asp, Met, Gin, or Arg; His, Phe, Cys, Phe, Leu, Ile, Gin, Lys, Ile, Phe, Arg, Giy, Giu, Arg, Arg, Ala, Arg, Ala, Pro, Gly, or Gin; or Cys; or Aia; Giu, Gin, Asn, Trp, Pro, Ser, Ala, His, Asp, Asn, Gin, Val, Aia, Gly, Trp, Lys, Phe, Giy, His, Thr, Giy, Arg, Asn, His, Vai, Giy, Phe, Arg Leu, Leu, Thr, Arg, Ser, Gin, Arg, Gly, Arg, Thr, Ser, Gin Gly, Pro, Arg, Gly, Asp, Phe, or Leu; Pro, or -Ala; Ala, or Trp; or Ala; Pro, Val or Trp; or Val; Gin, Ser, Lea, or Lys; WO 97/12985 PCT/US96/1577 4 Xaa at position 31 is Pro, Asp, Gly, Ala, Xaa at position 32 is Leu, Val, Arg, Gin, Xaa at position 33 is Pro, Leu, Gin, Ala, Xaa at position 34 is Leu, Val, Gly, Ser, Arg, Ala, Phe, Ile or Met; Xaa at position 35 is Leu, Ala, Gly, Asn, Xaa at position 36 is Asp, Leu, or Val; Xaa at position 37 is Phe, Ser, Pro, Trp, Xaa at position 38 is Asn, or Ala; Arg, Asn, Thr, Lys, Leu, or Gin; Gly, Ala, or Glu; or Glu; Glu, Gln, Thr, Pro, Gin, or Val; or Ile; Xaa at position 40 is Leu, Trp, or Arg; Xaa at position 41 is Asn, Cys, Arg, Leu, His, Met, or Pro; Xaa at position 42 is Gly, Asp, Ser, Cys, Asn, Lys, Thr, Leu, Val, Glu, Phe, Tyr, Ile, Met or Ala; Xaa at position 43 is Glu, Asn, Tyr, Leu, Phe, Asp, Ala, Cys, Gin, Arg, Thr, Gly or Ser; Xaa at position 44 is Asp, Ser, Leu, Arg, Lys, Thr, Met, Trp, Glu, Asn, Gin, Ala or Pro; Xaa at position 45 is Gin, Pro, Phe, Val, Met, Leu, Thr,.Lys, Trp, Acp, Asn, Arg, Ser, Ala, Ile, Glu or His; Xaa at position 46 is Asp, Phe, Ser, Thr, Cys, Glu, Asn, Gin, Lys, His, Ala, Tyr, Ile, Val or Gly; Xaa at position 47 is Ile, Gly, Val, Ser, Arg, Pro, or His; Xaa at position 48 is Leu, Ser, Cys, Arg, Ile, His, Phe, Glu, Lys, Thr, Ala, Met, Val or Asn; Xaa at position 49 is Met, Arg, Ala, Gly, Pro, Asn, His, or A Xaa at position 50 is Glu, Leu, Thr, Asp, Tyr, Lys, Asn, Ser, Ala, Ile, Val, His, Phe, Met or Gin; Xaa at position 51 is Asn, Arg, Met, Pro, Ser, Thr, or His; Xaa at position 52 is Asn, His, Arg, Leu, Gly, Ser, or Thr; Xaa at position 53 is Leu, Thr, Ala, Gly, Glu, Pro, Lys, Ser, Xaa at position 54 is Arg, Asp, Ile, Ser, Val, Thr, Gin, Asn, Lys, His, Ala or Leu; Xaa at position 55 is Arg, Thr, Val, Ser, Leu, or Gly; Xaa at position 56 is Pro, Gly, Cys, Ser, Gin, Glu, Arg, His, Thr, Ala, Tyr, Phe, Leu, Val or Lys; sp; or Met; WO 97/12985 PCT/US96/15774 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa at position 57 is at position 58 is at position 59 is at position 60 is at position 61 is at position 62 is at position 63 is at position 64 is at position 65 is at position 66 is at position 67 is at position 68 is at position 69 is at position 70 is at position 71 is Trp, or Asn; at position 72 is at position 73 is at position 74 is at position 75 is Gin, or Leu; at position 76 is at position 77 is at position 78 is at position 79 is at position 80 is at position 81 is at position 82 is His, Thr, Ser, at position 83 is at position 84 is at position 85 is at position 86 is at position 87 is at position 88 is Asn or Gly; Leu, Ser, Asp, Arg, Gin, Val, or Cys; Glu Tyr, His, Leu, Pro, or Arg; Ala Phe, Asn, Arg, Ala, Val, Lys, Ser, Leu, Gin, Asn, Ala, Ser, Ala, Ile, Glu, Ser, Ile, Leu, Lys, Asn, Leu, Leu, Ala, Pro, Cys, Leu, Pro, Leu Ala, Ser, Asn, His, Tyr, Asn, Thr, Ile, Ala, SVal, Ala, Leu, Met, Glu, Glu, Met, SLys, Val, Ser, Ala, Thr, STrp, Gin, Gin, Tyr, Ala, Glu, SAsn, SCys, Ser, SLys, Pro, Glu, Val, Trp, Pro, Pro, Arg, Phe, Trp, Pro, Val, Leu, Met, Asp, Thr, Gly, Ala, Arg, Ser, Asn, Val, Gly, Lys, Phe, Thr, Gly, Val, Arg, Trp, Arg, Tyr, Pro, Arg, Lys, Ser, His, Val, Val, Ser, Thr, Trp, Pro, Ala, Leu, Pro, Asp, Asn, Thr, Glu, Met, Gly, Ala, Trp, Ile, Asn, or Thr; Lys, Pro, Ser, or Ly Leu, Asn, Gly, Ile, Glu, Pro, Arg, His, Ser, Arg, Pro, Arg, Thr, His, ys; or Ser; Asp, or Ile; Pro, or Val; Phe, or Ser; Glu, or Ser; Asn, Ile, Pro, or His; Phe, Thr, or His; Arg; 'Trp, Gly, or Leu; or Ala; Glu, Thr, Gin, Asn, Gly, Gly, Trp, Arg, Thr, Ala; Arg, Asp; Arg; Ser, Trp, Glu, or Leu; Phe, Gly, Arg, Ile, Thr, Leu, Trp, Arg, Arg, Asp, Pro, Gly, or Asp; or Arg; Gly, or Asp; Glu, or Arg; Val, or Lys; Glu, Asn, Met or Val; Trp, Arg, or Met; Arg, Met, or Val; or Gin; Ala, or Lys; or Gly; Val, or Trp; WO 97/12985 PCT/US96/15774 Xaa at position 89 is Thr, Asp, Cys, Leu, Val, Glu, His, Xaa at position 90 is Ala, Pro, Ser, Thr, Gly, Asp, Ile, Xaa at position 91 is Ala, Pro, Ser, Thr, Phe, Leu, Asp, Xaa at position 92 is Pro, Phe, Arg, Ser, Lys, His, Ala, Leu; Xaa at position 93 is Thr, Asp, Ser, Asn, Pro, Ala, Leu, Xaa at position 94 is Arg, Ile, Ser, Glu, Leu, Val, Gin, Ala, or Pro; Xaa at position 95 is His, Gin, Pro, Arg, Val, Leu, Gly, Lys, Ser, Ala, Trp, Phe, Ile, or Tyr; Xaa at position 96 is Pro, Lys, Tyr, Gly, Ile, or Thr; Xaa at position 97 is Ile, Val, Lys, Ala, or Asn; Xaa at position 98 is His, Ile, Asn, Leu, Asp, Ala. Thr, Glu, Gin, Ser, Phe, Met, Val, Lys, Arg, Tyr or Pro; Xaa at position 99 is Ile, Leu, Arg, Asp, Val, Pro, Gln, Gly, Ser, Phe, or His; Xaa at position 100 is Lys, Tyr, Leu, His, Arg, Ile, Ser, Xaa at positc-n 101 is Asp, Pro, Met, Lys, His, Thr, Val, Tyr, Glu, Asn, Ser, Ala, Gly, Ile, Leu, or Gin; Asn, or Ser or Met; or His; Gly, Ile or or Arg; Lys, His, Thr, Asn, Gin, or Pro; Xaa at position 102 is Gly, Leu, Glu, Xaa at position 103 is Asp, or Ser; Xaa at position 104 is Trp, Val, Cys, Gin, Lys, Ala, Phe, or Gly; Xaa at position 105 is Asn, Pro, Ala, Leu, Lys, Ile, Asp, or His; Xaa at position 106 is Glu, Ser, Ala, Xaa at position 108 is Arg, Lys, Asp, Ala or Pro; Xaa at position 109 is Arg, Thr, Pro, Xaa at position 110 is Lys, Ala, Asn, Ser, or Trp; Xaa at position 111 is Leu, Ile, Arg, Xaa at position 112 is Thr, Val, Gin, Xaa at position 113 is Phe, Ser, Cys, Lys, Leu, Ile, Val or Asn; Lys, Ser, Tyr, or Pro; Tyr, Thr, Met, Pro, Leu, Phe, Ser, Trp, Gin, Tyr, Lys, Leu, Glu, Thr, Asp, Tyr, His, Thr, Ile, Thr, Ile, Tyr, Leu, Leu, Arg, or Met; Glu, His, Gly, Trp, Gly, Gin, Ser, Gin, Ser, Tyr, or Pro; His, Ser, or Gly; His, Glu, or Phe; Asp, WO 97/12985 PCT/IUSO6/1'7'7A 23 Xaa at position 114 is Tyr, Cys, His, Ser, Trp, Arg, or Leu; Xaa at position 115 is Leu, Asn, Val, Pro, Arg, Ala, His, Thr, Trp, or Met; Xaa at position 116 is Lys, Leu, Pro, Thr, Met, Asp, Val, Glu, Arg, Trp, Ser, Asn, His, Ala, Tyr, Phe, Gin, or Ile; Xaa at position 117 is Thr, Ser, Asn, Ile, Trp, Lys, or Pro; Xaa at position 118 is Leu, Ser, Pro, Ala, Glu, Cys, Asp, or Tyr; Xaa at position 119 is Glu, Ser, Lys, Pro, Leu, Thr, Tyr, or Arg; Xaa at position 120 is Asn, Ala, Pro, Leu, His, Val, or Gin; Xaa at position 121 is Ala, Ser, Ile, Asn, Pro, Lys, Asp, or Gly; Xaa at position 122 is Gin, Ser, Met, Trp, Arg, Phe, Pro, His, lie, Tyr, or Cys; Xaa at position 123 is Ala, Met, Glu, His, Ser, Pro.,-Tyr, or Leu; wherein optionally from 1 to 14 amino acids can be deleted from the N-terminus and/or from 1 to 15 amino acids can be deleted from the C-terminus; and wherein from 1 to 44 of the amino acids designated by Xaa are different from the corresponding amino acids of native (1-133) human interleukin-3; or a colony stimulating factor; and wherein L 1 is a linker capable of linking R 1 to R2; with the proviso that at least R 1 or R2 is selected from the polypeptide of formula or (III); and said hematopoietic protein can optionally be immediately preceded by (methionine- 1 (alanine- 1 or (methionine 2 alanine- 1 The more preferred breakpoints at which new Cterminus and N-terminus can be made in the polypeptide

(I)

WO 97/12985 PCT/US96/1i77A 24 above are; 38-39, 39-40, 40-41, 41-42, 48-49, 53-54, 54-55, 55-56, 56-57, 57-58, 58-59, 59-60, 60-61, 61-62, 62-63, 64- 65-66, 66-67, 67-68, 68-69, 69-70, 96-97, 125-126, 126- 127, 127-128, 128-129, 129-130, 130-131, 131-132, 132-133, 133-134, 134-135, 135-136, 136-137, 137-138, 138-139, 139- 140, 140-141 and 141-142.

The most preferred breakpoints at which new C-terminus and N-terminus can be made in the polypeptide above are; 38-39, 48-49, 96-97, 125-126, 132-133 and 141-142.

The more preferred breakpoints at which new C-terminus and N-terminus can be made in the polypeptide (II) above are; 28-29, 29-30, 30-31, 31-32, 32-33, 33-34, 34-35, 35-36, 36-37, 37-38, 38-39, 39-40, 66-67, 67-68, 68-69, 69-70, 71, 84-85, 85-86, 86-87, 87-88, 88-89, 89-90, 90-91, 98-99, 99-100, 100-101 and 101-102.

The most preferred breakpoints at which new C-terminus and N-terminus can be made in the polypeptide (II) above are; 34-35, 69-70 and 90-91.

The more preferred breakpoints at which new C-terminus and N-terminus can be made in the polypeptide (III) above or the amino acid sequence of (SEQ ID NO:256) are; 80-81, 81-82, 82-83, 83-84, 84-85, 85-86, 86-87, 108-109, 109-110, 110-111, 111-112, 112-113, 113-114, 114-115, 115-116, 116- 117, 117-118, 118-119, 119-120, 120-121, 121-122, 122-123, 123-124, 124-125, 125-126 and 126-127.

The most preferred breakpoints at which new C-terminus and N-terminus can be made in the polypeptide (III) above or the amino acid sequence of (SEQ ID NO:256) are; 81-82, 108-109, 115-116, 119-120, 122-123 and 125-126.

WO 97/12985 PCT/US96/1 5774 The multifunctional receptor agonist of the present invention can also be represented by the following formula:

(T

1 a- (L 1 )b-X 1 c-X 2

(L

2 (T2) e

X

1 -(L)c-X 2 1 -(L)c-Y 2 in which:

X

1 is a peptide comprising an amino acid sequence corresponding to the sequence of residues n+l through J of the original protein having amino acids residues numbered sequentially 1 through J with an amino terminus at residue 1; L is an optional linker;

X

2 is a peptide comprising an amino acid sequence of residues 1 through n of the original protein; yl is a peptide comprising an amino acid sequence corresponding to the sequence of residues n=l through K of the original protein having amino acids residues numbered sequentially 1 through K with an amino terminus at residue 1;

Y

2 is a peptide comprising an amino acid sequence of residues 1 through n of the original protein;

L

1 and L 2 are optional peptide spacers: n is an integer ranging from 1 to J-l; b, c, and d are each independently 0 or 1; a and e are either 0 or 1, provided that both a and e cannot both be 0; and

T

1 and T 2 are proteins.

Additionally, the present invention relates to recombinant expression vectors comprising nucleotide sequences encoding the multi-functional hematopoietic receptor agonists, related microbial expression systems, and processes for making the multi-functional hematopoietic WO 97/12985 PCT/IUSqO/1 .77A 26 receptor agonists. The invention also relates to pharmaceutical compositions containing the multi-functional hematopoietic receptor agonists, and methods for using the multi-functional hematopoietic receptor agonists.

In addition to the use of the multi-functional hematopoietic receptor agonists of the present invention in vivo, it is envisioned that in vitro uses would include the ability to stimulate bone marrow and blood cell activation and growth before infusion into patients.

WO 97/12985 PCT/US96/15774 27 Brief Description of the Figures Figure 1 schematically illustrates the sequence rearrangement of a protein. The N-terminus and the Cterminus of the native protein are joined through a linker, or joined directly. The protein is opened at a breakpoint creating a new N-terminus (new N) and a new Cterminus (new-C) resulting in a protein with a new linear amino acid sequence. A rearranged molecule may be synthesized de novo as linear molecule and not go through the steps of joining the original N-terminus and the Cterminus and opening of the protein at the breakpoint.

Figure 2 shows a schematic of Method I, for creating new proteins in which the original N-terminus and C-terminus of the native protein are joined with a linker and different N-terminus and C-terminus of the protein are created. In the example shown the sequence rearrangement results in a new gene encoding a protein with a new N-terminus created at amino acid 97 of the original protein, the original Cterminus 174) joined to the amino acid 11 1- are deleted) through a linker region and a new C-terminus created at amino acid 96 of the original sequence.

Figure 3 shows a schematic of Method II, for creating new proteins in which the original N-terminus and C-terminus of the native protein are joined without a linker and different N-terminus and C-terminus of the protein are created. In the example shown the sequence rearrangement results in a new gene encoding a protein with a new Nterminus created at amino acid 97 of the original protein, the original C-terminus 174) joined to the original Nterminus and a new C-terminus created at amino acid 96 of the original sequence.

WO 97/12985 PCT/Uo9/15774A 28 J Figure 4 shows a schematic of Method III, for creating new proteins in which the original N-terminus and C-terminus of the native protein are joined with a linker and different N-terminus and C-terminus of the protein are created. In the example shown the sequence rearrangement results in a new gene encoding a protein with a new N-terminus created at amino acid 97 of the original protein, the original

C-

terminus 174) joined to amino acid 1 through a linker region and a new C-terminus created at amino acid 96 of the original sequence.

WO 97/12985 PCT~/Ufi qT'Ta WO 97/ 2985PCTIJS96Vi 57'7A 29 Detailed DescriDtion of the Invention The present invention encompasses multi-functional hematopoietic receptor agonists formed from covalently linked polypeptides, each of which may act through a different and specific cell receptor to initiate complementary biological activities. Hematopoiesis requires a complex series of cellular events in which stem cells generate continuously into large populations of maturing cells in all major lineages. There are currently at least known regulators with hematopoietic proliferative activity.

Most of these proliferative regulators can 3nly stimulate one or another type of colony formation in vitro, the precise pattern of colony formation stimulated by each regulator is quite distinctive. No two regulators stimulate exactly the same pattern of colony formation, as evaluated by colony numbers or, more importantly, by the lineage and maturation pattern of the cells making up the developing colonies. Proliferative responses can most readily be analyzed in simplified in vitro culture systems. Three quite different parameters can be distinguished: alteration in colony size, alteration in colony numbers and cell lineage.

Two or more factors may act on the progenitor cell, inducing the formation of larger number of progeny thereby increasing the colony size. Two or more factors may allow increased number of progenitor cells to proliferate either because distinct subsets of progenitors cells exist that respond exclusively to one factor or because some progenitors require stimulation by two or more factors before being able to respond. Activation of additional receptors on a cell by the use of two or more factors is likely to enhance the mitotic signal because of coalescence of initially differing signal pathways into a common final pathway reaching the nucleus (Metcalf, Nature 339:27, 1989). Other mechanisms WO 97/12985 PCT/US96/1 5774 could explain synergy. For example, if one signaling pathway is limited by an intermediate activation of an additional signaling pathway which is caused by a second factor, then this may result in a super additive response. In some cases, activation of one receptor type can induce an enhanced expression of other receptors (Metcalf, Blood 82:3515-3523, 1993). Two or more factors may result in a different pattern of cell lineages than from a single factor. The use of multi-functional hematopoietic receptor agonists may have a potential clinical advantage resulting from a proliferative response that is not possible by any single factor.

The receptors of hematopoietic and other growth factors can be grouped into two distinct families o.f- related proteins: tyrosine kinase receptors, including those for epidermal growth factor, M-CSF (Sherr, Blood 75:1, 1990) and SCF (Yarden et al., EMBO J. 6:3341, 1987): and (2) hematopoietic receptors, not containing a tyrosine kinase domain, but exhibiting obvious homology in their extracellular domain (Bazan, PNAS USA 87:6934-6938, 1990).

Included in this latter group are erythropoietin

(EPO)

(D'Andrea et al., Cell 57:277, 1989), GM-CSF (Gearing et al., EMBO J. 8:3667, 1989), IL-3 (Kitamura et al., Cell 66:1165, 1991), G-CSF (Fukunaga et al., J. Bio. Chem.

265:14008-15, 1990), IL-4 (Harada et al., PNAS USA 87:857, 1990), IL-5 (Takaki et al., EMBO J. 9:4367, 1990), IL-6 (Yamasaki et al., Science 241:825, 1988), IL-7 (Goodwin et al., Cell 60:941-51, 1990), LIF (Gearing et al., EMBO J.

10:2839, 1991) and IL-2 (Cosman et al., Mol-Immunol. 23: 935-94, 1986). Most of the latter group of receptors exists in a high-affinity form as heterodimers. After ligand binding, the specific a-chains become associated with at least one other receptor chain (-chain, y-chain). Many of these factors share a common receptor subunit. The a-chains for GM-CSF, IL-3 and IL-5 share the same p-chain (Kitamura et al., Cell 66:1165, 1991), Takaki et al., EMBO J.

WO 97/12985 P""r/i Tcn< /1 31 JU 10:2833-8, 1991) and receptor complexes for IL-6, LIF and IL-11 share a common P-chain (gpl30) (Taga et al., Cell 58:573-81, 1989; Gearing et al., Science 255:1434-7, 1992) The receptor complexes of IL-2, IL-4, IL-7, IL-9 and share a common y-chain (Kondo et al., Science 262:1874, 1993; Russell et al., Science 266: 1042-1045, 1993; Noguchi et al., Science 262:1877, 1993; Giri et al., EMBO J. 13:2822-2830, 1994).

The use of a multiply acting hematopoietic factor may also have a potential advantage by reducing the demands placed on factor-producing cells and their induction systems. If there are limitations in the ability of a cell to produce a factor, then by lowering the required concentrations of each of the factors, and using them in combination may usefully reduce demands on the factorproducing cells. The use of a multiply acting hematopoietic factor may lower the amount of the factors that would be needed, probably reducing the likelihood of adverse sideeffects.

Novel compounds of this invention are represented by a formula selected from the group consisting of: R1-L1-R2, R2-L1-R1, R1-R2, and R2-R1 Where R1 and R2 are as defined above.

R2 is preferably a colony stimulating factor with a different but complementary activity than R1. By complementary activity is meant activity which enhances or changes the response to another cell modulator. The R 1 polypeptide is joined either directly or through a linker segment to the R2 polypeptide. The term "directly" defines multi-functional hematopoietic receptor agonists in which the polypeptides are joined without a peptide linker. Thus L1 represents a chemical bond or polypeptide segment to which both R 1 and R2 are joined in frame, most commonly L1 WO 97/12985 PCTT/US96/1 774 32 is a linear peptide to which R1 and R2 are joined by amide bonds linking the carboxy terminus of R 1 to the amino terminus of L1 and carboxy terminus of L 1 to the amino terminus of R2. By "joined in frame" is meant that there is no translation termination or disruption between the reading frames of the DNA encoding R 1 and R2.

A non-exclusive list of other growth factors, i.e.

colony stimulating factors (CSFs), are cytokines, lymphokines, interleukins, hematopoietic growth factors which can be joined to (II) or (III) include GM-CSF, G- CSF, c-mpl ligand (also known as TPO or MGDF), M-CSF, erythropoietin (EPO), IL-1, IL-4, IL-2, IL-; IL-5, IL 6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-15, LIF, flt3/flk2 ligand, human growth hormone, B-cell growth factor, B-cell differentiation factor, eosinophil differentiation factor and stem cell factor (SCF) also known as steel factor or c-kit ligand. Additionally, this invention encompasses the use of modified R 1 or R2 molecules or mutated or modified DNA sequences encoding these R1 or R2 molecules. The present invention also includes multifunctional hematopoietic receptor agonists in which R 1 or R2 is an hIL-3 variant, c-mpl ligand variant, or G-CSF variant.

A "hIL-3 variant" is defined as a hIL-3 molecule which has amino acid substitutions and/or portions of hIL-3 deleted as disclosed in WO 94/12638, WO 94/12639 and WO 95/00646, as well as other variants known in the art. A "c-mpl ligand variant" is defined an c-mpl ligand molecule which has amino acid substitutions and/or portions of c-mpl ligand deleted, disclosed in United States Application Serial Number 08/383,035 as well as other variants known in the art. A "G- CSF variant" is defined an G-CSF molecule which has amino acid substitutions and/or portions of G-CSF deleted, as disclosed herein, as well as other variants known in the art.

WO 97/12985 PCT/U TSo/1 I CA 33 The linking group (LI) is generally a polypeptide of between 1 and 500 amino acids in length. The linkers joining the two molecules are preferably designed to allow the two molecules to fold and act independently of each other, not have a propensity for developing an ordered secondary structure which could interfere with the functional domains of the two proteins, have minimal hydrophobic characteristics which could interact with the functional protein domains and provide steric separation of R 1 and R2 such that R 1 and R2 could interact simultaneously with their corresponding receptors on a single cell. Typically surface amino acids in flexible protein regions include Gly, Asn and Ser. Virtually any permutation of amino acid sequences containing Gly, Asn and Ser would be expected to satisfy the above criteria for a linker sequence. Other neutral amino acids, such as Thr and Ala, may also be used in the linker sequence. Additional amino acids may also be included in the linkers due to the addition of unique restriction sites in the linker sequence to facilitate construction of the multi-functional hematopoietic receptor agonists.

Preferred L1 linkers of the present invention include sequences selected from the group of formulas: (Gly 3 ser)n (SEQ ID NO:4), (Gly 4 Ser)n (SEQ ID (SEQ ID NO:6), (GlynSer)n (SEQ ID NO:7) or (AlaGlySer)n (SEQ ID NO:8).

One example of a highly-flexible linker is the glycine and serine-rich spacer region present within the pIII protein of the filamentous bacteriophages, e.g.

bacteriophages M13 or fd (Schaller et al., PNAS USA 72: 737- 741, 1975). This region provides a long, flexible spacer region between two domains of the pIII surface protein. The spacer region consists of the amino acid sequence: GlyGlyGlySerGlyGlyGlySerGlyGlyGlySerGluGlyGlyGlySerGlu WO 97/12985 PCT/IUS9 /1i94 34 J--,vi x, 1 GlyGlyGlySerGluGGlyGlySerGluGlyGlyGlySerGlyGlyGlySer (SEQ ID NO:9).

The present invention also includes linkers in which an endopeptidase recognition sequence is included. Such a cleavage site may be valuable to separate the individual components of the multi-functional hematopoietic receptor agonist to determine if they are properly folded and active in vitro. Examples of various endopeptidases include, but are not limited to, plasmin, enterokinase, kallikrein, urokinase, tissue plasminogen activator, clostripain, chymosin, collagenase, Russell's viper venom protease, postproline cleavage enzyme, V8 protease, Thrombin and factor Xa.

Peptide linker segments from the hinge region of heavy chain immunoglobulins IgG, IgA, IgM, IgD or IgE provide an angular relationship between the attached polypeptides.

Especially useful are those hinge regions where the cysteines are replaced with serines. Preferred linkers of the present invention include sequences derived from murine IgG gamma 2b hinge region in which the cysteines have been changed to serines. These linkers may also include an endopeptidase cleavage site. Examples of such linkers include the following sequences: IleSerGluProSerGlyProIleSerThrIleAsnProSerProProSerLys GluSerHisLysSerPro (SEQ ID NO:10) and IleGluGlyArgIleSerGluProSerGlyProlleSerThrlleAsnProSer ProProSerLysGluSerHisLysSerPro (SEQ ID NO:11).

The present invention is, however, not limited by the form, size or number of linker sequences employed and the only requirement of the linker is that functionally it does not interfere with the folding and function of the individual molecules of the multi-functional hematopoietic WO 97/12985 PCT/US96/1 774 receptor agonist.

Determination of the Linker L,.

The length of the amino acid sequence of the linker L2 to be used in R1 and/or R2 can be selected empirically or with guidance from structural information, or by using a combination of the two approaches.

When no structural information is available, a small series of linkers can be prepared for testing using a design whose length is varied in order to span a range from 0 to A and whose sequence is chosen in order to be consistent with surface exposure (hydrophilicity, Hopp.& Woods, Mol.

Immunol. 20: 483-489, 1983), Kyte Doolittle, J. Mol. Biol.

157:105-132; solvent exposed surface area, Lee Richards, J. Mol. Biol. 55:379-400, 1971) and the ability to adopt the necessary conformation with out deranging the conformation of R 1 or R 2 (conformationally flexible; Karplus Schulz, Naturwissenschaften 72:212-213, 1985). Assuming an average of translation of 2.0 to 3.8 A per residue, this would mean the length to test would be between 0 to residues, with 0 to 15 residues being the preferred range.

Exemplary of such an empirical series would be to construct linkers using a cassette sequence such as Gly-Gly-Gly-Ser (SEQ ID NO:12) repeated n times, where n is 1, 2, 3 or 4.

Those skilled in the art will recognize that there are many such sequences that vary in length or composition that can serve as linkers with the primary consideration being that they be neither excessively long nor short Sandhu, Critical Rev. Biotech. 12: 437-462, 1992); if they are too long, entropy effects will likely destabilize the threedimensional fold, and may also make folding kinetically impractical, and if they are too short, they will likely destabilize the molecule because of torsional or steric strain.

WO 97/12985 PCT[[ Qe'</IIMr 36 Those skilled in the analysis of protein structural information will recognize that using the distance between the chain ends, defined as the distance between the c-alpha carbons, can be used to define the length of the sequence to be used, or at least to limit the number of possibilities that must be tested in an empirical selection of linkers.

They will also recognize that it is sometimes the case that the positions of the ends of the polypeptide chain are illdefined in structural models derived from x-ray diffraction or nuclear magnetic resonance spectroscopy data, and that when true, this situation will therefore need to be taken into account in order to properly estimate-the length of the linker required. From those residues whose positions are well defined are selected two residues that are close in sequence to the chain ends, and the distance between their c-alpha carbons is used to calculate an approximate length for a linker between them. Using the calculated length as a guide, linkers with a range of number of residues (calculated using 2 to 3.8A per residue) are then selected.

These linkers may be composed of the original sequence, shortened or lengthened as necessary, and when lengthened the additional residues may be chosen to be flexible and hydrophilic as described above; or optionally the original sequence may be substituted for using a series of linkers, one example being the Gly-Gly-Gly-Ser (SEQ ID NO:12) cassette approach mentioned above; or optionally a combination of the original sequence and new sequence having the appropriate total length may be used.

Determination of the Amino and Carboxvl Termini of R_ and R_ Sequences of R1 and R2 capable of folding to biologically active states can be prepared by appropriate WO 97/12985 PCT/US94/1 AV77A 37. selection of the beginning (amino terminus) and ending (carboxyl terminus) positions from within the original polypeptide chain while using the linker sequence L2 as described above. Amino and carboxyl termini are selected from within a common stretch of sequence, referred to as a breakpoint region, using the guidelines described below.

A

novel amino, acid sequence is thus generated by selecting amino and carboxyl termini from within the same breakpoint region. In many cases the selection of the new termini will be such that the original position of the carboxyl terminus immediately preceded that of the amino terminus. However, those skilled in the art will recognize that selections of termini anywhere within the region may function, and that these will effectively lead to either deletions or additions to the amino or carboxyl portions of the new sequence.

It is a central tenet of molecular biology that the primary amino acid sequence of a protein dictates folding to the three-dimensional structure necessary for expression of its biological function. Methods are known to those skilled in the art to obtain and interpret three-dimensional structural information using x-ray diffraction of single protein crystals or nuclear magnetic resonance spectroscopy of protein solutions. Examples of structural information that are relevant to the identification of breakpoint regions include the location and type of protein secondary structure (alpha and 3-10 helices, parallel and antiparallel beta sheets, chain reversals and turns, and loops; Kabsch Sander, Biopolymers 22: 2577-2637, 1983), the degree of solvent exposure of amino acid residues, the extent and type of interactions of residues with one another (Chothia, Ann. Rev. Biochem. 53:537-572, 1984) and the static and dynamic distribution of conformations along the polypeptide chain (Alber Mathews, Methods Enzymol. 154: 511-533, 1987). In some cases additional information is known about solvent exposure of residues; one example is a WO 97/12985 P-'T/I c T 38 /Z/14 site of post-translational attachment of carbohydrate which is necessarily on the surface of the protein. When experimental structural information is not available, or is not feasible to obtain, methods are also available to analyze the primary amino acid sequence in order to make predictions of protein tertiary and secondary structure, solvent accessibility and the occurrence of tu!ns and loops.

Biochemical methods are also sometimes applicable for empirically determining surface exposure when direct structural methods are not feasible; for example, using the identification of sites of chain scission following limited proteolysis in order to infer surface exposure (Gentile Salvatore, Eur. J. Biochem. 218:603-621, L993) Thus using either the experimentally derived structural information or predictive methods Srinivisan Rose Proteins: Struct., Funct. Genetics, 22: 81-99, 1995) the parental amino acid sequence is inspected to classify regions according to whether or not they are integral to the maintenance of secondary and tertiary structure. The occurrence of sequences within regions that are known to be involved in periodic secondary structure (alpha and 3-10 helices, parallel and anti-parallel beta sheets) are regions that should be avoided. Similarly, regions of amino acid sequence that are observed or predicted to have a low degree of solvent exposure are more likely to be part of the socalled hydrophobic core of the protein and should also be avoided for selection of amino and carboxyl termini. In contrast, those regions that are known or predicted to be in surface turns or loops, and especially those regions that are known not to be required for biological activity, are the preferred sites for location of the extremes of the polypeptide chain. Continuous stretches of amino acid sequence that are preferred based on the above criteria are referred to as a breakpoint region.

WO 97/12985 PCT/IUS6/1 774a 39 Non-covalent Multifunctional hematopoietic growth factors An alternative method for connecting two hematopoietic growth factors is by means of a non-covalent interaction.

Such complexed proteins can be described by one of the formulae: RI-Cl R2-C2; or C1-RI C2-R2; C1-R1 R2-C2; or C1-R 1 R2-C2.

R1 and R2 are as is defined above. Domains Cl and C2 are either identical or non-identical chemical structures, typically proteinaceous, which can form a non-covalent, specific association. Complexes between Cl and C2 result in a one-to-one stoichiometric relationship between R1 and R2 for each complex. Examples of domains which associate are "leucine zipper" domains of transcription factors, dimerization domains of bacterial transcription repressors and immunoglobulin constant domains. Covalent bonds link R 1 and Cl, and R2 and C2, respectively. As indicated in the formulae, the domains Cl and C2 can be present either at the N-terminus or C-terminus of their corresponding hematopoietic growth factor These multimerization domains (Ci and C2) include those derived from the bZIP family of proteins (Abel et al., Nature 341:24-25, 1989; Landshulz et al., Science 240:1759-1764, 1988; Pu et al., Nuc. Acid Res. 21:4348-4355, 1993; Kozarides et al., Nature 336:646-651, 1988), as well as multimerization domains of the helix-loop-helix family of proteins (Abel et al., Nature 341:24-25, 1989; Murre et al., Cell 56:777-783,1989; Tapscott et al., Science 242:405-411, 1988; Fisher et al., Genes Dev. 5:2342-2352, 1991). Preferred multi-functional hematopoietic receptor agonists of the present invention include colony stimulating factors dimerized by virtue of their incorporation as translational multi-functional WO 97/12985 PCT/UTSOA/I 177A

J

hematopoietic receptor agonists with the leucine zipper dimerization domains of the bZIP family proteins Fos and Jun. The leucine zipper domain of Jun is capable of interactinu with identical domains. On the other hand, the leucine zipper domain of Fos interacts with the Jun leucine zipper domain, but does not interact with other Fos leucine zipper domains. Mixtures of Fos and Jun predominantly result in formation of Fos-Jun heterodimers. Consequently, when joined to colony stimulating factors, the Jun domain can be used to direct the formation of either homo- or heterodimers. Preferential formation of heterodimers can be achieved if one of the colony stimulating factor partners is engineered to possess the Jun leucine zipper.domain while the other is engineered to possess the Fos zipper.

Additional peptide sequences may also be added to facilitate purification or identification of multifunctional hematopoietic receptor agonist proteins poly-His). A highly antigenic peptide may also be added that would enabic rapid assay and facile purification of the multi-functional hematopoietic receptor agonist protein by a specific monoclonal antibody.

"Mutant amino acid sequence," "mutant protein", "variant protein", "mutein", or "mutant polypeptide" refers to a polypeptide having an amino acid sequence which varies from a native sequence due to amino acid deletions, substitutions, or both, or is encoded by a nucleotide sequence intentionally made variant from a native sequence..

"Native sequence" refers to an amino acid or nucleic acid sequence which is identical to a wild-type or native form of a gene or protein.

Hematopoietic growth factors can be characterized by their ability to stimulate colony formation by human WO 97/12985 PCT/US/l T5774 41 hematopoietic progenitor cells. The colonies formed include erythroid, granulocyte, megakaryocyte, granulocytic macrophages and mixtures thereof. Many of the hematopoietic growth factors have demonstrated the ability to restore bone marrow function and peripheral blood cell populations to therapeutically beneficial levels in studies performed initially in primates and subsequently in humans. Many or all of these biological activities of hematopoietic growth factors involve signal transduction and high affinity receptor binding. Multi-functional hematopoietic receptor agonists of the present invention may exhibit useful properties such as having similar or greater biological activity when compared to a single factor or. by having improved half-life or decreased adverse side effects, or a combination of these properties.

Multi-functional hematopoietic receptor agonists which have little or no agonist activity maybe useful as antagonists, as antigens for the production of antibodies for use in immunology or immunotherapy, as genetic probes or as intermediates used to construct other useful hIL-3 muteins.

Biological activity of the multi-functional hematopoietic receptor agonist proteins of the present invention can be determined by DNA synthesis in factordependent cell lines or by counting the colony forming units in an in vitro bone marrow assay.

The multi-functional hematopoietic receptor agonists of the present invention may have an improved therapeutic profile as compared to single acting hematopoietic agonists.

For example, some multi-functional hematopoietic receptor agonists of the present invention may have a similar or more potent growth factor activity relative to other WO 97/12985 PCT/I USQ/1 '7'A 42 hematopoietic agonists without having a similar or corresponding increase in side-effects.

The present invention also includes the DNA sequences which code for the multi-functional hematopoietic receptor agonist proteins, DNA sequences which are substantially similar and perform substantially the same function, and DNA sequences which differ from the DNAs encoding the multi-functional hematopoietic receptor agonists of the invention only due to the degeneracy of the genetic code. Also included in the present invention are the oligonucleotide intermediates used to construct the mutant DNAs and the polypeptides coded for by these oligonucleotides.

Genetic engineering techniques now standard in the art (United States Patent 4,935,233 and Sambrook et al., "Molecular Cloning A Laboratory Manual", Cold Spring Harbor Laboratory, 1989) may be used in the construction of the DNA sequences of the present invention. One such method is cassette mutagenesis (Wells et al., Gene 34:315-323, 1985) in which a portion of the coding sequence in a plasmid is replaced with synthetic oligonucleotides that encode the desired amino acid substitutions in a portion of the gene between two restriction sites.

Pairs of complementary synthetic oligonucleotides encoding the desired gene can be made and annealed to each other. The DNA sequence of the oligonucleotide would encode sequence for amino acids of desired gene with the exception of those substituted and/or deleted from the sequence.

Plasmid DNA can be treated with the chosen restriction endonucleases then ligated to the annealed oligonucleotides.

The ligated mixtures can be used to transform competent JM101 cells to resistance to an appropriate antibiotic.

Single colonies can be picked and the plasmid DNA examined by restriction analysis and/or DNA sequencing to identify WO 97/12985 PCT/ITUS96/1 '74 43 plasmids with the desired genes.

Cloning of the DNA sequences of the novel multifunctional hematopoietic agonists wherein at least one of the with the DNA sequence of the other colony stimulating factor may be accomplished by the use of intermediate vectors. Alternatively one gene can be cloned directly into a vector containing the other gene. Linkers and adapters can be used for joining the DNA sequences, as well as replacing lost sequences, where a restriction site was internal to the region of interest. Thus genetic material (DNA) encoding one polypeptide, peptide linker, and the other polypeptide is inserted into a suitable expression vector which is used to transform bacteria,.yeast, insect cells or mammalian cells. The transformed organism is grown and the protein isolated by standard techniques. The resulting product is therefore a new protein which has a colony stimulating factor joined by a linker region to a second colony stimulating factor.

Another aspect of the present invention provides plasmid DNA vectors for use in the expression of these novel multi-functional hematopoietic receptor agonists. These vectors contain the novel DNA sequences described above which code for the novel polypeptides of the invention.

Appropriate vectors which can transform microorganisms capable of expressing the multi-functional hematopoietic receptor agonists include expression vectors comprising nucleotide sequences coding for the multi-functional hematopoietic receptor agonists joined to transcriptional and translational regulatory sequences which are selected according to the host cells used.

Vectors incorporating modified sequences as described above are included in the present invention and are useful in the production of the multi-functional hematopoietic receptor agonist polypeptides. The vector employed in the method also contains selected regulatory sequences in WO 97/12985 PCT/US96/1 1774 44 operative association with the DNA coding sequences of the invention and which are capable of directing the replication and expression thereof in selected host cells.

As another aspect of the present invention, there is provided a method for producing the novel multi-functional hematopoietic receptor agonists. The method of the present invention involves culturing suitable cells or cell line, which has been transformed with a vector containing a DNA sequence coding for expression of a novel multi-functional hematopoietic receptor agonist. Suitable cells or cell lines may be bacterial cells. For example, the various strains of E. coli are well-known as host cells in the field of biotechnology. Examples of such strains.include E. coli strains JM101 (Yanish-Perron et al. Gene 33: 103-119, 1985) and MON105 (Obukowicz et al., Applied Environmental Microbiology 58: 1511-1523, 1992). Also included in the present invention is the expression of the multi-functional hematopoietic receptor agonist protein utilizing a chromosomal expression vector for E. coli based on the bacteriophage Mu (Weinberg et al., Gene 126: 25-33, 1993).

Various strains of B. subtilis may also be employed in this method. Many strains of yeast cells known to those skilled in the art are also available as host cells for expression of the polypeptides of the present invention. When expressed in the E. coli cytoplasm, the gene encoding the multi-functional hematopoietic receptor agonists of the present invention may also be constructed such that at the end of the gene codons are added to encode Met-2-Ala or -i Met at the N-terminus of the protein. The N termini of proteins made in the cytoplasm of E. coli are affected by post-translational processing by methionine aminopeptidase (Ben Bassat et al., J. Bac. 169:751-757, 1987) and possibly by other peptidases so that upon expression the methionine is cleaved off the N-terminus. The multi-functional hematopoietic receptor agonists of the present invention may WO 97/12985 PCT/ITS9Q6/1 774d include multi-functional hematopoietic receptor agonist polypeptides having Met Ala 1 or Met-2-Ala I at the Nterminus. These mutant multi-functional hematopoietic receptor agonists may also be expressed in E. coli by fusing a secretion signal peptide to the N-terminus. This signal peptide is cleaved from the polypeptide as part of the secretion process.

Also suitable for use in the present invention are mammalian cells, such as Chinese hamster ovary cells (CHO).

General methods for expression of foreign genes in mammalian cells are reviewed in Kaufman, R. 1987) Genetic Engineering, Principles and Methods, Vol. 9, J. K. Setlow, editor, Plenum Press, New York. An expression vector is constructed in which a strong promoter capable of functioning in mammalian cells drives transcription of a eukaryotic secretion signal peptide coding region, which is translationally joined to the coding region for the multifunctional hematopoietic receptor agonist. For example, plasmids such as pcDNA I/Neo, pRc/RSV, and pRc/CMV (obtained from Invitr-ogen Corp., San Diego, California) can be used.

The eukaryotic secretion signal peptide coding region can be from the gene itself or it can be from another secreted mammalian protein (Bayne, M. L. et al., Proc. Natl. Acad.

Sci. USA 84: 2638-2642, 1987). After construction of the vector containing the gene, the vector DNA is transfected into mammalian cells. Such cells can be, for example, the COS7, HeLa, BHK, CHO, or mouse L lines. The cells can be cultured, for example, in DMEM media (JRH Scientific). The polypeptide secreted into the media can be recovered by standard biochemical approaches following transient expression for 24 72 hours after transfection of the cells or after establishment of stable cell lines following selection for antibiotic resistance. The selection of suitable mammalian host cells and methods for transformation, culture, amplification, screening and WO 97/12985 46 PCT/US96/157 7 4 product production and purification are known in the art.

See, Gething and Sambrook, Nature, 293:620-625, 1981), or alternatively, Kaufman et al, Mol. Cell. Biol., 5(7):1750-1759, 1985) or Howley et al., U.S. Pat. No.

4,419,446. Another suitable mammalian cell line is the monkey COS-1 cell line. A similarly useful mammalian cell line is the CV-1 cell line.

Where desired, insect cells may be utilized as host cells in the method of the present invention. See, e.g., Miller et al., Genetic Engineering, 8:277-298 (Plenum Press 1986) and ieferences cited therein. In addition, general methods for expression of foreign genes in insect cells using Baculovirus vectors are described in:.Summers, M. D.

and Smith, G. 1987) A manual of methods for Baculovirus vectors and insect cell culture procedures, Texas Agricultural Experiment Station Bulletin No. 1555. An expression vector is constructed comprising a Baculovirus transfer vector, in which a strong Baculovirus promoter (such as the polyhedron promoter) drives transcription of a eukaryotic secretion signal peptide coding region, which is translationally joined to the coding region for the multifunctional hematopoietic receptor agonist polypeptide. For example, the plasmid pVL1392 (obtained from Invitrogen Corp., San Diego, California) can be used. After construction of the vector carrying the gene encoding the multi-functional hematopoietic receptor agonist polypeptide, two micrograms of this DNA is co-transfected with one microgram of Baculovirus DNA (see Summers Smith, 1987) into insect cells, strain SF9. Pure recombinant Baculovirus carrying the multi-functional hematopoietic receptor agonist is used to infect cells cultured, for example, in Excell 401 serum-free medium (JRH Biosciences, Lenexa, Kansas). The multi-functional hematopoietic receptor agonist secreted into the medium can be recovered by standard biochemical approaches. Supernatants from mammalian or insect cells WO 97/12985 PCT/IUQQo;/1 '7t 47 expressing the multi-functional hematopoietic receptor agonist protein can be first concentrated using any of a number of commercial concentration units.

The multi-functional hematopoietic receptor agonists of the present invention may be useful in the treatment of diseases characterized by decreased levels of either myeloid, erythroid, lymphoid, or megakaryocyte cells of the hematopoietic system or combinations thereof. In addition, they may be used to activate mature myeloid and/or lymphoid cells. Among conditions susceptible to treatment with the polypeptides of the present invention is leukopenia, a reduction in the number of circulating leukocytes (white cells) in the peripheral blood. Leukopenia may be induced by exposure to certain viruses or to radiation. It is often a side effect of various forms of cancer therapy, e.g., exposure to chemotherapeutic drugs, radiation and of infection or hemorrhage. Therapeutic treatment of leukopenia with these multi-functional hematopoietic receptor agonists of the present invention may avoid undesirable side effects caused by treatment with presently available drugs.

The multi-functional hematopoietic receptor agonists of the present invention may be useful in the treatment of neutropenia and, for example, in the treatment of such conditions as aplastic anemia, cyclic neutropenia, idiopathic neutropenia, Chediak-Higashi syndrome, systemic lupus erythematosus (SLE), leukemia, myelodysplastic syndrome and myelofibrosis.

The multi-functional hematopoietic receptor agonist of the present invention may be useful in the treatment or prevention of thrombocytopenia. Currently the only therapy for thrombocytopenia is platelet transfusion which are costly and carry the significant risks of infection

(HIV,

HBV) and alloimunization. The multi-functional hematopoietic WO 97/12985 PCT/IUSO/1C 7A 48 8P i i78receptor agonist may alleviate or diminish the need for platelet transfusion. Severe thrombocytopenia may result from genetic defects such as Fanconi's Anemia, Wiscott- Aldrich, or May Hegglin syndromes. Acquired thrombocytopenia may result from auto- or allo-antibodies as in Immune Thrombocytopenia Purpura, Systemic Lupus Erythromatosis, hemolytic anemia, or fetal maternal incompatibility. In addition, splenomegaly, disseminated intravascular coagulation, thrombotic thrombocytopenic purpura, infection or prosthetic heart valves may result in thrombocytopenia.

Severe thrombocytopenia may also result from chemotherapy and/or radiation therapy or cancer. Thrombocytopenia may also result from marrow invasion by carcinoma, lymphoma, leukemia or fibrosis.

The multi-functional hematopoietic receptor agonists of the present invention may be useful in the mobilization of hematopoietic progenitors and stem cells in peripheral blood. Peripheral blood derived progenitors have been shown to be effective in reconstituting patients in the setting of autologous marrow transplantation. Hematopoietic growth factors including G-CSF and GM-CSF have been shown to enhance the number of circulating progenitors and stem cells in the peripheral blood. This has simplified the procedure for peripheral stem cell collection and dramatically decreased the cost of the procedure by decreasing the number of pheresis required. The multi-functional hematopoietic receptor agonist may be useful in mobilization of stem cells and further enhance the efficacy of peripheral stem cell transplantation.

The multi-functional hematopoietic receptor agonists of the present invention may also be useful in the ex vivo expansion of hematopoietic progenitors and stem cells.

Colony stimulating factors (CSFs), such as hIL-3, have been WO 97/12985 PCT/US96/15774 49 administered alone, co-administered with other CSFs, or in combination with bone marrow transplants subsequent to high dose chemotherapy to treat the neutropenia and thrombocytopenia which are often the result of such treatment. However the period of severe neutropenia and thrombocytopenia may not be totally eliminated. The myeloid lineage, which is comprised of monocytes (macrophages), granulocytes (including neutrophils) and megakaryocytes, is critical in preventing infections and bleeding which can be life-threatening. Neutropenia and thrombocytopenia may also be the result of disease, genetic disorders, drugs, toxins, radiation and many therapeutic treatments such as conventional oncology therapy. Bone marrow transplants have been used to treat this patient population. However, several problems are associated with the use of bone marrow to reconstitute a compromised hematopoietic system including: 1) the number of stem cells in bone marrow, spleen, or peripheral blood is limited, 2) Graft Versus Host Disease, 3) graft rejection and 4) possible contamination with tumor cells. Stem cells make up a very small percentage of the nucleated cells in the bone marrow, spleen and peripheral blood. It is clear that a dose response exists such that a greater number of stem cells will enhance hematopoietic recovery. Therefore, the in vitro expansion of stem cells should enhance hematopoietic recovery and patient survival. Bone marrow from an allogeneic donor has been used to provide bone marrow for transplant. However, Graft Versus Host Disease and graft rejection limit bone marrow transplantation even in recipients with HLA-matched sibling donors. An alternative to allogeneic bone marrow transplants is autologous bone marrow transplants. In autologous bone marrow transplants, some of the patient's own marrow is harvested prior to myeloablative therapy, e.g. high dose chemotherapy, and is transplanted back into the patient afterwards. Autologous WO 97/12985 PCT/US9Q6/1 77A transplants eliminate the risk of Graft Versus Host Disease and graft rejection. However, autologous bone marrow transplants still present problems in terms of the limited number of stems cells in the marrow and possible contamination with tumor cells. The limited number of stem cells may be overcome by ex-vivo expansion of the stem cells. In addition, stem cells can be specifically isolated, based on the presence of specific surface antigens such as CD34+ in order to decrease tumor cell contamination of the marrow graft.

The following patents contain further details on separating stem cells, CD34+ cells, culturing the cells with hematopoietic factors, the use of the cells for the treatment of patients with hematopoietic disorders and the use of hematopoietic factors for cell expansion and gene therapy.

5,061,620 relates to compositions comprising human hematopoietic stem cells provided by separating the stem cells from dedicated cells.

5,199,942 describes a method for autologous hematopoietic cell transplantation comprising: obtaining hematopoietic progenitor cells from a patient; ex-vivo expansion of cells with a growth factor selected from the group consisting of IL-3, flt3 ligand, c-kit ligand, GM-CSF, IL-1, GM-CSF/IL-3 fusion protein and combinations thereof; (3) administering cellular preparation to a patient.

5,240,856 relates to a cell separator that includes an apparatus for automatically controlling the cell separation process.

WO 91/16116 describes devices and methods for selectively WO 97/12985 PCT/ TCQ/l I q1 51 J isolating and separating target cells from a mixture of cells.

WO 91/18972 describes methods for in vitro culturing of bone marrow, by incubating suspension of bone marrow cells, using a hollow fiber bioreactor.

WO 92/18615 relates to a process for maintaining and expanding bone marrow cells, in a culture medium containing specific mixtures of cytokines, for use in transplants.

WO 93/0826L describes a method for selectively expanding stem cells, comprising the steps of separating CD34+ stem cells from other cells and incubating the separated cells in a selective medium, such that the stem cells are selectively expanded.

WO 93/18136 describes a process for in vitro support of mammalian cells derived from peripheral blood.

WO 93/18648 relates to a composition comprising human neutrophil precursor cells with a high content of myeloblasts and promyelocytes for treating genetic or acquired neutropenia.

WO 94/08039 describes a method of enrichment for human hematopoietic stem cells by selection for cells which express c-kit protein.

WO 94/11493 describes a stem cell population that are CD34+ and small in size, which are isolated using a counterflow elutriation method.

WO 94/27698 relates to a method combining immunoaffinity separation and continuous flow centrifugal separation for WO 97/12985 PCT/US96/15774 52 the selective separation of a nucleated heterogeneous cell population from a heterogeneous cell mixture.

WO 94/25848 describes a cell separation apparatus for collection and manipulation of target cells.

The long term culturing of highly enriched CD34+ precursors of hematopoietic progenitor cells from human bone marrow in cultures containing IL-la, IL-3, IL-6 or GM-CSF is discussed in Brandt et al J. Clin. Invest. 86:932-941, 1990).

One aspect of the present invention provides a method for selective ex-vivo expansion of stem cells. The term "stem cell" refers to the totipotent hematopoietic stem cells as well as early precursors and progenitor cells which can be isolated from bone marrow, spleen or peripheral blood. The term "expansion" refers to the differentiation and proliferation of the cells. The present invention provides a method for selective ex-vivo expansion of stem cells, comprising the steps of: separating stem cells from other cells, culturing said separated stem cells with a selective media which contains multi-functional hematopoietic receptor agonist protein(s) and harvesting said stems cells. Stem cells, as well as committed progenitor cells destined to become neutrophils, erythrocytes, platelets, etc. may be distinguished from most other cells by the presence or absence of particular progenitor marker antigens, such as CD34, that are present on the surface of these cells and/or by morphological characteristics. The phenotype for a highly enriched human stem cell fraction is reported as CD34+, Thy-l+ and lin-, but it is to be understood that the present invention is not limited to the expansion of this stem cell population. The CD34+ enriched human stem cell fraction can be separated by a number of reported methods, including affinity columns or WO 97/12985 PCT/US96/15774 53 beads, magnetic beads or flow cytometry using antibodies directed to surface antigens such as the CD34+. Further, physical separation methods such as counterflow elutriation may be used to enrich hematopoietic progenitors. The CD34+ progenitors are heterogeneous, and may be divided into several sub-populations characterized by the presence or absence of co-expression of different lineage associated cell surface associated molecules. The most immature progenitor cells do not express any known lineage associated markers, such as HLA-DR or CD38, but they may express Other surface antigens such as CD33, CD38, CD41, CD71, HLA-DR or c-kit can also be used to selectively isolate hematopoietic progenitors. The separated cells can be incubated in selected medium in a culture flask, sterile bag or in hollow fibers. Various colony stimulating factors may be utilized in order to selectively expand cells.

Representative factors that have been utilized for ex-vivo expansion of bone marrow include, c-kit ligand, IL-3, G-CSF, GM-CSF, IL-1, IL-6, IL-11, flt-3 ligand or combinations thereof. The proliferation of the stem cells can be monitored by enumerating the number of stem cells and other cells, by standard techniques hemacytometer,

CFU,

LTCIC) or by flow cytometry prior and subsequent to incubation.

Several methods for ex-vivo expansion of stem cells have been reported utilizing a number of selection methods and expansion using various colony stimulating factors including c-kit ligand (Brandt et al., Blood 83:1507-1514 [1994], McKenna et al., Blood 86:3413-3420 [1995]), IL-3 (Brandt et al., Blood 83:1507-1514 [1994], Sato et al., Blood 82:3600-3609 [1993]), G-CSF (Sato et al., Blood 82:3600-3609 [1993]), GM-CSF (Sato et al., Blood 82:3600- 3609 [1993]), IL-1 (Muench et al., Blood 81:3463-3473 [1993]), IL-6 (Sato et al., Blood 82:3600-3609 [1993]), IL- WO 97/12985 PCT/US96/1 77A 54 11 (Lemoli et al., Exp. Hem. 21:1668-1672 [1993], Sato et al., Blood 82:3600-3609 [1993]), flt-3 ligand (McKenna et al., Blood 86:3413 3420 [1995]) and/or combinations thereof (Brandt et al., Blood 83:1507 1514 [1994], Haylock et al., Blood 80:1405-1412 [1992], Koller et al., Biotechnology 11:358-363 [1993], (Lemoli et al., Exp. Hem. 21:1668-1672 [1993]), McKenna et al., Blood 86:3413-3420 [1995], Muench et al., Blood 81:3463-3473 [1993], Patchen et al., Biotherapy 7:13-26 [1994], Sato et al., Blood 82:3600-3609 [1993], Smith et al., Exp. Hem. 21:870-877 [1993], Steen et al., Stem Cells 12:214-224 [1994], Tsujino et al., Exp. Hem.

21:1379-1386 [1993]). Among the individual colony stimulating factors, hIL-3 has been shown to- be one of the most potent in expanding peripheral blood CD34+ cells (Sato et al., Blood 82:3600-3609 [1993], Kobayashi et al., Blood 73:1836-1841 [1989]). However, no single factor has been shown to be as effective as the combination of multiple factors. The present invention provides methods for ex vivo expansion that utilize multi-functional hematopoietic receptor agonists that are more effective than a single factor alone.

Another aspect of the invention provides methods of sustaining and/or expanding hematopoietic precursor cells which includes inoculating the cells into a culture vessel which contains a culture medium that has been conditioned by exposure to a stromal cell line such as HS-5 (WO 96/02662, Roecklein and Torok-Strob, Blood 85:997-1105, 1995) that has been supplemented with a multi-functional hematopoietic receptor agonist of the present invention.

Another projected clinical use of growth factors has been in the in vitro activation of hematopoietic progenitors and stem cells for gene therapy. Due to the long life-span of hematopoietic progenitor cells and the distribution of WO 97/12985 PCT/US96/15774 their daughter cells throughout the entire body, hematopoietic progenitor cells are good candidates for ex vivo gene transfection. In order to have the gene of interest incorporated into the genome of the hematopoietic progenitor or stem cell one needs to stimulate cell division and DNA replication. Hematopoietic stem cells cycle at a very low frequency which means that growth factors may be useful to promote gene transduction and thereby enhance the clinical prospects for gene therapy. Potential applications of gene therapy (review Crystal, Science 270:404-410 [1995]) include; 1) the treatment of many congenital metabolic disorders and immunodeficiencies (Kay and Woo, Trends Genet. 10:253-257 [1994]), 2) neurological disorders (Friedmann, Trends Genet. 10:210-214 [1994]), 3) cancer (Culver and Blaese, Trends Genet. 10:174-178 [1994]) and 4) infectious diseases (Gilboa and Smith, Trends Genet. 10:139- 144 [1994]).

There are a variety of methods, known to those with skill in the art, for introducing genetic material into a host cell. A number of vectors, both viral and non-viral have been developed for transferring therapeutic genes into primary cells. Viral based vectors include; 1) replication deficient recombinant retrovirus (Boris-Lawrie and Temin, Curr. Opin. Genet. Dev. 3:102-109 [1993], Boris-Lawrie and Temin, Annal. New York Acad. Sci. 716:59-71 [1994], Miller, Current Top. Microbiol. Immunol. 158:1-24 [1992]) and replication-deficient recombinant adenovirus (Berkner, BioTechniques 6:616-629 [1988], Berkner, Current Top.

Microbiol. Immunol. 158:39-66 [1992], Brody and Crystal, Annal. New York Acad. Sci. 716:90-103 [1994]). Non-viral based vectors include protein/DNA complexes (Cristiano et al., PNAS USA. 90:2122-2126 [1993], Curiel et al., PNAS USA 88:8850-8854 [1991], Curiel, Annal. New York Acad. Sci.

716:36-58 [1994]), electroporation and liposome mediated delivery such as cationic liposomes (Farhood et al., Annal.

WO 97/12985 PCT/US 6/7 4inA 56 New York Acad. Sci. 716:23-35 [1994]).

The present invention provides an improvement to the existing methods of expanding hematopoietic cells, which new genetic material has been introduced, in that it provides methods utilizing multi-functional hematopoietic receptor agonist proteins that have improved biological activity, including an activity not seen by any single colony stimulation factor.

Many drugs may cause bone marrow suppression or hematopoietic deficiencies. Examples of such drugs are AZT, DDI, alkylating agents and anti-metabolites used in chemotherapy, antibiotics such as chloramphenicol, penicillin, gancyclovir, daunomycin and sulfa drugs, phenothiazones, tranquilizers such as meprobamate, analgesics such as aminopyrine and dipyrone, anticonvulsants such as phenytoin or carbamazepine, antithyroids such as propylthiouracil and methimazole and diuretics. The multi-functional hematopoietic receptor agonists of the present invention may be useful in preventing or treating the bone marrow suppression or hematopoietic deficiencies which often occur in patients treated with these drugs.

Hematopoietic deficiencies may also occur as a result of viral, microbial or parasitic infections and as a result of treatment for renal disease or renal failure, e.g., dialysis. The multi-functional hematopoietic receptor agonists of the present invention may be useful in treating such hematopoietic deficiencies.

The treatment of hematopoietic deficiency may include administration of a pharmaceutical composition containing the multi-functional hematopoietic receptor agonists to a patient. The multi-functional hematopoietic receptor agonists of the present invention may also be useful for the activation and amplification of hematopoietic precursor cells by treating these cells in vitro with the multifunctional hematopoietic receptor agonist proteins of the WO 97/12985 PCTIUS96/1 5774 57 present invention prior to injecting the cells into a patient.

Various immunodeficiencies, in T and/or B lymphocytes, or immune disorders, rheumatoid arthritis, may also be beneficially affected by treatment with the multi-functional hematopoietic receptor agonists of the present invention. Immunodeficiencies may be the result of viral infections, HTLVI, HTLVII, HTLVIII, severe exposure to radiation, cancer therapy or the result of other medical treatment. The multi-functional hematopoietic receptor agonists of the present invention may also be employed, alone or in combination with other colony stimulating factors, in the treatment of other blood cell deficiencies, including thrombocytopenia (platelet deficiency), or anemia. Other uses for these novel polypeptides are the in vivo and ex vivo treatment of patients recovering from bone marrow transplants, and in the development of monoclonal and polyclonal antibodies generated by standard methods for diagnostic or therapeutic use.

Other aspects of the present invention are methods and therapeutic compositions for treating the conditions referred to above. Such compositions comprise a therapeutically effective amount of one or more of the multi-functional hematopoietic receptor agonists of the present invention in a mixture with a pharmaceutically acceptable carrier. This composition can be administered either parenterally, intravenously or subcutaneously. When administered, the therapeutic composition for use in this invention is preferably in the form of a pyrogen-free, parenterally acceptable aqueous solution. The preparation of such a parenterally acceptable protein solution, having due regard to pH, -isotonicity, stability and the like, is within the skill of the art.

The dosage regimen involved in a method for treating WO 97/12985 PCT/US96/1 5774 58 the above-described conditions will be determined by the attending physician considering various factors which modify the action of drugs, the condition, body weight, sex and diet of the patient, the severity of any infection, time of administration and other clinical factors. Generally, a daily regimen may be in the range of 0.2 150 gg/kg of multi-functional hematopoietic receptor agonist-protein per kilogram of body weight. Dosages would be adjusted relative to the activity of a given multi-functional hematopoietic receptor agonist protein and it would not be unreasonable to note that dosage regimens may include doses as low as 0.1 microgram and as high as 1 milligram per kilogram of body weight per day. In addition, there may exist specific circumstances where dosages of multi-functional hematopoietic receptor agonist would be adjusted higher or lower than the range of 0.2 150 micrograms per kilogram of body weight. These include co-administration with other colony stimulating factors or IL-3 variants or growth factors; co-administration with chemotherapeutic drugs and/or radiation; the use of glycosylated multi-functional hematopoietic receptor agonist protein; and various patientrelated issues mentioned earlier in this section. As indicated above, the therapeutic method and compositions may also include co-administration with other human factors. A non-exclusive list of other appropriate colony stimulating factors (CSFs), cytokines, lymphokines, hematopoietic growth factors and interleukins for simultaneous or serial coadministration with the polypeptides of the present invention includes GM-CSF, G-CSF, c-mpl ligand (also known as TPO or MGDF), M-CSF, erythropoietin (EPO), IL-1, IL-4, IL-2, IL-3, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL- 12, IL-13, IL-15, IL-16, LIF, flt3/flk2 ligand, B-cell growth factor, B-cell differentiation factor and eosinophil differentiation factor, stem cell factor (SCF) also known as steel factor or c-kit ligand, or combinations thereof. The WO 97/12985 PCT/US96/15774 59 dosage recited above would be adjusted to compensate for such additional components in the therapeutic composition.

Progress of the treated patient can be monitored by periodic assessment of the hematological profile, differential cell count and the like.

MATERIALS AND METHODS Unless noted otherwise, all specialty chemicals were obtained from Sigma, Co. (St. Louis, MO). Restriction endonucleases and T4 DNA ligase were obtained from New England Biolabs (Beverly, MA) or Boehringer-Mannheim (Indianapolis, IN).

Transformation of E. coli strains E. coli strains, such as DH5a T M (Life Technologies, Gaithersburg, MD) and TG1 (Amersham Corp., Arlington Heights, IL) are used for transformation of ligation reactions and are the source of plasmid DNA for transfecting mammalian cells. E. coli strains, such as JM101 (Yanisch- Perron, et al., Gene, 33: 103-119, 1985) and MON105 (Obukowicz, et al., Appl. and Envir. Micr., 58: 1511-1523, 1992) can be used for expressing the multi-functional hematopoietic receptor agonist of the present invention in the cytoplasm or periplasmic space.

MON105 ATCC#55204: lambda-,IN(rrnD, rrE)l, rpoD+, rpoH358 phi80dlacZdeltaM15, delta(lacZYA-argF)U169, deoR, recAl, endAl, hsdRl7(rk-,mk+), phoA, supE441amda-, thi-l, gyrA96, relAl WO 97/12985 PCT/US9i/ 15774 TG1: delta(lac-pro), supE, thi-l, hsdD5/F'(traD36, proA+B+, lacIq, JM101 ATCC#33876: delta (pro lac), supE, thi, F'(traD36, proA+B+, laclq, T M Subcloning efficiency cells are purchased as competent cells and are ready for transformation using the manufacturer's protocol, while both E. coli strains TG1 and MON105 are rendered competent to take up DNA using a CaCl2 method. Typically, 20 to 50 mL of cells are grown in LB medium bacto-tryptone, 0.5% bacto-yeast extract, 150 mM NaCl) to a density of approximately 1.0 optical density unit at 600 nanometers (OD600) as measured by a Baush Lomb Spectronic spectrophotometer (Rochester, NY). The cells are collected by centrifugation and resuspended in one-fifth culture volume of CaCl2 solution (50 mM CaCl2, 10 mM Tris- Cl, pH7.4) and are held at 4'C for 30 minutes. The cells are again collected by centrifugation and resuspended in one-tenth culture volume of CaC12 solution. Ligated DNA is added to 0.2 mL of these cells, and the samples are held at 4'C for 30-60 minutes. The samples are shifted to 42'C for two minutes and 1.0 mL of LB is added prior to shaking the samples at 37'C for one hour. Cells from these samples are spread on plates (LB medium plus 1.5% bacto-agar) containing either ampicillin (100 micrograms/mL, ug/mL) when selecting for ampicillin-resistant transformants, or spectinomycin ug/mL) when selecting for spectinomycin-resistant transformants. The plates are incubated overnight at 37'C.

Colonies are picked and inoculated into LB plus appropriate antibiotic (100 ug/mL ampicillin or 75 ug/mL spectinomycin) and are grown at 37 0 C while shaking.

Methods for creation of genes with new N-terminus/C-terminus WO 97/12985 PCT/US96/1 5774 61 Method I. Creation of genes with new N-terminus/C-terminus which contain a linker region (L2).

Genes with new N-terminus/C-terminus which contain a linker region (L2) separating the original C-terminus and Nterminus can be made essentially following the method described in L. S. Mullins, et al J. Am. Chem. Soc. 116, 5529-5533, 1994). Multiple steps of polymerase chain reaction (PCR) amplifications are used to rearrange the DNA sequence encoding the primary amino acid sequence of the protein. The steps are illustrated in Figure 2.

In the first step, the first primer set ("new start" and "linker start") is used to create and amplify, from the original gene sequence, the DNA fragment ("Fragment Start") that contains the sequence encoding the new N-terminal portion of the new protein followed by the linker (L2) that connects the C-terminal and N-terminal ends of the original protein. In the second step, the second primer set ("new stop" and "linker stop") is used to create and amplify, from the original gene sequence, the DNA fragment ("Fragment Stop") that encodes the same linker as used above, followed by the new C-terminal portion of the new protein. The "new start" and "new stop" primers are designed to include the appropriate restriction sites which allow cloning of the new gene into expression plasmids. Typical PCR conditions are one cycle 95 0 C melting for two minutes; 25 cycles 94°C denaturatier for one minute, 50 0 C annealing for one minute and 72 0 C extension for one minute; plus one cycle 72 0

C

extension for seven minutes. A Perkin Elmer GeneAmp PCR Core Reagents kit is used. A 100 ul reaction contains 100 pmole of each primer and one ug of template DNA; and Ix PCR buffer, 200 uM dGTP, 200 uM dATP, 200 uM dTTP, 200 uM dCTP, units AmpliTaq DNA polymerase and 2 mM MgC12. PCR reactions are performed in a Model 480 DNA thermal cycler (Perkin Elmer Corporation, Norwalk, CT).

WO 97/12985 PCT/YJS96/1 5774 62 "Fragment Start" and "Fragment Stop", which have complementary sequence in the linker region and the coding sequence for the two amino acids on both sides of the linker, are joined together in a third PCR step to make the full-length gene encoding the new protein. The DNA fragments "Fragment Start" and "Fragment Stop" are resolved on a 1% TAE gel, stained with ethidium bromide and isolated using a Qiaex Gel Extraction kit (Qiagen). These fragments are combined in equimolar quantities, heated at 70 0 C for ten minutes and slow cooled to allow annealing through their shared sequence in "linker start" and "linker stop". In the third PCR step, primers "new start" and "new-stop" are added to the annealed fragments to create and amplify the fulllength new N-terminus/C-terminus gene. Typical PCR conditions are one cycle 95 0 C melting for two minutes; cycles 94 0 C denaturation for one minute, 60 0 C annealing for one minute and 72 0 C extension for one minute; plus one cycle 72 0 C extension for seven minutes. A Perkin Elmer GeneAmp PCR Core Reagents kit is used. A 100 ul reaction contains 100 pmole of each primer and approximately 0.5 ug of DNA; and Ix PCR buffer, 200 uM dGTP, 200 uM dATP, 200 uM dTTP, 200 uM dCTP, 2.5 units AmpliTaq DNA polymerase and 2 mM MgC12. PCR reactions are purified using a Wizard PCR Preps kit (Promega).

Method II. Creation of genes with new N-terminus/C-terminus without a linker region.

New N-terminus/C-terminus genes without a .linker joining the original N-terminus and C-terminus can be made using two steps of PCR amplification and a blunt end ligation. The steps are illustrated in Figure 3. In the first step, the primer set ("new start" and "P-bl start") is used to create and amplify, from the original gene sequence, WO 97/12985 PCTIS96/15774 63 the DNA fragment ("Fragment Start") that contains the sequence encoding the new N-terminal portion of the new protein. In the second step, the primer set ("new stop" and "P-bl stop") is used to create and amplify, from gene sequence, the DNA fragment ("Fragment Stop") that contains the sequence encoding the new C-terminal portion of the new protein. The "new start" and "new stop" primers are designed to include appropriate restriction sites which allow cloning of the new gene into expression vectors. Typical PCR conditions are one cycle 95 0 C melting for two minutes; cycles 94 0 C denaturation for one minute, 50 0 C annealing for seconds and 720C extension for 45 seconds. Deep Vent polymerase (New England Biolabs) is used to-reduce the occurrence of overhangs in conditions recommended by the manufacturer. The "P-bl start" and "P-bl stop" primers are phosphorylated at the 5' end to aid in the subsequent blunt end ligation of "Fragment Start" and "Fragment Stop" to each other. A 100 ul reaction contained 150 pmole of each primer and one ug of template DNA; and Ix Vent buffer (New England Biolabs), 300 uM dGTP, 300 uM dATP, 300 uM dTTP, 300 uM dCTP, and 1 unit Deep Vent polymerase. PCR reactions are performed in a Model 480 DNA thermal cycler (Perkin Elmer Corporation, Norwalk, CT). PCR reaction products are purified using a Wizard PCR Preps kit (Promega).

The primers are designed to include appropriate restriction sites which allow for the cloning of the new gene into expression vectors. Typically "Fragment Start" is designed to create NcoI restriction site and "Fragment Stop" is designed to create a HindIII restriction site.

Restriction digest reactions are purified using a Magic DNA Clean-up System kit (Promega). Fragments Start and Stop are resolved on a 1% TAE gel, stained with ethidium bromide and isolated using a Qiaex Gel Extraction kit (Qiagen). These fragments are combined with and annealed to the ends of the WO 97/12985 PCT/USq96/15 77A 64 3800 base pair NcoI/HindIII vector fragment of pMON3934 by heating at 50 0 C for ten minutes and allowed to slow cool.

The three fragments are ligated together using T4 DNA ligase (Boehringer Mannheim). The result is a plasmid containing the full-length new N-terminus/C-terminus gene. A portion of the ligation reaction is used to transform E. coli strain cells (Life Technologies, Gaithersburg, MD]. Plasmid DNA is purified and sequence confirmed as below.

Method III. Creation of new N-terminus/C-terminus genes by tandem-duplication method New N-terminus/C-terminus genes can be-made based on the method described in R. A. Horlick, et al Protein Eng.

5:427-431, 1992). Polymerase chain reaction

(PCR)

amplification of the new N-terminus/C-terminus genes is performed using a tandemly duplicated template DNA. The steps are illustrated in Figure 3.

The tandemly-duplicated template DNA is created by cloning and contains two copies of the gene separated by DNA sequence encoding a linker connecting the original C- and Nterminal ends of the two copies of the gene. Specific primer sets are used to create and amplify a full-length new N terminus/C-terminus gene from the tandemly-duplicated template DNA. These primers are designed to include appropriate restriction sites which allow for the cloning of the new gene into expression vectors. Typical PCR conditions are one cycle 95 0 C melting for two minutes; 25 cycles 94 0

C

denaturation for one minute, 50 0 C annealing for one minute and 72 0 C extension for one minute; plus one cycle 72°C extension for seven minutes. A Perkin Elmer GeneAmp PCR Core Reagents kit (Perkin Elmer Corporation, Norwalk, CT) is used. A 100 ul reaction contains 100 pmole of each primer and one ug of template DNA; and Ix PCR buffer, 200 uM dGTP, WO 97/12985 PCT/USn /15774 200 uM dATP, 200 uM dTTP, 200 uM dCTP, 2.5 units AmpliTaq DNA polymerase and 2 mM MgCl 2 PCR reactions are performed in a Model 480 DNA thermal cycler (Perkin Elmer Corporation, Norwalk, CT). PCR reactions are purified using a Wizard PCR Preps kit (Promega).

Cloning of new N-terminus/C-terminus genes into-multifunctional receptor agonist expression vectors.

The new N-terminus/C-terminus gene is digested with restriction endonucleases to create ends that are compatible to insertion into an expression vector containing another colony stimulating factor gene. This expression vector is likewise digested with restriction endonucleases to form compatible ends. After purification, the gene and the vector DNAs are combined and ligated using T4 DNA ligase. A portion of the ligation reaction is used to transform

E.

coli. Plasmid DNA is purified and sequenced to confirm the correct insert. The correct clones are grown for protein expression.

DNA isolation and characterization Plasmid DNA can be isolated by a number of different methods and using commercially available kits known to those skilled in the art. A few such methods are shown herein.

Plasmid DNA is isolated using the Promega Wizard T M Miniprep kit (Madison, WI), the Qiagen QIAwell Plasmid isolation kits (Chatsworth, CA) or Qiagen Plasmid Midi kit. These kits follow the same general procedure for plasmid DNA isolation.

Briefly, cells are pelleted by centrifugation (5000 x g), plasmid DNA released with sequential NaOH/acid treatment, and cellular debris is removed by centrifugation (10000 x The supernatant (containing the plasmid DNA) is loaded WO 97/12985 PCT/IIU.QA/I I A 66 onto a column containing a DNA-binding resin, the column is washed, and plasmid DNA eluted with TE. After screening for the colonies with the plasmid of interest, the E. coli cells are inoculated into 50-100 mis of LB plus appropriate antibiotic for overnight growth at 37 0 C in an air incubator while shaking. The purified plasmid DNA is used for DNA sequencing, further restriction enzyme digestion, additional subcloning of DNA fragments and transfection into mammalian, E. coli or other cells.

Seauence confirmation.

Purified plasmid DNA is resuspended in dH20 and quantitated by measuring the absorbance at 260/280 nm in a Bausch and Lomb Spectronic 601 UV spectrometer. DNA samples are sequenced using ABI PRISM TM DyeDeoxy T terminator sequencing chemistry (Applied Biosystems Division of Perkin Elmer Corporation, Lincoln City, CA) kits (Part Number 401388 or 402078) according to the manufacturers suggested protocol usually modified by the addition of 5% DMSO to the sequencing mixture. Sequencing reactions are performed in a Model 480 DNA thermal cycler (Perkin Elmer Corporation, Norwalk, CT) following the recommended amplification conditions. Samples are purified to remove excess dye terminators with Centri-SepTM spin columns (Princeton Separations, Adelphia, NJ) and lyophilized. Fluorescent dye labeled sequencing reactions are resuspended in deionized formamide, and sequenced on denaturing 4.75% polyacrylamide- 8M urea gels using an ABI Model 373A automated DNA sequencer. Overlapping DNA sequence fragments are analyzed and assembled into master DNA contigs using Sequencher v2.1 DNA analysis software (Gene Codes Corporation, Ann Arbor,

MI).

Expression of multi-functional receptor aaonists in mammalian cells WO 97/12985 PCTIUS96/1 5774 67 Mammalian Cell Transfection/Production of Conditioned Media The BHK-21 cell line can be obtained from the ATCC (Rockville, MD). The cells are cultured in Dulbecco's modified Eagle media (DMEM/high-glucose), supplemented to 2 mM (mM) L-glutamine and 10% fetal bovine serum (FBS). This formulation is designated BHK growth media. Selective media is BHK growth media supplemented with 453 units/mL hygromycin B (Calbiochem, San Diego, CA). The BHK-21 cell line was previously stably transfected with the HSV transactivating protein VP16, which transactivates the IE110 promoter found on the plasmid pMON3359 (See Hippenmeyer et al., Bio/Technology, pp.1037-1041, 1993). The VP16 protein drives expression of genes inserted behind the IE110 promoter. BHK-21 cells expressing the transactivating protein VP16 are designated BHK-VP16. The plasmid pMON1118 (See Highkin et al., Poultry Sci., 70: 970-981, 1991) expresses the hygromycin resistance gene from the promoter. A similar plasmid is available from ATCC, pSV2hph.

BHK-VP16 cells are seeded into a 60 millimeter (mm) tissue culture dish at 3 X 105 cells per dish 24 hours prior to transfection. Cells are transfected for 16 hours in 3 mL of "OPTIMEM"™ (Gibco-BRL, Gaithersburg, MD) containing ug of plasmid DNA containing the gene of interest, 3 ug hygromycin resistance plasmid, pMONl118, and 80 ug of Gibco- BRL "LIPOFECTAMINE" m per dish. The media is subsequently aspirated and replaced with 3 mL of growth media. At 48 hours post-transfection, media from each dish is collected and assayed for activity (transient conditioned media). The cells are removed from the dish by trypsin-EDTA, diluted 1:10 and transferred to 100 mm tissue culture dishes containing 10 mL of selective media. After approximately 7 days in selective media, resistant cells grow into colonies WO 97/12985 PCT/US96/1 5774 68 several millimeters in diameter. The colonies are removed from the dish with filter paper (cut to approximately the same size as the colonies and soaked in trypsin/EDTA) and transferred to individual wells of a 24 well plate containing 1 mL of selective media. After the clones are grown to confluence, the conditioned media is re-assayed, and positive clones are expanded into growth media.

Expression of multi-functional receptor aaonists in E. coli E. coli strain MON105 or JM101 harboring the plasmid of interest are grown at 370C in M9 plus casamino acids medium with shaking in a air incubator Model G25 from New Brunswick Scientific (Edison, New Jersey). Growth is monitored at OD600 until it reaches a value of 1.0 at which time Nalidixic acid (10 milligrams/mL) in 0.1 N NaOH is added to a final concentration of 50 Jg/mL. The cultures are then shaken at 370C for three to four additional hours. A high degree of aeration is maintained throughout culture period in order to achieve maximal production of the desired gene product. The cells are examined under a light microscope for the presence of inclusion bodies One mL aliquots of the culture are removed for analysis of protein content by boiling the pelleted cells, treating them with reducing buffer and electrophoresis via SDS-PAGE (see Maniatis et al.

Molecular Cloning: A Laboratory Manual, 1982). The culture is centrifuged (5000 x g) to pellet the cells.

Inclusion Body preparation. Extraction, Refolding. Dialysis, DEAE Chromatography, and Characterization of the multifunctional hematopoietic receptor aqonists which accumulate as inclusion bodies in E. coli.

Isolation of Inclusion Bodies: WO 97/12985 PCT/US96/15774 69 The cell pellet from a 330 mL E. coli culture is resuspended in 15 mL of sonication buffer (10 mM 2 -amino-2- (hydroxymethyl) 1,3-propanediol hydrochloride (Tris-HC1), pH 8.0 1 mM ethylenediaminetetraacetic acid (EDTA). These resuspended cells are sonicated using the microtip probe of a Sonicator Cell Disruptor (Model W-375, Heat Systems- Ultrasonics, Inc., Farmingdale, New York). Three rounds of sonication in sonication buffer followed by centrifugation are employed to disrupt the cells and wash the inclusion bodies The first round of sonication is a 3 minute burst followed by a 1 minute burst, and the final two rounds of sonication are for 1 minute each.

Extraction and refolding of proteins from inclusion body pellets: Following the final centrifugation step, the IB pellet is resuspended in 10 mL of 50 mM Tris-HCl, pH 9.5, 8 M urea and 5 mM dithiothreitol (DTT) and stirred at room temperature for approximately 45 minutes to allow for denaturation of the expressed protein.

The extraction solution is transferred to a beaker containing 70 mL of 5 mM Tris-HCl, pH 9.5 and 2.3 M urea and gently stirred while exposed to air at 4 0 C for 18 to 48 hours to allow the proteins to refold. Refolding is monitored by analysis on a Vydac (Hesperia, Ca.) C18 reversed phase high pressure liquid chromatography (RP-HPLC) column (0.46x25 cm). A linear gradient of 40% to acetonitrile, containing 0.1% trifluoroacetic acid (TFA), is employed to monitor the refold. This gradient is developed over 30 minutes at a flow rate of 1.5 mL per minute.

Denatured proteins generally elute later in the gradient than the refolded proteins.

WO 97/12985 PCT/UIS96/1n 77 Purification: Following the refold, contaminating E. coli proteins are removed by acid precipitation. The pH of the refold solution is titrated to between pH 5.0 and pH 5.2 using acetic acid (HOAc). This solution is stirred at 4 0

C

for 2 hours and then centrifuged for 20 minutes at 12,000 x g to pellet any insoluble protein.

The supernatant from the acid precipitation step is dialyzed using a Spectra/Por 3 membrane with a molecular weight cut off (MWCO) of 3,500 daltons. The dialysis is against 2 changes of 4 liters (a 50-fold excess) of 10 mM Tris-HC1, pH 8.0 for a total of 18 hours. Dialysis lowers the sample conductivity and removes urea prior to DEAE chromatography. The sample is then centrifuged (20 minutes at 12,000 x g) to pellet any insoluble protein following dialysis.

A Bio-Rad Bio-Scale DEAE2 column (7 x 52 mm) is used for ion exchange chromatography. The column is equilibrated in a buffer containing 10 mM Tris-HCl, pH 8.0, and a 0-to- 500 mM sodium chloride (NaC1) gradient, in equilibration buffer, over 45 column volumes is used to elute the protein.

A flow rate of 1.0 mL per minute is used throughout the run.

Column fractions (2.0 mL per fraction) are collected across the gradient and analyzed by RP HPLC on a Vydac (Hesperia, Ca.) C18 column (0.46 x 25 cm). A linear gradient of 40% to acetonitrile, containing 0.1% trifluoroacetic acid (TFA), is employed. This gradient is developed over minutes at a flow rate of 1.5 mL per minute. Pooled fractions are then dialyzed against 2 changes of 4 liters (50-to-500-fold excess) of 10 mM ammonium acetate (NH4Ac), pH 4.0 for a total of 18 hours. Dialysis is performed using a Spectra/Por 3 membrane with a MWCO of 3,500 daltons.

Finally, the sample is sterile filtered using a 0.22pLm syringe filter ([LStar LB syringe filter, Costar, Cambridge, WO 97/12985 PCT/UIS96/1774 71 and stored at 4 0

C.

In some cases the folded proteins can be affinity purified using affinity reagents such as mAbs or receptor subunits attached to a suitable matrix. Alternatively, (or in addition) purification can be accomplished using any of a variety of chromatographic methods such as: ion exchange, gel filtration or hydrophobic chromatography or reversed phase HPLC.

These and other protein purification methods are described in detail in Methods in Enzymology, Volume 182 'Guide to Protein Purification' edited by Murray Deutscher, Academic Press, San Diego, CA (1990).

Protein Characterization: The purified protein is analyzed by RP-HPLC, electrospray mass spectrometry, and SDS-PAGE. The protein quantitation is done by amino acid composition, RP-HPLC, and Bradford protein determination. In some cases tryptic peptide mapping is performed in conjunction with electrospray mass spectrometry to confirm the identity of the protein.

AML Proliferation Assay for Bioactive Human Interleukin-3 The factor-dependent cell line AML 193 was obtained from the American Type Culture Collection (ATCC, Rockville, MD). This cell line, established from a patient with acute myelogenous leukemia, is a growth factor dependent cell line which displayed enhanced growth in GM-CSF supplemented medium (Lange, et al., Blood 70: 192, 1987; Valtieri, et al., J. Immunol. 138:4042, 1987). The ability of AML 193 cells to proliferate in the presence of human IL-3 has also been documented. (Santoli, et al., J. Immunol.

139: 348, 1987). A cell line variant was used, AML 193 WO 97/12985 PCT/I USlQ;/1 7 72 1.3, which was adapted for long term growth in IL-3 by washing out the growth factors and starving the cytokine dependent AML 193 cells for growth factors for 24 hours.

The cells are then replated at 1x10 5 cells/well in a 24 well plate in media containing 100 U/mL IL-3. It took approximately 2 months for the cells to grow rapidly in IL- 3. These cells are maintained as AML 193 1.3 thereafter by supplementing tissue culture medium (see below) with human IL-3.

AML 193 1.3 cells are washed 6 times in cold Hanks balanced salt solution (HBSS, Gibco, Grand Island, NY) by centrifuging cell suspensions at 250 x g for 10 minutes followed by decantation of the supernatant.- -Pelleted cells are resuspended in HBSS and the procedure is repeated until six wash cycles are completed. Cells washed six times by this procedure are resuspended in tissue culture medium at a density ranging from 2 x 105 to 5 x 105 viable cells/mL.

This medium is prepared by supplementing Iscove's modified Dulbecco's Medium (IMDM, Hazelton, Lenexa, KS) with albumin, transferrin, lipids and 2-mercaptoethanol. Bovine albumin (Boehringer-Mannheim, Indianapolis, IN) is added at 500 gg/mL; human transferrin (Boehringer-Mannheim, Indianapolis, IN) is added at 100 gg/mL; soybean lipid (Boehringer- Mannheim, Indianapolis, IN) is added at 50 g/mL; and 2mercaptoethanol (Sigma, St. Louis, MO) is added at 5 x 10-5

M.

Serial dilutions of human interleukin-3 or multifunctional hematopoietic receptor agonist proteins are made in triplicate series in tissue culture medium supplemented as stated above in 96 well Costar 3596 tissue culture plates. Each well contained 50 pg of medium containing interleukin-3 or multi-functional hematopoietic receptor agonist proteins once serial dilutions are completed.

Control wells contained tissue culture medium alone (negative control). AML 193 1.3 cell suspensions prepared WO 97/12985 PCT/US96/15774 73 as above are added to each well by pipetting 50 pl (2.5 x 104 cells) into each well. Tissue culture plates are incubated at 37 0 C with 5% CO2 in humidified air for 3 days.

On day 3, 0.5 Ci 3 H-thymidine (2 Ci/mM, New England Nuclear, Boston, MA) is added in 50 p4 of tissue culture medium. Cultures are incubated at 37 0 C with 5% C02 in humidified air for 18-24 hours. Cellular DNA i5 harvested onto glass filter mats (Pharmacia LKB, Gaithersburg,

MD)

using a TOMTEC cell harvester (TOMTEC, Orange, CT) which utilized a water wash cycle followed by a 70% ethanol wash cycle. Filter mats are allowed to air dry and then placed into sample bags to which scintillation fluid (Scintiverse II, Fisher Scientific, St. Louis, MO or BetaPlate Scintillation Fluid, Pharmacia LKB, Gaithersburg, MD) is added. Beta emissions of samples from individual tissue culture wells are counted in a LKB BetaPlate model 1205 scintillation counter (Pharmacia LKB, Gaithersburg, MD) and data is expressed as counts per minute of 3 H-thymidine incorporated into cells from each tissue culture well.

Activity of each human interleukin-3 preparation or multifunctional hematopoietic receptor agonist protein preparation is quantitated by measuring cell proliferation 3 H-thymidine incorporation) induced by graded concentrations of interleukin-3 or multi-functional hematopoietic receptor agonist. Typically, concentration ranges from 0.05 pM 105 pM are quantitated in these assays. Activity is determined by measuring the dose of interleukin-3 or multi-functional hematopoietic receptor agonist protein which provides 50% of maximal proliferation (EC50 0.5 x (maximum average counts per minute of 3

H-

thymidine incorporated per well among triplicate cultures of all concentrations of interleukin-3 tested background proliferation measured by 3 H-thymidine incorporation observed in triplicate cultures lacking interleukin-3).

This EC50 value is also equivalent to 1 unit of bioactivity.

WO 97/12985 PCT/US9f6/1 57r4A 74 Every assay is performed with native interleukin-3-as a reference standard so that relative activity levels could be assigned.

Typically, the multi-functional hematopoietic receptor agonist proteins were tested in a concentration range of 2000 pM to 0.06 pM titrated in serial 2 fold dilutions.

Activity for each sample was determined by the concentration which gave 50% of the maximal response by fitting a four-parameter logistic model to the data. It was observed that the upper plateau (maximal response) for the sample and the standard with which it was compared did not differ. Therefore relative potency calculation for each sample was determined from EC50 estimations for the sample and the standard as indicated above. AML 193.1.3 cells proliferate in response to hIL-3, hGM-CSF and hG-CSF.

Therefore the following additional assays were performed for some samples to demonstrate that the G-CSF receptor agonist portion of the multi-functional hematopoietic receptor agonist proteins was active. The proliferation assay was performed with the multi-functional hematopoietic receptor agonist plus and minus neutralizing monoclonal antibodies to the hIL-3 receptor agonist portion. In addition, a fusion molecule with the factor Xa cleavage site was cleaved then purified and the halves of the molecule were assayed for proliferative activity. These experiments showed that both components of the multi-functional hematopoietic receptor agonist proteins were active.

TF1 c-mpl licand dependent Proliferation assay The c-mpl ligand proliferative activity can be assayed using a subclone of the pluripotential human cell line TF1 (Kitamura et al., J. Cell Physiol 140:323-334. [1989]). TF1 cells are maintained in h-IL3 (100 U/mL). To establish a sub-clone responsive to c-mpl ligand, cells are maintained WO 97/12985 PCT/US96/1 5774 in passage media containing 10% supernatant from BHK cells transfected with the gene expressing the 1-153 form of c-mpl ligand (pMON26448). Most of the cells die, but a subset of cells survive. After dilution cloning, a c-mpl ligand responsive clone is selected, and these cells are split into passage media to a density of 0.3 x 106 cells/mL the day prior to assay set-up. Passage media for these cells is the following: RPMI 1640 (Gibco), 10% FBS (Harlan, Lot #91206), c-mpl ligand supernatant from transfected BHK cells, 1 mM sodium pyruvate (Gibco), 2 mM glutamine (Gibco), and 100 ug/mL penicillin-streptomycin (Gibco). The next day, cells are harvested and washed twice in RPMI or IMDM media with a final wash in the ATL, or assay media. ATL. medium consists of the following:IMDM (Gibco), 500 ug/mL of bovine serum albumin, 100 ug/mL of human transferrin, 50 ug/mL soybean lipids, 4 x 10-8M beta-mercaptoethanol and 2 mL of A9909 (Sigma, antibiotic solution) per 1000 mL of ATL. Cells are diluted in assay media to a final density of 0.25 x 106 cells/mL in a 96-well low evaporation plate (Costar) to a final volume of 50 ul. Transient supernatants (conditioned media) from transfected clones are added at a volume of ul as duplicate samples at a final concentration of 50% and diluted three-fold to a final dilution of Triplicate samples of a dose curve of IL-3 variant pMON13288 starting at 1 ng/mL and diluted using three-fold dilutions to 0.0014ng/mL is included as a positive control. Plates are incubated at 5% CO 2 and 370 C. At day six of culture, the plate is pulsed with 0.5 Ci of 3H/well (NEN) in a volume of ul/well and allowed to incubate at 5% CO 2 and 370 C for four hours. The plate is harvested and counted on a Betaplate counter.

Other in vitro cell based proliferation assays Other in vitro cell based assays, known to those WO 97/12985 PCTIUS9Q6/1 7- 76 skilled in the art, may also be useful to determine the activity of the multi-functional hematopoietic receptor agonists depending on the factors that comprise the molecule in a similar manner as described in the AML 193.1.3 cell proliferation assay. The following are examples of other useful assays.

TF1 proliferation assay: TF1 is a pluripotential human cell line (Kitamura et al., J. Cell Physiol 140:323-334. [1989]) that responds to hIL-3.

32D proliferation assay: 32D is a murine IL-3 dependent cell line which does not respond to human IL-3 but does respond to human G-CSF which is not species restricted.

Baf/3 proliferation assay: Baf/3 is a murine IL-3 dependent cell line which does not respond to human IL-3 or human cmpl ligand but does respond to human G-CSF which is not species restricted.

T1165 proliferation assay: T1165 cells are a IL-6 dependent murine cell line (Nordan et al., 1986) which respond to IL-6 and IL-11.

Human Plasma Clot meg-CSF Assay: Used to assay megakaryocyte colony formation activity (Mazur et al., 1981).

Transfected cell lines: Cell lines such as the murine Baf/3 cell line can be transfected with a colony stimulating factor receptor, such as the human G-CSF receptor or human c-mpl receptor, which the cell line does not have. These transfected cell lines can be used to determine the activity of the ligand for which the receptor has been transfected into the cell line.

One such transfected Baf/3 cell line was made by WO 97/12985 PCT/US96/1 5774 77 cloning the cDNA encoding c-mpl from a library made from a c-mpl responsive cell line and cloned into the multiple cloning site of the plasmid pcDNA3 (Invitrogen, San Diego Baf/3 cells were transfected with the plasmid via electroporation. The cells were grown under G418 selection in the presence of mouse IL-3 in Wehi conditioned media.

Clones were established through limited dilution.

In a similar manner the human G-CSF receptor can be transfected into the Baf/3 cell line and used to determine the bioactivity of the multi-functional hematopoietic receptor agoinsts.

Analysis of c-mpl liaand Droliferative activity Methods 1. Bone marrow proliferation assay a. CD34+ Cell Purification: Bone nmrrow aspirates (15-20 mL) were obtained from normal allogeneic marrow donors after informed consent.

Cells were diluted 1:3 in phosphate buffered saline (PBS, Gibco-BRL), 30 mL were layered over 15 mL Histopaque-1077 (Sigma) and centrifuged for 30 minutes at 300 RCF. The mononuclear interface layer was collected and washed in PBS.

CD34+ cells were enriched from the mononuclear cell preparation using an affinity column per manufacturers instructions (CellPro, Inc, Bothell WA). After enrichment, the purity of CD34+ cells was 70% on average as determined by using flow cytometric analysis using anti-CD34 monoclonal antibody conjugated to fluorescein and anti-CD38 conjugated to phycoerythrin (Becton Dickinson, San Jose CA).

Cells were resuspended at 40,000 cells/mL in X-Vivo media (Bio-Whittaker, Walkersville, MD) and 1 mL was plated in 12-well tissue culture plates (Costar). The growth WO 97/12985 PT/"STnr t A 78 u/ 13 /4 factor rhIL-3 was added at 100 ng/mL (pMON5873) was added to some wells. hIL3 variants were used at 10 ng/mL to 100 ng/mL. Conditioned media from BHK cells transfected with plasmid encoding c-mpl ligand or multi-functional hematopoietic receptor agonists were tested by addition of 100 kl of supernatant added to 1 mL cultures (approximately a 10% dilution). Cells were incubated at 37 0 C for 8-14 days at 5% C02 in a 37 0 C humidified incubator.

b. Cell Harvest and Analysis: At the end of the culture period a total cell count was obtained for each condition. For fluorescence analysis and ploidy determination cells were washed in megakaryocyte buffer (MK buffer, 13.6 mM sodium citrate, 1 mM theophylline, 2.2 pm PGE1, 11 mM glucose, 3% w/v BSA, in PBS, pH (Tomer et al., Blood 70: 1735-1742, 1987) resuspended in 500 gl of MK buffer containing anti-CD41a FITC antibody (1:200, AMAC, Westbrook, ME) and washed in MK buffer. For DNA analysis cells were permeablized in MK buffer containing 0.5% Tween 20 (Fisher, Fair Lawn NJ)for min. on ice followed by fixation in 0.5% Tween-20 and 1% paraformaldehyde (Fisher Chemical) for 30 minutes followed by incubation in propidium iodide (Calbiochem La Jolla Ca) gg/mL) with RNA-ase (400 U/mL) in 55% v/v MK buffer 2 00mosm) for 1-2 hours on ice. Cells were analyzed on a FACScan or Vantage flow cytometer (Becton Dickinson, San Jose, CA). Green fluorescence (CD41a-FITC) was collected along with linear and log signals for red fluorescence

(PI)

to determine DNA ploidy. All cells were collected to determine the percent of cells that were CD41+. Data analysis was performed using software by LYSIS (Becton Dickinson, San Jose, CA). Percent of cells expressing the CD41 antigen was obtained from flow cytometry analysis(Percent). Absolute (Abs) number of CD41+ cells/mL was calculated by: (Abs)=(Cell Count)*(Percent)/100.

WO 97/12985 PCT/US96/15774 79 2. Megakaryocyte fibrin clot assay.

CD34+ enriched population were isolated as described above.

Cells were suspended at 25,000 cells/mL with or without cytokine(s) in a media consisting of a base Iscoves IMDM media supplemented with 0.3% BSA, 0.4mg/mL apo-Eransferrin, 6.67 LM FeCl2, 25Jg/mL CaC12, 25[g/mL L-asparagine, 500gg/mL E-amino-n-caproic acid and penicillin/streptomycin. Prior to plating into 35mm plates, thrombin was added (0.25 Units/mL) to initiate clot formation. Cells were incubated at 370C for 13 days at 5% C02 in a 37 0 C humidified incubator.

At the end of the culture period plates were fixed with methanol:acetone air dried and stored at -200C until staining. A peroxidase immunocytochemistry staining procedure vas used (Zymed, Histostain-SP. San Francisco, CA) using a cocktail of primary monoclonal antibodies consisting of anti-CD41a, CD42 and CD61. Colonies were counted after staining and classified as negative, CFU-MK (small colonies, 1-2 foci and less that approx. 25 cells), BFU-MK (large, multi-foci colonies with 25 cells) or mixed colonies (mixture of both positive and negative cells.

Methvlcellulose Assay This assay reflects the ability of colony stimulating factors to stimulate normal bone marrow cells to produce different types of hematopoietic colonies in vitro (Bradley et al., Aust. Exp Biol. Sci. 44:287-300, 1966), Pluznik et al., J. Cell Comp. Physio 66:319-324, 1965).

Methods Approximately 30 mL of fresh, normal, healthy bone marrow WO 97/12985 PrT/US m Ii /4 aspirate are obtained from individuals following informed consent. Under sterile conditions samples are diluted with a 1X PBS (#14040.059 Life Technologies, Gaithersburg, MD.) solution in a 50 mL conical tube (#25339-50 Corning, Corning MD). Ficoll (Histopaque 1077 Sigma H-8889) is layered under the diluted sample and centrifuged, 300 x g for 30 min. The mononuclear cell band is removed and washed two times in 1X PBS and once with 1% BSA PBS (CellPro Co., Bothel, WA). Mononuclear cells are counted and CD34+ cells are selected using the Ceprate LC (CD34) Kit (CellPro Co., Bothel, WA) column. This fractionation is performed since all stem and progenitor cells within the bone marrow display CD34 surface antigen.

Cultures are set up in triplicate with a final volume of mL in a 35 X 10 mm petri dish (Nunc#174926). Culture medium is purchased from Terry Fox Labs. (HCC-4230 medium (Terry Fox Labs, Vancouver, Canada) and erythropoietin (Amgen, Thousand Oaks, CA.) is added to the culture media.

3,000-10,000 CD34+ cells are added per dish. Recombinant

IL-

3, purified from mammalian cells or E. coli, and multifunctional hematopoietic receptor agonist proteins, in conditioned media from transfected mammalian cells or purified from conditioned media from transfected mammalian cells or E. coli, are added to give final concentrations ranging from .001 nM to 10 nM. Recombinant hIL-3,

GM-CSF,

c-mpl ligand and multi-functional hematopoietic receptor agonist are supplied in house. G-CSF (Neupogen) is from Amgen (Thousand Oaks Calf.). Cultures are resuspended using a 3cc syringe and 1.0 mL is dispensed per dish. Control (baseline response) cultures received no colony stimulating factors. Positive control cultures received conditioned media (PHA stimulated human cells: Terry Fox Lab. H2400).

Cultures are incubated at 37 0 C, 5% C02 in humidified air.

Hematopoietic colonies which are defined as greater than WO 97/12985 nr F 'T /Tn ir r. f r .W 97/12 5 81 r /u'YT/S9615774 cells are counted on the day of peak response (days-10-11)using a Nikon inverted phase microscope with a 40x objective combination. Groups of cells containing fewer than 50 cells are referred to as clusters. Alternatively colonies can be identified by spreading the colonies on a slide and stained or they can be picked, resuspended and spun onto cytospin slides for staining.

Human Cord Blood Hemopoietic Growth Factor Assays Bone marrow cells are traditionally used for in vitro assays of hematopoietic colony stimulating factor (CSF) activity.

However, human bone marrow is not always available, and there is considerable variability between donors. Umbilical cord blood is comparable to bone marrow as a source of hematopoietic stem cells and progenitors (Broxmeyer et al., PNAS USA 89:4109-113, 1992; Mayani et al., Blood 81:3252- 3258, 1993). In contrast to bone marrow, cord blood is more readily available on a regular basis. There is also a potential to reduce assay variability by pooling cells obtained fresh from several donors, or to create a bank of cryopreserved cells for this purpose. By modifying the culture conditions, and/or analyzing for lineage specific markers, it is be possible to assay specifically for granulocyte macrophage colonies (CFU-GM), for megakaryocyte CSF activity, or for high proliferative potential colony forming cell (HPP-CFC) activity.

Methods Mononuclear cells (MNC) are isolated from cord blood within 24 hr. of collection, using a standard density gradient (1.077 g/mL Histopaque). Cord blood MNC have been further enriched for stem cells and progenitors by several procedures, including immunomagnetic selection for CD14-, CD34+ cells; panning for SBA-, CD34+ fraction using coated WO 97/12985 n/ <T Tr-i/* u 82 r i/US96t/15774 flasks from Applied Immune Science (Santa Clara, CA); and CD34+ selection using a CellPro (Bothell, WA) avidin column.

Either freshly isolated or cryopreserved CD34+ cell enriched fractions are used for the assay. Duplicate cultures for each serial dilution of sample (concentration range from 1 PM to 1204 pM) are prepared with 1x104 cells in 1ml of 0.9% methycellulose containing medium without additibnal growth factors (Methocult H4230 from Stem Cell Technologies, Vancouver, In some experiments, Methocult H4330 containing erythropoietin (EPO) was used instead of Methocult H4230, or Stem Cell Factor (SCF), 50 ng/mL (Biosource International, Camarillo, CA) was added. After culturing for 7-9 days, colonies containing. 30 cells are counted. In order to rule out subjective bias in scoring, assays are scored blind.

Additional details about recombinant DNA methods which may be used to create the variants, express them in bacteria, mammalian cells or insect cells, purification and refold of the desired proteins and assays for determining the bioactvity of the proteins may be found in co-filed Applications WO 95/00646, WO 94/12639, WO 94/12638,

WO

95/20976, WO 95/21197, WO 95/20977, WO 95/21254 and US 08/383,035 which are hereby incorporated by reference in their entirety.

Further details known to those skilled in the art may be found in T. Maniatis, et al., Molecular Cloning, A Laboratory Manual, Cold Spring Harbor Laboratory, 1982) and references cited therein, incorporated herein by reference; and in J. Sambrook, et al., Molecular Cloning, A Laboratory Manual, 2nd edition, Cold Spring Harbor Laboratory, 1989) and references cited therein, incorporated herein by reference.

WO 97/12985 83 TABLE 1

OLIGONUCLEOTIDES

WO 9712985PCT/US96/15774 C-mplNcoT

ACGTCCATGGCNTCNCCNGCNCCNCCTGCTTGTGCACTCCGAGTC

(SEQ ID NO:13) N=A,C,G or T Ecornpl c-rnplHindIII 4L-3' 5L-5' 5L-3' 8L-3' 31-5' 31-3' 35-5, 35-3, 39-5, 39-3' 43-5' 43-3, 45-5' 45-3,' 49-5, 49-3,

ATGCACGAATTCCCTGACGCAGAGGGTGGA

(SEQ ID NO:14)

TGACAAGCTTACCTGACGCAGAGGGTGGACCCT

(SEQ ID AATTCGGCAA (SEQ ID NO:16) CATGTTGCCG (SEQ ID NO:17) AATTCGGCGGCAA (SEQ ID NO:18) CATGTTGCCGCCG (SEQ ID NO:19) AATTCCCCGCCAACGGCGGCAA (SEQ ID CATGTTGCCGCCGTTGCCGCCG (SEQ ID NO:21) CGATCCATGGAGGTTCACCCTTTGCCT (SEQ ID NO:22) GATCAAGCTTATCGGCACTGGCTCAGTCT (SEQ ID NO:23) CGATACATGTTGCCTACACCTGTCCTG (SEQ ID NO:24) GATCAAGCTTAAGGGTGAACCTCTGGGCA (SEQ ID CGATCCATGGTCCTGCTGCCTGCTGTG (SEQ ID NO:26) GATCAAGCTTAAGGTGTAGGCAAAGGGTG (SEQ ID NO:27)

CGATCCATGGCTGTGGACTTTAGCTTGGGA

(SEQ ID NO:28) GATCAAGCTTAAGGCAGCAGGACAGGTGT (SEQ ID NO: 29) CGATCCATGGACTTTAGCTTGGGAGAA~ (SEQ ID GATCAAGCTTACACAGCAGGCAOCAGGAC (SEQ ID NO:31) CGATCCATGGGAGAATGGAAAACCCAG (SEQ ID NO:32) GATCAAGCTTACAAGCTAAAGTCCACAGC (SEQ ID NO:33) WO 97/12985 82-5' 82-3 109-5' 109-3' 116-5 116-3 120-5 84 PCT/US96,'1577 4 CGATCCATGGGACCCACTTGCCTCTCA (SEQ ID NO:34) GATCAAGCTTACAGTTGTCCCCGTGCTGC (SEQ ID CAGTCCATGGGAACCCAGCTTCCTCCA (SEQ ID NO:36) GATCAAGCTTAAAGGAGGCTCTGCAGGGC (SEQ ID NO:37) CGATCCATGGGCAGGACCACAGCTCAc (SEQ ID NO: 38)

GATCAAGCTTACTGTGGAGGAAGCTGGGTT

(SEQ ID NO:39) CGATCCATGGC TCACAAGGATCCCAATGC

C

(SEQ ID GATCAAGCTTATGTGGTCCTGCCCTGTGG (SEQ ID NO:41)

CGATCCATGGATCCCAATGCCATCTTCCTG

(SEQ ID NO:42) GATCAAGCTTACTTGTGAGCTGTGGTCCT (SEQ ID NO:43)

CGATCCATGGCCATCTTCCTGAGCTTCCAA

(SEQ ID NO:44) 120-3 123-5' 123 -3 126-5' 126-3'

GATCAAGCTTAATTGGGATCCTTGTGAGCTGT

(SEQ ID SYNNOXAl.REQ SYNNOXA2.REQ Lisyn. f or AATTCCGTCG TAAACTGACC TTCTATCTGA

AAACCTTGGA

GAACGCGCAG GCTCAACAGT ACGTAGAGGG

CGGTGGAGGC

TCC (SEQ ID NO:46) CCGGGGAGCC TCCACCGCCC TCTACGTACT

GTTGAGCCTG

CGCGTTCTCC AAGGTTTTCA GATAGAAGGT

CAGTTTACGA

CGG (SEQ ID NO:47) GTTACCCTTG AGCAAGCGCA GGAACAACAG

GGTGGTGGCT

CTAACTGCTC TATAATGAT (SEQ ID NO:48) CGATCATTAT AGAGCAGTTA.GAGCCACCAC

CCTGTTGTTC

CTGCGCTTGC TCAAGG (SEQ ID NO:49) GTTACCCTTG AGCAAGCGCA GGAACAACAG

GGTGGTGGCT

CTGGCGGTGG CAGCGGCGGC GGTTCTAACT

GCTCTATAAT

GAT (SEQ ID CG ATCATTAT AGAGCAGTTA GAACCGCCGC

CGCTGCCACC

GCCAGAGCCA CCACCCTGTT GTTCCTGCGC

TTGCTCAAGG

(SEQ ID NO:51) Lisyn .rev L3syn.for L3 syn .rev WO 97/12985 seq 3 4rev. seq .seq 69rev-seq 91start .seq 9 Orev. seq l01start .seq seq L-llstart.seq L-listop. seq P-blstart .seq P-blstop. seq 39start.seq 38stop.Seq PCTIUS96/15774 GATOGACCAT GGCTCTGGAC CCGAACAACC

TC-

(SEQ ID NO:52) CTCGATTACG TACAAAGGTG

CAGGTGGT

(SEQ ID NO:53) GATCGACCAT GGCTAATGCA TCAGGTATTG

AG

(SEQ ID NO:54) CTCGATTACG TATTCTAAGT

TCTTGACA

(SEQ ID GATCGACCAT GGCTGCACCC TCTCGACATC

CA

(SEQ ID NO:56) CTCGATTACG TAGGCCCTGG

CAGAGGGC

(SEQ ID NO:57) GATCGACCAT GGCTGCAGGT GACTGCMG

AA

(SEQ ID NO:58) CTCGATTACG TACTTGATGA

TGATTGGA

(SEQ ID NO:59) GCTCTGAGAG CCGCCAGAGC

CGCCAGAGGG

CTGCGCAAGG TGGCGTAGAA CGCG (SEQ ID CAGCCCTCTG GCGGCTCTGG

CGGCTCTCAG

AGCTTCCTGC TCAAGTCTTT AGAG (SEQ ID NO:61) GGGCTGCGCA AGGTGGCG (SEQ ID NO:62) ACACCATTGG GCCCTGCCAG C (SEQ ID NO:63) GATCGACCAT GGCTTACAAG CTGTGCCACC

CC

(SEQ ID NO:64) CGATCGAAGC TTATTAGGTG GCACACAGCT

TCTCCT

(SEQ ID GATCGACCAT GGCTCCCGAG TTGGGTCCCA

CC

(SEQ ID NO:66) CGATCGAAGC TTATTAGGAT ATCCCTTCCA GGGCCT (SEQ ID NO:67) GATCGACCAT GGCTATGGCC CCTGCCCTGC

AG

(SEQ ID NO:68) CGATCGAAGC TTATTATCCC AGTTCTTCCA TCTGCT (SEQ ID NO:69) 97 start. seq 96stop.Seq 126start .seq l 2 5stop.Seq WO 97/12985 l33start Seq l32stop. seq l42start seq l 4 lstop.Seq GLYXAl GLYXA2 iGGGS for 1GGGSrev Syrinoxal req 86 PCTIUS96/1 5774 GATCGACCAT GGCTACCCAG GGTGCCATGC

CG

(SEQ ID CGATCGAAGC TTATTAGGGC TGCAGGGCAG

GGGCCA

(SEQ ID NO:71) GATCGACCAT GGCTTCTGCT TTCCAGCGCC

GG

(SEQ ID NO:72) CGATCGAAGC TTATTAGGCG AAGGCCGGC9

TGGCAC

(SEQ ID NO:73) GTAGAGGGCG GTGGAGGCTC C (SEQ ID NO:74) CCGGGGAGCC TCCACCGCCC TOTAC (SEQ ID TTCTACGCCA CCTTGCGCAG CCCGGCGGCG

GCTCTGACAT

GTCTACACCA TTG (SEQ ID NO:76) CAATGGTGTA GACATGTCAG AGCCGCCGCC

GGGCTGCGCA

AGGTGGCGTA GAA (SEQ ID NO:77) AATTCCGTCG TAAACTGACC TTCTATCTGA

AAACCTTGGA

GAACGCGCAG GCTCAACAGT ACGTAGAGGG

CGGTGGAGGC

TCC (SEQ ID NO:240) CCGGGGAGCC TCCACCCCCC TCTACGTACT

GTTGAGCCTG

CGCGTTCTCC AAGGTTTTCA GATAGAAGGT

CAGTTTACGA

CGG (SEQ ID NO:241) Synnoxa2.req WO 97/12985 Pd-,r/rTcn.c 87 TABLE 2 GENE SEQUENCES pMON30304

CGACTTCCAAACCTGGAGAGCTTCGTGGGCTGTCAAGAAATCTAG

ATTGAGGCAATTCTTCGTAATCTCCACCATGTCTGCCCTCTGCCCGCCCCC

CGACATCCAATCATCATCAAGGCAGGTGACTGGCAGATTCCGGAAkATAGT

TATCTGGTTACCCTTGAGCAAGCGCAGGAJACACAGTACGTAGAGGGTGGCC

CCGGGTGA1ACCGTCTGGTCCJXATCTCTACTATCAJACCCGTCTCCTCTTAGAC CATAAATCTCCA3LACATGT (SEQ ID NO:78) pMON2 6458

TCCCCAGCTCCACCTGCTTGTGACCTCCGAGTCCTCAGTAAATCTCTGCCCA

GTCCTTCACAGCAGACTGAGCCAGTGCCCAGAGGTTCACCCTTGCACTTCG

CTGCCTGCTGTGGA TTTA TTGGoGAACCAAGAGAACAGC

CTGGGACCCACTTGCCTCTCATCCCTCCTGGGGCAGCTTTCTGGAGTCTTCC

CTTGGGGCCCTGCAGAGCCTCCTTGGAACCCAGCTTCCTCCACAGGGAGCAAC

CACAAGGATCCCAATGCCATCTTCCTGAGCTTCCAACACCTGCTCGGAAGGG

TTCCTGATGCTTGTAGGAGGGTCCACCCTCTGCGTCAGGGAATT (SEQ ID NO: 79) pMON2 8548

TCCCCAGCTCCACCTGCTTGTGACCTCCGAGTCCTCAGTAJLACTGCTCTATCA

GTCCTTCACAGCAGACTGAGCCAGTGCCCAGAGGTTCACCCTTTGCCACTGCG

CTGCCTGCTGTGGACTTTAGCTTGGGAGATGGAAAACCCAGATGGAGGCAGC

CAGGACATTCTGGGAGCAGTGACC

CTTCTGCTGGAGGGAGTGATGGCAGCACGGGGACAA

CTGGGACCCACTTGCCTCTCATCC

CTCCTGGGGCAGCTTTCTGGACAGGTCCGTCTCCTC

CTTGGGGCCCTGCAGAGCCTCCTTGGAACCCAGCTTCCTCCACAGGGAACCGT

CACAAGGATCCCAATGCCATCTTCCTGAGCTTCCJACACCTGCTCGGAGTCT

TTCCTGATGCTTGTAGGAGGGTCCACCCTCTGCGTCAGGGAJATTCGGGCAAGC

TCTCCCGCTCCGCCTGCTTGACCTCGGTCCATAATCTCTGCCCA

CTGCCTGCTGTGGACTTTAGCTTGGGAGATGGAAJLCCCAGATGAAACAGI-

CAGGACATTCTGGGAGCAGTGACCCTTCTGCTGGAGGGAGTGATGGCGAGGAA

CTGGGACCCACTTGCCTCTCATCCCTCCTGGGGCAGCTTTCTGGACAGCTTCC

CTTGGGGCCCTGCAGAGC

CTCCTTGGAACCCAGGGCAGGACCACAGCTCACAAGGATCCC

AATGCCATCTTCCTGAGCTTCCJACACCTGCTCCGAGGAAAGGTGCGTCTAGT

GTAGGAGGGTCCACCCTCTGCGTCAGG (SEQ ID pMON2 8500

TCCCCAGCTCCACCTGCTTGTGACCTCCGAGTCCTCAGTAAACTGTTGTGACTCCCAT

GTCCTTCACAGCAGACTGAGCCAGTGCCCAGAGGTTCACCCTTTGCAACGCT

CTGCCTGCTGTGGACTTTAGCTTGGGAGATGGAACCCAGATGAGGCAGC

WO 97/1 2985 PrTfFTqac/ 88 JO

CAGGACATTCTGGGAGCAGTGACCCTTCTGCTGGAGGGAGTGATGGCAGCA(GGAA

CTGGGACCCACTTGCCTCTCATCCCTCCTGGGGCAGCTTTCTGGACAGGTCGCCT

CTTGGGGCCCTGCAGAGCCTCCTTGGAACCCAGCTTCCTCCACAGGGCAGCCAT

CACAAGGATCCCAATGCCATCTTCCTGAGCTTCCAACACCTGCTCCGAGGAAGGG

TTCCTGATGCTTGTAGGAGGGTCCACCCTCTGCGTCAGGGAATTCGCCATGG

CCCGCTCCGCCTGCTTGTGACCTCCGAOTCCTCAGTAAIACTGCTTCGTGACCCTT

CTTCACAGCAGACTGAC AGTGAAcCcAoCoTTCTCACGCCG

GACATTCTGGGAGCAGTGACCCTTCTGCTGGAGGGAGTGATGGCAGCACGGGGCAT

GGACCCACTTGCCTCTCATCCCTCCTGGGGCAGCTTTCTGGACAGGTCCGTCTCT

GGGGCCCTGCAGAGCCTCCTTGGACCCAGCTTCCTCCACAOGGGCAGGACCAGTC

AAGGATCCCAATGCCATCTTCCTGAGCTTCCACACCTGCTCCGAGGAGTCTT

CTGATGCTTGTAGGAGGGTCCACCCTCTGCGTCAGG (SEQ ID NO: 81) pM0N28501

TCCCCAGCTCCACCTGCTTGTGACCTCCGAOTCCTCAGTAAACTGCTTCTACCT

GTCCTTCACAGCAGACTGAGCCAGTGCCCAGAGGTTCACCCTTTGCCTACACGCT

CTGCCTGCTGTGGACTTTAGCTTGGGAGATGGAAAACCCAGATGGAGGAGCAGC

CAGGACATTCTGGGAGCAGTGACCCTTCTGCTGGAGGGAGTGATGGCAGCAGGCA

CTGGGACCCACTTGCCTCTCATCCCTCCTGGGGCAGCTTTCTGGACAGCTTCC

CTTGGGGCCCTGCAGAGCCTCCTTGGACCCAGCTTCCTCCACAGGGCAGGCAGT

CACAAGGATCCCAATGCCATCTTC

CTGAGCTTCCAACACCTGCTCCGAGGAAAGGTGCGT

TTCCTGATGCTTGTAGGAGGGTCCACCCTCTGCGTCAGGGA.TTCGGCGCAAAGC

TCTCCCGCTCCGCCTGCTTGTGACCTCCGAGTCCTCAGTAJAACTGCTTCGTGATCT

GTCCTTCACAGCAGACTGAGCCAGTGCCCAGAGGTTCACCCTTTGCCTACACCGCT

CTGCCTGCTGTGGACTTTAGCTTGGGAGATGGAAAACCCAGATGGAGGAGACAGC

CAGGACATTCTGGGAGCAGTGACCCTTCTGCTGGAGGGAGTGATGGCAGCACGGGAA

CTGGGACCCACTTGCCTCTCATCCCTCCTGGGGCAGCTTTCTGGACAGGTCCGCTCT

CTTGGGcCCCTGCAGAGCCTCCTTGGAACCCAGCTTCCTCCACAGGGCAGGACAAC

CACAAGGATCCCAATGCCATCTTCCTGAGCTTCCACACCTGCTCCGAGGAAAJGGTGO

TTCCTGATGCTTGTAGGAGGGTCCACCCTCTGCGTCAGG (SEQ ID NO: 82) pMON2 8502

TCCCCAGCGCCGCCTGCTTGTGACCTCCGAGTCCTCAGTAACTGCTTCGTGACTCA

GTCCTTCACAGCAGACTGAGCCAGTGCCCAGAGGTTCACCCTTTGCCTACACCTGTCCT

CTGCCTGCTGTGGACTTTAGCTTGGGAGATGGAACCCAGATGGAGGAGACCAAGC

CAGGACATTCTGGGAGCAGTGACCCTTCTGCTGGAGGGAGTGATGGCAGCACGGGGAA

CTGGGACCCACTTGCCTCTCATCCCTCCTGGGGCAGCTTTCTGGACAGGTCCGTCTCCT

CTTGGGGCCCTGCAGAGCCTCCTTGGACCCAGCTTCCTCCACAGGGCAGGACCACA

GC

CACAAGGATCCCATGCCATCTTCCTGAGCTTCCACACCTGCTCCGAGGAJAGGTGT

TTCCTGATGCTTGTAGGAGGGTCCACCCTCTGCGTCAGGGAJATTCGGCGGCAACGGCGG

AACATGGCGTCCCCAGCGCCGCCTGCTTGTGACCTCC

CAGTCCTCAGTAAJACTGCTTCGT

GACTCCCATGTCCTTCACAGCAGACTGAGCCAGTGCCCAGAGGTTCACCCTTTGCCTACA

CCTGTCCTGCTGCCTGCTGTGGACTTTAGCTTGGGAGATGGAAAAICCCAGATGGAGGA

ACCAAGGCACAGGACATTCTGGGAGCAGTGACCCTTCTGCTGGAGGGAGTGATGGCAGC

CGGGGACAACTGGGACCCACTTGC

CTCTCATCCCTCCTGGGGCAGCTTTCTGGACAGGTC

CGTCTCCTCCTTGGGGCCCTGCAGAGCCTC

CTTGGAACCCAGCTTCCTCCACAGGGCAGG

ACCACAGCTCACAGGATCCCAJATGCCATCTTCCTGAGCTTCCAACACCTGCTCCGAGGA

AAGGTGCGTTTCCTGATGCTTGTAGGAGGGTCCACCCTCTGCGTCAGG

(SEQ ID NO:83) WO 97/12985 WO 9712985PCT/US96/15774 Syntani 1 51 101 151 201 251 301 351 401 451 501 551 601 651

CATGGCTAAC

GACCACCTGC

TCTATCCTGA

AAGGGCTGTC

GTAATCTCCA

C CAATC ATCA

GTTCTATCTG

CTAACTGCTC

CCTGCACCTT

CCTGATGGAC

CTGTCAAGAA

CTCCAACCAT

CATCATCAAG

ATCTGGTTAC

TGCTCTATAA

ACCTTTGCTG

TGGACCGAAA

AAGAACTTAG

ACCATGTCTG

TCAAGGCAGG

GTTACCCTTG

TATAATGATC

TGCTGGACCC

CGAAACCTTC

CTTAGAAAAT

GTCTGCCCTC

GCAGGTGACT

CCTTGAGCAA

TGATCGATGA

GACCCGAACA

CCTTCGACTT

AAAATG CAT C

CCCTCTGCCA

TGACTGGCAA

AG CAAGCGC A

GATGAAATTA

GAACAACCTC

GACTTCCAAA

GCATCAGGTA

TGCCACGGCC

GGCAAGAATT

GCGCAGGAAC

AATTATACAT

AC CTCAATGA

CCAAACCTGG

AGGTATTGAG

CGGCCGCACC

GAATTCCGe.

G

GGAACAACAG

TACATCACTT

AATGACGAAG

CCTGGAGAGC

TTGAGGCAAT

GCACCCTCTC

CCGGGAAAAA

AACAGTAC

CACTTAAAGA

CGAAGACGTC

AGAGCTTCGT

GCAATTCTTC

CTCTCGACAT

AAAAACTGAC

GGTGGTGGCT

AAAGAGACCA

ACGTCTCTAT

TTCGTAAGGG

TCTTCGTAAT

GACATCCAAT

CTGACGTTCT

(SEQ ID NO:84) Synt an3 1 51 101 151 201 251 301 351 401 451 501 551 601 651 701

CATGGCTAAC

GACCACCTGC

TCTATCCTGA

AAGGGCTGTC

GTAATCTCCA

CCAATCATCA

GTTCTATCTG

CTGGCGGTGG

ATTATACATC

CCTCAATGAC

CAAACCTGGA

GGTATTGAGG

GGCCGCACCC

AATTCCGGGA

GAACAACAGT

TGCTCTATAA

ACCTTTGCTG

TGGACCGAAA

AAGAACTTAG

ACCATGTCTG

TCAAGGCAGG

GTTACCCTTG

CAGCGGC GGtC

ACTTAALAGAG

GAAGACGTCT

GAGCTTCGTA

CAATTCTTCG

TCTCGACATC

AAAACTGACG

AC (SEQ ID

TGATCGATGA

GACCCGAACA

CCTTCGACTT

AAAATGCATC

CCCTCTGCCA

TGACTGGCAA

AGCAAGCGCA

GGTTCTAACT

ACCACCTGCA

CTATCCTGAT

AGGGCTGTCA

TAATCTCCAA

CAATCATCAT

TTCTATCTGG

NO:

AATTATACAT

ACCTCAATGA

CCAAACCTGG

AGGTATTGAG

CGGCCGCACC

GALATTCCGGG

GGAACAACAG

GCTCTATAAT

CCTTTGCTGG

GGACCGAAAC

AGAACTTAGA

CCATGTCTGC

CAAGGCAGGT

TTACCCTTGA

CACTTAAAGA

CGAAGACGTC

AGAGCTTCGT

GCAATTCTTC

CTCTCGACAT

AAAALACTGAC

GGTGGTGGCT

GATCGATGALA

AC CCGALAC AA

CTTCGACTTC

AAATGCATCA

CCTCTGCCAC

GACTGGCAAG

GCAAGCGCAG

PMON3 1104 1 51 101 151 201 251 301 351 401 451

ATGGCTCTGG

GGACCGAAAC

AGAACTTAGA

CCATGTCTGC

CAAGGCAGGT

TTACCCTTGA

ATAATGATCG

GTACGTAGAG

CTACTATCAA

ATGGCTACCC

ACCCGAACAA

CTTCGACTTC

AAATGCATCA

C CTCTCCCAC

GACTGGCAAG

GCAAGCGCAG

ATGAAATTAT

GCCCTGGAG

CCCCTCTCCT

AGGGTGCCAT

CCTCAATGAC

CAAACCTGGA

GGTATTCAGG

GGCCGCACCC

AATTCCGGGA

CAACAACAGG

ACATCACTTA

GCTCCCCGCG

CCGTCTAA.AG

GCCGGCCTTC

GAAGACGTCT

GAGCTTCGTA

CAATTCTTCC

TCTCGACATC

AAAACTGACG

GTGGTGGCTC

AAGAGACCAC

TGAACCGTCT

AATCTCATAA

GCCTCTGCTT

CTATCCTGAT

AGGGCTGTCA

TAATCTCCAA

CAATCATCAT

TTCTATCTGG

TAACTGCTCT

CTGCACCTTT

GGTCCAATCT

ATCTCCAAAC

TCCAGCGCCG

WO 97/12985 PCT/US96/15 7 7 4 501 551 601 651 701 751 801 851 901 951

GGCAGGAGCG

CGTACCGCGT

TCTCAGAGCT

CGATGGCGCA

ACCCCGAGGA

CCCCTGAGCT

CCAACTCCAT

AAGGGATATC

GTCGCCGACT

GGCCCCTGCC

GTCCTGGTTG

TCTACGCCAC

TCCTGCTCA.A

GCCTCCAGG

GCTGGTGCTG

CCTGCCCCAG

AGCGGCCTTT

CC CCGAGTTG

TTGCCACCAC

CTGCAGCCCT

CTAGCCATCT

CT TC CAG C

GTCTTTAGAG

AGAAGCTGTG

CTCGGACACT

CCAGGCCCTG

TCCTCTACCA

GGTCCCACCT

CATCTGGCAG

AATAA (SEQ

GCAGAGCTTC

CCTCTGGCGG

CAAGTGAGAA

TGCCACCTAC

CTCTGGGCAT

CAGC TGGCAG

GGGCTCCTG

TGGACACACT

CAGATGGAAG

ID NO:86)

C-TGGAGGTGT

CTCTGCGC

AGATCCAGGG

AAGCTCTGCC

CCCCTGGGCT

GCTGCTTGAG

CAGGCCCTCG

GCAGCTGGAC

AACTGGGAAT

pMON3 1105 1 51 101 151 201 251 301 351 401 451 501 551 601 651 701 751 801 851 901 951

ATGGCTAATG

TCTGCCCTCT

CAGGTGACTG

CTTGAGCAAG

GATCGATGAIA

ACCCGAIACA

CTTCGACTTC

ATACGTAGAG

CTACTATCAA

ATGGCTACCC

GGCAGGAGCG

CGTACCGCGT

TCTCAGAGCT

CGATGGCGCA

ACCCCGAGGA

CCCCTGAGCT

CCAACTCCAT

AAGGGATATC

GTCGCCGACT

GGCCCCTGCC

CATCAGGTAT

GCCACGGCCG

GCAAGAATTC

CGCAGGAACA

ATTATACATC

CCTCAATGAC

CAAACCTGGA

GGCGGTGGAG

CCCGTCTCCT

AGGGTGCCAT

GTCCTGGTTG

TCTACGCCAC

TCCTGCTCAA

GCGCTCCAGG

GCTGGTGCTG

CCTGCCCCAG

AGCGGCCTTT

CCCCGAGTTG

TTGCCACCAC

CTGCAGCCCT

TGAGGCAATT

CACCCTCTCG

CGGGAAAAAC

ACAGGGTGGT

ACTTAAAGAG

GAAGACGTCT

GAGCTTCGTA

GCTCCCCGGG

CCGTCTAAAG

GCCGGCCTTC

CTAGCCATCT

CTTGCGCAGC

GTCTTTAGAG

AGAAGCTGTG

CTCGGACACT

CCAGGCCCTG

TCCTCTACCA

GGTCCCACCT

CATCTGGCAG

AATAA (SEQ CTTC

GTAATC

ACATCCAATC

TGACGTTCTA

GGCTCTAACT

ACCACCTGCA

CTATCCTGAT

AGGGCTGTCA

TGAACCGTCT

AATCTCATA

GCCTCTGCTT

GCAGAGCTTC

CCTCTGGCGG

CAAGTGAGAJA

TGCCACCTAC

CTCTGGGCAT

CAGCTGGCAG

GGGGCTCCTG

TGGACACACT

CAGATGGAJAC

ID NO:87)

TCCAACCATG

ATCATCAAGG

TGGTTACC

GCTCTATAAT

CCTTTGCTGG

GGACCGAAAC~

AGAACTTAGA

GGTCCAATCT

ATCTCCAAAC

TCCAGCCC

CTGGAGGTGT

CTCTGGCGGC

AGATCCAGGG

AAGCTGTGCC

CCCCTGGGCT

GCTGCTTGAG

CAGGCCCTGG

GCAGCTGGAC

AACTGGGAAT

PMON3 1106 1 51 101 151 201 251 301 351 401 451 501 551 601 651

ATGGCTGCAC

AGAATTCCGG

AGGAACAACA

ATACATCACT

CAATGACGAAg

ACCTGGAGAG

ATTGAGGCAA

CTACGTAGAG

CTACTATCAA

ATGGCTACcC

GGCAGGAGGG

CGTACCGCGT

TCTCAGAGCT

CGATGGCGCA

CCTCTCGACA

GAAAAACTGA

GGGTGGTGGC

TAAAGAGACC

GACGTCTCTA

CTTCGTAACG

TTCTTCGTA

GGCGGTGGAG

CCCGTCTCCT

AGGGTGC

CAT

GTCCTGGTTG

TCTACCCAC

TCCTGCTCAA

GCGCTCCAGG

TCCAATCATC

CGTTCTATCT

TCTAACTGCT

ACCTGCACCT

TCCTGATGGA

GCTGTCAAGA

TCTCCAACCA

GCTCCCCGGG

CCGTCTAAAG

GCCGGCCTTC

CTAGCCATCT

CTTGCGCAC

GTCTTTAGAG

AGAAGCTGTG

ATCAAGGCAG

GGTTACCCTT

CTATAATGAT

TTGCTGGACC

CCGAAACCTT

ACTTAGAAAA

TGTCTGCCCT

TGAACCGTCT

AATCTCATAjA

GCCTCTGCTT

GCAGAGCTTC

CCTCTGGCGG

CAAGTGAGAA

TGCCACCTAC

GTGACTGGCA

GAGCAAGCGC

CGATGAAATT

CGAACAACCT

CGACTTCCAA

TGCATCAGGT

CTGCCACGC

GGTCCAATCT

ATCTCCAAAC

TCCAGCGCCG

CTGGAGGTGT

CTCTGGCGGC

AGATCCAGGG

AAGCTGTGCC

WO 97/12985 WO 9712985PCTIUS96/1 5774 701 751 801 851 901 951

ACCCCGAGGA

CCCCTGAGCT

C CAAC T CCAT

AAGGGATATC

GTCGCCGACT

GGCCCCTGCC

GCTGGTGCTG

CCTGCCCCAG

AGCGGCCTTT

CCCCGAGTTG

TTGCCACCAC

CTGCAGCCCT

CTCGGACACT

CCAGGCCCTG

TCCTCTACCA

GGTCCCACCT

CATCTGGCAG

AATAA (SEQ

CTCTGGGCAT

CAGCTGGCAG

GGGGCTCCTG

TGGACACACT

CAGATGGAAG

ID NO:88)

CCCCTGGGCT

GCTGCTTGAG

C AG GC C CTGG

GCAGCTGGAC

AACTGGGAAT

pMON3 1107 1 51 101 151 201 251 301 351 401 451 501 551 601 651 701 751 801 851 901 951 ATGCT G CAG

GGTTACCCTT

CTATAATGAT

TTGCTGGACC

CCGAAACCTT

ACTTAGAAAA

TGTCTGCCCT

GTACGTAGAG

CTACTATCAA

AT GGC TACC C

GGCAGGAGGG

CGTACCGCGT

TCTCAGAGCT

CGATGGCGCA

ACCCCGAGGA

CCCCTGAGCT

CCAACTCCAT

AAGGGATATC

GTCGCCGACT

GGCCCCTGCC

GTGACTGGCA

GAGCAAGCC

CGATGAAATT

CGAACAACCT

CGACTTCCAA

TGCATCAGGT

CTGCCACGGC

GGCGGTGGAG

CCCGTCTCCT

AGGGTGCCAT

GTCCTGGTTG

TCTACGCCAC

TCCTGCTCA.A

GCGCTCCAGG

GCTGGTGCTG

CCTGCCCCAG

AGCGGCCTTT

CCCCGAGTTG

T TG CCAC CAC C TGCAG C CCT

AGAATTCCGG

AGGAACAACA

ATACATCACT

CAATGACGAA

ACCTGGAGAG

ATTGAGGCAA

CGCACCCTCT

GCTCCCCGGG

CCGTCTAAAG

GCCGGCCTTC

CTAGCCATCT

CTTGCGCAGC

GTCTTTAGAG

AGAAGCTGTG

CTCGGACACT

CCAGGCCCTG

TCCTCTACCA

GGTCCCACCT

CATCTGGCAG

AATAA (SEQ

GAAAAACTGA

GGGTGGTGGC

TAAAGAGACC

GACGTCTCTA

CTTCGTAAGG

TTCTTCGTAA

CGACATCCAA

TGAACCGTCT

AATCTC-ATAA

GCCTCTGCTT

GCAGAGCTTC

CCTCTGGCGG

CAAGTGAGAA

TGCCACCTAC

CTCTGGGCAT

CAGCTGGCAG

GGGGCTCCTG

TGGACACACT

CAGATGGAAG

ID NO:89)

CGTTCTATCT

TCTA-ACTGCT

AC CTGCCAC CT

TCCTGATGGA

GCTGTCAAGA

TCTCCAACCA

TCATCATCAA

GGTCCAATCT

ATCTCCAAAC

TCC AGC G CC

CTGGAGGTGT

CTCTGGCGGC

AGATCCAGGG

AAGCTGTGCC

CCCCTGGGCT

GCTGCTTGAG

CAGGCCCTGG

GCAGC TGGAC

AACTGGGAAT

pMON3 1108 1 51 101 151 201 251 301 351 401 451 501 551 601 651 701 751 801 851

ATGGCTCTGG

GGACCGAAAC

AGAACTTAGA

CCATGTCTGC

CAAGGCAGGT

TTACCCTTGA

AGCGGCGGCG

CTTAAAGAGA

CGGGTGAACC

AAAGAATCTC

CTTCGCCTCT

ATCTGCAGAG

CAGCCCTCTG

AGAGCAAGTG

TGTGTGCCAC

CACTCTCTGG

CCTGCAGCTG

ACCAGGGGCT

ACCCGAACAA

CTTCGACTTC

AAATGCATCA

C CT CTGC CAC

GACTGGCAAG

GCAAGCGCAG

GTTCTAACTG

C CAC CTGC AC

GTCTGGTCCA

ATAAATCTCC

GCTTTCCAGC

C TTC CTG GAG

GCGGCTCTGG

AGAAAGATCC

CTACAAGCTG

GC AT CC C CTG

GCAGGCTGCT

CCTGCAGGCC

CCTCAATGAC

CAAACCTGGA

GGTATTGAGG

GGCCGCACCC

AATTCCGGGA

GAACAACAGG

CTCTATAATG

CTTTGTACGT

ATCTCTACTA

AAACATGGCT

GCCGGGCAGG

GTGTCGTACC

CGGCTCTCAG

AGGGCGATGG

TGC CAC C C C

GGCTCCCCTG

TGAGCCAACT

CTGGAAGGGA

GAAGACGTCT

GAGCTTCGTA

CAATTCTTCG

TCTCGACATC

AAAACTGACG

GTGGTGCCTC

ATCGATGAAA

AGAGGGCGGT

TCAACCCGTC

ACCCAGGGTG

AGGGGTCCTG

GCGTTCTACG

AGCTTCCTGC

CGCAGCGCTC

AGGAGCTGGT

AGCTCCTGCC

CCATAGCGGC

TATCCCCCGA

CTATCCTGAT

AGGGCTGTCA

TAATCTCCAA

CAATCATCAT

TTCTATCTGG

TGGCGGTGGC

TTATACATCA

GGAGGCTCCC

TCCTCCGTCT

CCATGCCGGC

GTTGCTAGCC

CCACCTTGCG

TCAAGTCTTT

CAGGAGAAGC

GCTGCTCGGA

CCAGCCAGGC

CTTTTCCTCT

GTTGGGTCCC

WO 97/12985 WO 9712985PCTIUS96/1 5774 901 ACCTTCGACA CACTGCAGCT 951 GCAGCAGATG GAACAACTGC (SEQ ID GGACCTCGCC GACTTTGCCA CCACCATCTG GAATGCCCCC TCCCCTGCAC CCCTAATAA pMON3 1109 1 51 101 151 201 251 301 351 401 451 501 551 601 651 701 751 801 851 901 951

ATGGCTAATG

TCTGCCCTCT

CAGCTCACTG

CTTGACCAAC

CGCCTTCT

AGAGACCACC

CTCTCTATCC

CGTAAGCGCT

CGGGTGAACC

AAAGAAT CT C

CTTCCCCTCT

ATCTGCAGAC

CAGCCCTCTG

ACAGCAAGTG

TGTGTCCCAC

CACTCTCTG

CCTGCAGCTG

ACCACGGGCT

ACCTTCGACA

GCACCAGATG

CATCAGGTAT

GCCACGCCCG

CCAAGAATTC

CCCAGCAACA

AAC TCC T CTA

TGCACCTTTC

TGATGGACCG

CTCAACAACT

CTCTGGTCCA

ATAAATCTCC

GCTTTCCAC

CTTCCTGGAG

GCCCTCTGC

ACAAAGATCC

CTACAAGCTG

GCATCCCCTG

GCAGGCTGCT

C CT GCAGCC

CACTCCACCT

CAACAACTCC

TCACGCAATT

CACCCTCTCC

CCCCAAAAAC

ACACCCTCCT

TAATGATCCA

CTCCACCCCA

AAACCTTCCA

TAGAATACCT

ATCTCTACTA

AAACATCCCT

CCCCCGCACC

CTCTCCTACC

CCCCTCTCAC

AC CGATC C TGCC ACC CC C

CCCTCCCCTC

TGACCCAACT

CTCCAACCCA

CCACGTCGC C

CAATGCCCCC

CTTCCTAATC

ACATCCAATC

TCACCTTCTA

CCCTCTCCCCG

TCAAATTATA

ACAACCTCAA

CTTCCAAACC

AGACCCCCCT

TCAACCCCTC

ACCCACCCTC

ACCGGTCCTC

CCTTCTACG

ACCTPCCTC

CCCACCGCTC

ACCACCTCCT

ACCTCCTGCC

CCATACC

TATCCCCCGA

GACTTTCCCA

TGCCCTCCAC

TCC AAC CAT C AT CAT CAACC

TCTCCTTACC

CTCCCACCGC

CATCACTTAA

TGACGAAGAC

TCCACACCTT

GACCCTCCC

TCCTCCCTCT

CCATCCCGC

CTTCCTACC

C CAC CTTGC C

TCAACTCTTT

CACCAGAAC

CCTCCTCCCA

CCACCCAGC

CTTTTCCTCT

CTTCCCTCCC

CCACCATCTG

CCC TAATAA (SEQ ID NO:91) pMON3 1110 1 51 101 151 201 251 301 351 401 451 501 551 601 651 701 751 801 851 901 951

ATCCCTCCAC

ACAATTCCCC

ACCAACAACA

TGCTCTATAA

ACCTTTGCTC

TCCACCGAAA

AACAACTTAC

ACCATGTCTC

CCCCTCAACC

AAAGAATCTC

CTTCGCCTCT

ATCTCCAGAC

CACCCCTCTC

ACACCAACTC

TCTCTCCCAC

C AC TCTCT CC

CCTGCAGCTC

ACCAGGCCCT

ACCTTCGACA

CCACCACATC

CCTCTCCACA

CAAAAACTCA

CCGTCGTCGC

TCATCGATCA

GACCCCAACA

CCTTCGACTT

AAAATCCATC

CCCTCTCCCA

CTCTCGTCCA

ATAAATCTCC

GCTTTCCAC

CTTCCTCCAC

CCCCTCTCC

ACAAACATCC

CTACAACCTC

CCATC CCCTC

CCAGCCTCCT

CCTGCAGCC

CACTCCACCT

CAACAACTCC

TCCAATCATC

CCTTCTATCT

TCTCGCGCTC

AATTATACAT

AC CTCAATCA CC AAAC C TGC

ACCTATTCAC

CGCCCTACGT

ATCTCTACTA

AAACATGGCT

CCCCCCACC

CTCTCCTAC C

CCCCTCTCAC

ACCCCCATCC

TCCCACCCCC

GCCTCCCCTC

TCACCCAACT

CTCCAACCCA

GCACGTCCC

CAATCCCCCC

ATCAACCCAC

CC TTAC C CTT CACC C

CACTTA-AACA

CCAACACCTC

ACAC TTC CT

CCAATTCTTC

ACAGCCCCCT

TCAACCCCTC

ACCCAGCCTC

ACCCCTCCTC

CTTCTACC

ACCTTCCTC

CCCACCCTC

ACCACCTGGT

ACCTCCTCC

CCATACC

TATCCCCCCA

CAC TTTCC A TCC C T CAC

CTCACTCCCA

CACCAACC

CCCTTCTAAC

GACCACCTC

TCTATCCTCA

AACCCCTCTC

CTAATCTCCA

CCACCCTCCC

TCCTCCCTCT

C CATC CCC

CTTCCTACC

CCACCTTCC

TCAACTCTTT

CACCACAAC

CCTCCTCCCA

CCACCCAGC

CTTTTCCTCT

CTTCCCTCCC

CC AC CATCTC

CCCTAATAA

(SEQ ID NO:92) WO 97/12985PCUS/157 PCT/US96/15774 pMON3 1111 1 51 101 151 201 251 301 351 401 451 501 551 601 651 701 751 801 851 901 951 ATGGCTGCAG CTGACTGGCA AGAATTCCGG GAAAAACTGA CGTTCTATCT GGTTACCCTT GAGCAAGCGC AGGAACAACA GGGTGGTGGC TCTGCCGGTG GCAGCGGCGG CGGTTCTAAC TGCTCTATAA TGATCGATGA AATTATACAT CACTTAAAGA GACCACCTGC ACCTTTGCTG GACCCGAACA ACCTCAATCA CGAAGACGTC TCTATCCTGA TGGACCGAAA CCTTCGACTT CCAAACCTGG AGAGCTTCGT AAGGGCTGTC AAGAACTTAG AAAATGCATC AGGTATTGAG GCAATTCTTC GTAATCTCCA ACCATGTCTG CCCTCTGCCA CGGCCGCACC CTCTCGACAT CCAATCATCA TCAAGTACGT AGAGGGCGGT GGAGGCTCCC CGGCTGAACC GTCTGGTCCA ATCTCTACTA TCAACCCGTC TCCTCCGTCT AAAGAATCTC ATAAATCTCC AAACATGGCT ACCCAGGGTG CCATGCCGGC CTTCGCCTCT GCTTTCCAGC GCCGGGCAGG AGGGGTCCTG GTTGCTAGCC ATCTGCAGAG CTTCCTGGAG GTGTCGTACC GCGTTCTACG CCACCTTGCC CAGCCCTCTG GCGGCTCTGG CGGCTCTCAG AGCTTCCTGC TCAAGTCTTT AGAGCAAGTG AGAAAGATCC AGGGCGATGG CGCAGCGCTC CAGGACAAGC TGTGTGCCAC CTACAAGCTG TGCCACCCCG ACGAGCTGGT GCTGCTCGGA CACTCTCTGG GCATCCCCTG GGCTCCCCTG AGCTCCTCCC CCAGCCAGGC CCTG(.L-GCTG GCAGGCTGCT TGAGCCAACT CCATAGCGGC CTTTTCCTCT ACCAGGGGCT CCTGCAGGCC CTGGAAGGGA TATCCCCCGA GTTGGGTCCC ACCTTGGACA CACTGCAGCT GGACGTCGCC GACTTTGCCA CCACCATCTG GCAGCAGATG GAAGAACTGG CAATGGCCCC TGCCCTGCAG CCCTAATAA (SEQ ID NO:93) pMON13182 1 51 101 151 201 251 301 351 401 451 501 551 601 651 701 751 801 851 901 AT GOCTAACT AC CACCTGCA

CTATCCTGAT

AGGGCTGTCA

TAATCTCCAA

CAATCATCAT

TTCTATCTGG

CGGTGGAGGC

ACAAGCTGTG

ATCCCCTGGG

AGGCTGCTTG

TGCAGGCCCT

CTGCAGCTGG

AGAACTGGGA

CCTTCGCCTC

CATCTGCAGA

GCAGCCCTCT

TAGAGCAAGT

CTGTGTGCCA

GCTC TAT AAT

CCTTTGCTGG

GGACCGAAAC

AGAACTTAGA

CCATGTCTGC

CAAGGCAGGT

TTACCCTTGA

TCCCCGGGTG

CCACCCCGAG

CTCCCCTGAG

AGCCAACTCC

GGAAGGGATA

ACGTCGCCGA

ATGGCCCCTG

TGCTTTCCAG

GCTTCCTGGA

GGCGGCTCTG

GAGAAAGATC

GATCGATGAA

AC CCGAACAA

CTTCGACTTC

AAATGCAT CA CC TC TGC CAC

GACTGGCAAG

GCAAGCGCAG

GTGGTTCTGG

GAGCTGGTGC

CTCCTGCCCC

ATAGCGGCCT

TCCCCCGAGT

CTTTGCCACC

CCCTGCAGCC

CGCCGGGCAG

GGTGTCGTAC

GCGGCTCTCA

CAGGGCGATG

ATTATACATC ACTTAAAGAG CCTCAATGAC GAAGACGTCT CAAACCTGGA GAGCTTCGTA GGTATTGAGG CAATTCTTCG GGCCGCACCC TCTCGACATC AATTCCGGGA AAAACTGACG GAACAACAGT ACGTAGAGGG CGGCGGCTCC AACATGGCTT TGCTCGGACA CTCTCTGGGC AGCCAGGCCC TGCAGCTGGC TTTCCTCTAC CAGGGGCTCC TGGGTCCCAC CTTGGACACA ACCATCTGGC AGCAGATGGA CACCCAGGGT GCCATGCCGG GAGGGGTCCT GGTTGCTAGO CGCGTTCTAC GCCACCTTGC GAGCTTCCTG CTCAAGTCTT GCGCAGCGCT CCAGGAGAAG CCTAATA.A (SEQ ID NO:94) PMON13 183 1 ATGGCTAACT GCTCTATAAT GATCGATGAA ATTATACATC ACTTAAAGAG 51 ACCACCTGCA CCTTTGCTGG ACCCGAACAA CCTCAATGAC GAAGACGTCT 101 CTATCCTGAT GGACCGAAAC CTTCGACTTC CAAACCTGGA GAGCTTCGTA WO 97/12985 WO 9712985PCTIUS96/15774 151 201 251 301 351 401 451 501 551 601 651 701 751 801 851 901 951

AGGGCTGTCA

TAATCTCCAA

CAATCATCAT

TTCTATCTGG

CGGTGGAGGC

CGTCTCCTCC

CTGTGCCACC

CTGGGCTCCC

GCTTGAGCCA

GCCCTGGAAG

GCTGGACGTC

TGGGAATGGC

GCCTCTGCTT

GCAGAGCTTC

CCTCTGGCGG

CAAGTGAGAA

TGCCACCTAA

AGAACTTAGA

CCATGTCTGC

CAAGGCAGGT

TTACCCTTGA

TCCCCGGGTG

GTCTAAAGAA

COGAGGAGOT

CTGAGCTCCT

ACTCCATAGC

GGATATCCCC

GCCGACTTTG

CCCTGCOCTG

TCCAGCGCCG

CTGGAGGTGT

CTCTGGCGGC

AGATCCAGGG

AAATGCATCA

CTCTCCAC

GACTGGCAAG

GO AAGC GOAG

AACCGTCTGG

TCTCATAAAT

GGTGCTGOTC

GOCCCCAGCCA

GGCCTTTTCC

CGAGTTGGGT

OCACOACCAT

CAGOOCACOCC

GGCAGGAGGG

OGTACOGCGT

TCTOAGAGCT

CGATGGCGCA

GOTATTOAGG

GGCC GOACC

AATTCCGGGA

GAACAACAGT

TCCAATCTCT

CTCCAAACAT

GGACACTCTC

GGCCCTGCAG

TCTACCAGGG

C CCAC CTTGG

OTGGOAGCAG

AGGGTG~CAT

GTCCTGGTTG

TCTACGCCAC

TCCTGCTCAA

GOGCTCCAGG

CAAT T CTT C

TCTCGACATC

AAAACTGACG

ACGTAGAGGG

AC TAT CAAOCC

GGCTTACAAG

TGGOATCO

CTGGCAGGCT

GCTOCTOCAG

ACAOACTGCA

ATGGAAGAAC

GOOGGOOTTC

C TACCATC T

CTTGCGCAGC

GTCTTTAGAC

AGAACCTGTG

TAA (SEQ ID pMON13184 1 51 101 151 201 251 301 351 401 451 501 551 601 651 701 751 801 851 901

ATGGCTAACT

AOOACCTGCA

C TAT C CTGAT

AGGGCTGTOA

TAATCTCCAA

CAATCATCAT

TTOTATOTGG

OGGTGGAGGC

OOGAGTTGGG

GOCACOACCA

GOAGOOCACO

GGGOAGGAGG

TCTACOGOG

OTOTOAGAGO

GOGATGGCGC

OACOOOGAGG

TOCOCTGAGC

GCCAACTCCA

GAAGGGATAT

GCTCTATAAT

OCTTTGOTGG

GGACCGAAAC

AGAACTTAGA

CCATGTCTGC

CAAGGCAGGT

TTAC 0 0T TGA

TCCOGGGTG

TCCCAOOTTG

TCTGGOAGCA

OAGGGTGOOA

GGTCOTGGTT

TTOTAOGOCA

TTCOTGOTCA

AGO GO TOCAG

AGCTGGTGOT

TOOTGOCCCA

TAGCGGOCTT

GATCGATGAA

AC CC GAACAA

OTTOGACTTO

AAATGCAT CA

CCTCTGOCAO

GACTGGCAAG

GCAAGOGCAG

GTGGTTOTGG

GAOACACTGC

GATGGAAGAA

TGCCGGCOTT

GOTAGOCATO

CCTTGCGOAG

AGTOTTTAGA

GAGAAGCTGT

GOTOGGACAC

GOCAGGCOT

TTOOTOTACC

ATTATACATO

CCTCAATGAC

OAAACCTGGA

GGTATTGAGG

GGCO GOAC CC

AATTCOGGGA

GAACAACAGT

OGGOGGOTC

AGOTGGACGT

OTGGGAATGC

CGOCTOTGOT

TGCAGAGOTT

OCCTOTGGCG

GCAAGTGAGA

CTCCACOTA

TCTOTGGGOA

GOAGOTGGCA

AGGGGCTCCT

AOTTAAAGAG

GAAGACGTCT

GAGOTTCTA

C AAT TOTTC G TO TOGACATO

AAAACTGACG

ACGTAGAGGG

AACATGGCTC

CGCCGACTTT

CCOCTGCCCT

TTCCAGCGCC

CCTGGAGCTG

GOTCTGGCGC

AAGATCCAGG

CAAGOTGTGC

TOCCCTGGGC

GGOTGCTTGA

CAGC CC TG COTAATAA (SEQ ID NO:96) PMON13 185 1 51 101 151 201 251 301 351

ATGGCTAACT

ACCACOTGCA

CTATCOTGAT

AGGGCTGTCA

TAATCTCCAA

CAATCATOAT

TTCTATOTGG

CGGTGGAGGC

GCTCTATAAT

OOTTTGOTGG

GGACCGAAAC

AGAACTTAGA

CCATGTOTGC

CAAGGCAGGT

TTAOCCOTT GA

TCCCCGGGTG

GATCGATGAA

ACCCGAACAA

OTTO GAOTT C

AAATGCATCA

OOTCTGOOAC

GACTGGCAAG

GCAAGCGCAG

AACCGCTGG

ATTATACATO

COTCAATGAC

CAAACCTGGA

GGTATTGAGG

GGOACC

AATTCCGGGA

GAACAACAGT

TCCAATCTCT

ACTTAAAGAG

GAAGACGTCT

GAGOTTCTA

OAATTCTTOG

TOTOGACATC

AAAACTGACG

ACGTAGAGGC

ACTATCAAC

WO 97/12985 WO 9712985PCT/US961 15774 401 451 501 551 601 651 701 751 801 851 901 951

CGTCTCCTCC

TTGCGTCCCA

C AC CAT CT GO

CCACCCAGOG

GCAGCGGTCC

CCGCCTTCTA

AGAGCTTCCT

GCCACCC

CGAGGAGCTG

TGAGCTCCTG

CT CCAT AGCG

GATATCCTAA

GTCTAAAGAA

CCTTCGACAC

CAGCAGATCO

TGCCATGCCG

TGGTTCCTAO

CGCCACCTTG

OCT CAAGTCT

TCCAGGAGAA

GTGCTGCTCG

CCCCAGCCAG

GCCTTTTCCT

TCTCATAAAT

ACTGCAGCTG

AAGAACTGGG

GCCTTCGCCT

CCATCTGCAG

CGCAGCCCTC

TTAGAGCAAG

GCTCTOTGCC

GACACTCTCT

GCCCTGCAGC

CTACCAOGGGG

CTCCAAACAT

CACGTCGCCO

AATGGCCCCT

CTGCTTTCCA

AGCTTCCTGG

TGGCGCCTCT

TGAGAAAGAT

ACCTACAAOC

GGGCATCCCC

TGGCAGGCTfG CTCC TGC AGO

GGCTCCCOAG

ACTTTGCCAC

CCCCTGC AG C

GCGCCGGGCA

AGGTGTCGTA

GGCGGCTCTC

CCACOGCGAT

TGTGCCACCC

TCGGCTCCCC

CTTGACCCAA

CCC TGGAAGG TAA (SEQ ID NO:97) pMON13186 1 51 101 151 201 251 301 351 401 451 501 551 601 651 701 751 801 851 901

ATGGCTAACT

ACCACCTGCA

CTATCCTGAT

AGGGCTCTCA

TAATCTCCAA

CAAT CAT CAT

TTCTATCTGO

CGGTGGAGGC

TOCCCCCTGC

GCTTTCCAGC

CTTCCTGGAG

GCGGCTCTGC

AGAAAGATCC

CTACAAGCTG

GCATCCCCTG

GCAGGCTGCT

CCTGCAGGCC

CACTGCAGCT

GAAGAACTGG

GCTC TAT AAT

CCTTTGCTGG

GGACCGAAAC

AGAACTTAGA

C CATCT C TG C

CAACCCAGGT

TTACCCTTOA

TCCCCGOCTG

C CT OCACCCC

GCCGGGCAGG

GTCTCGTACC

CGGCTCTCAG

AGOCATOC

TCCCACCCCO

GGCTCCCCTG

TGACCCAACT

CTCCAACOGA

GGACGTCCC

GATCOATGAA

ACCCGAACAA

CTTCGACTTC

AAATGCATCA

CCTCTGCCAC

GACTCGCAAG

CCAACCGCAC

GTGGTTCTGO

AC CCACCOTO

AGGGGTCCTG

GCOTTCTACG

AGCTTCCTGC

CGCAGCGCTC

AGGAOCTCCT

AGCTCCTOCC

CCATAGCGC

TATCCCCCCA

GACTTTGCCA

ATTATACATC

CCTCAATGAC

CAAACTGGA

GOTATTGAGO

OGCCGCACCC

AATTC COCOA

GAACAACACT

CGOCOGCTCC

CCATGCCCGC

GTTGCTAOCC

CCACCTTGCG

TCAACTCTTT

CAGGAGAAGC

OCTGCTCGGA

CCAGCCAGOC

CTTTTCCTCT

GTTCGGTCCC

CCACCATCTG

ACTTAAAGAG

OAAGACGTCT

GAGCTTCGTA

CAATTCTTCO

TCTCGACATC

AAAACTGACG

ACOTAGAGG

AACATCOCTA

CTTCGCCTCT

ATC TOCACAO CACC CCTC TO

AGAGCAAOTO

TGTOTOCCAC

CACTCTCTGC

CCTOCACCTC

ACCAGOGOCT

ACCTTCOACA

CAG CAGAT 0 OATAATAA (SEQ ID NO:98) PMON13 187 1 51 101 151 201 251 301 351 401 451 501 551 601

ATCCCTAACT

ACCACCTGCA

CTATCCTGAT

AGOCCTCTCA

TAATCTCCAA

CAATCATCAT

TTC TAT CTG

CCGTGGAOGC

CCTCTCCTCC

CCTCCCCTOC

C CAGCGCC C

TGGAGGTGTC

TCTGGCGGCT

GCTCTATAAT

CCTTTGCTGG

CCACCCAAAC

AGAACTTAGA

CCATOTCTGC

CAAGGCAGCT

TTACCCTTCA

TCCCCGGGTG

GTCTAAAGAA

AGCCCACCCA

GCACGAGGC

CTACCGCCTT

CTCAGAGCTT

GATCGATOAA

ACCCGAACAA

C TT CGAC TT C

AAATGCATCA

CCTCTGCCAC

GACTCGCAAG

GCAACCAC

AACCGTCTOC

TCTCATAAAT

GOTOCCATO

TCCTGGTTOC

CTACCCCACC

CCTGCTCAAG

ATTATACATC

CCTCAATOAC

CAAACCTCGA

GGTATTCAGG

CCCCGCACCC

AATTCCGGGA

GAACAACAGT

TCCAATCTCT

CTCCAAACAT

CCGCCCTTCG

TAGCCATCTG

TTCCAGCC

TCTTTAGACC

ACTTAAAGAO

OAAGACCTCT

GAGCTTCGTA

CAATTCTTCG

TCTCGACATC

AAAAC TGACG

ACGTAGAGOG

AC TAT CAAC C

GCCTATGGCC

CCTCTGCTTT

CAGAGCTTCC

CTCTGGCGGC

AAGTGAGAAA

WO 97/12985 WO 9712985PCT/US96/15774 651 701 751 801 851 901 951

GATCCAGGGC

AGO TGTC CA

CCCTGGGOTC

C TG CTT GAG C

AGGCCCTGGA

CAGCTGGACG

ACTGGGATAA

GATGGCGCAG CGCTCCAGGA CCCCGAGGAG CTGGTGCTGC CCOTGAGOTC CTGCCCCAGC CAACTCCATA

GCGGCCTTTT

AGGGATATCC

CCCGAGTTGG

TCGCCGACTT

TGCCACCACC

TAA (SEQ ID NO:99)

GAAGCTGTGT

TCGGACACTC

CAGGCCCTGC

COTCTACCAG

GTCCCACCTT

ATCTGGCAC

GCCACCTACA

TCTGGGCATC

AGO TGGCAGG

GGGCTCCTC

GGACACACTG

AGATGGAAGA

pMON13188 1 51 101 151 201 251 301 351 401 451 501 551 601 651 701 751 801 851 901

ATCCCTAACT

ACCACCTGCA

CTATCCTGAT

AGGGCTGTCA

TAATCTCCAA

CAATCATCAT

TTCTATCTGG

CGGTGGAGGC

CCCAGGGTGC

GGGGTCCTGG

C GTTC TAOCOC

GCTTCC'TGCT

CCAGCGCTCC

GGAGCTGGTG

GCTCCTGCCC

CATAGCGGCC

ATCCCGAG

ACTTTGCCAC

GOCCTGOAGC

GO TOTATAAT

CCTTTGCTGG

GGACCGAAAC

AGAACTTAGA

OOATGTOTGO

CAAGGCAGGT

TTAOOOTTGA

TCCCCCGGTG

O AT GC CGCC

TTGCTAGCCA

OACOTTGOGC

CA.AGTCTTTA

AGGAGAAGCT

CTGCTCGGAC

CAGOCAGGOC

TTTTOOTOTA

TTGGGTCCCA

C ACOATC TG G

GATCGATGAA

ACCCGAACAA

OTTCGAOTTC

AAATGOATCA

CO TOT GOCAC

GACTGGCAAG

GOAACGOAG

GTGGTTOTGC

TTOGOOTOTG

TOT GOAGAG C

AGCOOTCTGG

GAGOAAGTGA

GTGTGOOAOO

AC TO TOTGGG

OTGOAGOTGG

OOAGGGGOTO

OOTTCGCAAC

ATTATACATO

CCTOAATGAC

CAAACOTGGA

GGTATTCAGG

GCGC AC CO

AATTOOGGGA

GAAOAAOAGT

OGGGGOTC

CTTTCCAGOG

TTCOTGGAGG

OGGOTOTGGC

GAAAGATOCA

TAOAAGOTGT

OATOCOCTCG

OAGGOTCTT

CTGCAGGCCC

ACTGOAGCTG

AAGAACTGGG

AOTTAAAGAG

GAAGACCTCT

CAGOTTCTA

OAATTOTTOG

TOTOGACATO

AAAAO TGACG

ACGTAGAGGG

AAOATGGOTA

OOGGGOAGGA

TGTCGTAoC

GGOTOTCAGA

GGOCGATGGC

GOCACCOGA

GO TO 0 CT GA

GAGOOAACTC

TGGAAGGGAT

GAOGTCCCG

AATGGOCCOT

OCTAATAA (SEQ ID NO:100) PMON13 189 1 51 101 151 201 251 301 351 401 451 501 551 601 651 701 751 801 851

ATGGOTAAOT

AOCACCTGCA

OTATOOTGAT

AGGOCTGTCA

TAATCTOOAA

OAATOATCAT

TTOTATCTGG

OGGTGGACo

CTOTOCTC

GGTGCCATC

OCTGGTTGCT

TACCCACOT

OTGOTOAAGT

GOTOCAGGAG

TGGTGOTGCT

TOCCO AG CO

OGGOOTTTTC

CCGAGTTGGG

GCTCTATAAT

CCTTTGOTGG

GGAOOGAAAO

AGAAOTTAGA

COATCTCTC

OAAGGOAGGT

T TAOC C TTGA

TCOCGGGTG

GCTAAAGAA

OGGOOTTOGO

AGO CATO TGO

TCCAGOOO

CTTTAGAGOA

AAGCTGTGTG

OGGACACTOT

AGGOOCTOCA

OTOTACCAG

TCCOACCTTG

GATOGATGAA

AOOOGAAOAA

CTTOGACTTC

AAATGOATOA

COTCTGCCAC

GACTGGOAAG

GOAAGOGOAG

AAOOGTCTGG

TOTCATAAAT

CTOTGCTTTO

AGAGOTTOCT

TOTGGCGGCT

AGTGAGAAAG

OOAOOTAOAA

OTGGCCATOO

GOTGGOAGGC

GCTOCTGCA

GACAOACTC

ATTATACATO

OOTOAATGAO

OAAAOOTGGA

GGTATTGAGG

GGOCOACCC

AATTOOGGGA

GAAOAAOAGT

1'OOAATOTOT

OTOOAAAOAT

OAGCOCGGC

GGAGGTGTC

CTGGCGGCTO

ATOCAGGGOG

CTGTGC CAC

COTGGGCTCC

TGOTTGAGOO

GGOOCTGGAA

AGOTGGACGT-

AOTTAAAGAG

GAAGAOGTOT

GAGOTTCTA

OAATTOTTOG

TOTOGACATO

AAAAOTGAOG

ACGTAGAGGC

AOTATOAAOO

GGOTACCCAG

OAGGAGGGGT

TACCCCGTTO

TOAGACTTO

ATGGC GOAGO

COGAGGAGO

OOTGAGOTCC

AAOTOOATAG

GGGATATCCC

CGCCATTT

WO 97/12985 97 901 GCCACCACCA TCTGGCAGCA CATGCAAGAA 951 GCAGCCCTAA TAA (SEQ ID NO:101) PCTIUS96/1 5774 CTGGGAATGG

CCCCTGCCCT

pMON1319O 1 51 101 151 201 251 301 351 401 451 501 551 601 651 701 751 801 851 901

ATGGCTAACT

ACCACCTGCA

CTATCCTCAT

AGGCTGTCA

TAATCTCCAA

CAATCATCAT

TTCTATCTG

CCGTGGAGC

CTCCTTTCCA

AGCTTCCTG

TGGCGCCTCT

TGAGAAAGAT

ACCTACAAGC

GGCCATC CCC

TCGCAGGCTG

CTCCTGCAGG

CACACTGCAG

TGCAAGAACT

CCGGCCTTCG

GCTCTATAAT

CCTTTGCTG

GGACCGAAAC

AGAACTTAGA

CCATGTCTGC

CAAGGCAGGT

TTACCCTTGA

TCCCCGGGTC

GCGCCGGGCA

AGGTGTCGTA

GGCGGCTCTC

CCAGGGCGAT

TGTGCCACCC

TCGGCTCCCC

CTTGAGCCAA

CCCTGGAAGG

CTGGACGTCG

GGGAATGGCC

GATCGATGAA

AC CCGAACAA

CTTCGACTTC

AAATGCATCA

CCTCTCCCAC

GACTGGCAAG

GCAACCCAG

GTGGTTCTCC

GCAGCGTC C

CCGCGTTCTA

AGAGCTTCCT

GCCCAGCGC

CGAGCAGCTG

TGAGCTCCTG

CTCCATAGCG

GATATCCCCC

CCGACTTTGC

CCTGCCCTGC

ATTATACATC

CCTCAATGAC

CAAACCTGGA

GGTATTGAGG

GGCCGCACCC

AATTCCGGGA

GAACAAC ACT

CGCGCTCC

TGGTTCCTAG

CGCCACCTTG

GCTCAAGTCT

TCCAGGAGAA

GTGQTGCTCG

COCCAGOCAC

GCCTTTTCCT

GAGTTGGCTC

CACCACCATC

AG CC CAC CCA

ACTTAAAGAG

GAAGACCTCT

CAGCTTCGTA

CAATTCTTCG

TCTCGACATC

AAAACTGACG

ACGTAGAGGG

AACATGGCTT

CCATCTGCAG

CGCAGCCCTC

TTAGACCAAC

GCTGTGTGCC

GACACTCTCT

GCCCTGCAGC

CTACCAGCCC

CCACCTTGGA

TGGCAGCACA

GGGTGCCATC

CCTAATAA (SEQ ID NO:102) PMON13 191 1 51 101 151 201 251 301 351 401 451 501 551 601 651 701 751 801 851 901 951

ATCGCTAACT

ACCACCTGCA

CTATCCTGAT

AGGGCTCTCA

TAATCTCCAA

CAATCATCAT

TTCTATCTGC

CGCTGGAGGC

CCTCTCCTCC

TTC CACC C

CCTCCACCTG

GCTCTGGCCC

AAGATCCACC

CAACCTGTC

TCCCCTGGCC

GCCTGCTTGA

CCAGCCCCTC

TCCACCTCCA

CAACTGCAA

CTTCGCCTAA

GCTCTATAAT

CCTTTCCTCC

GCACCGAAAC

AGAACTTAGA

CCATGTCTC

CAAGGCAGGT

TTACCCTTGA

TCCCCGCCTC

GTCTAAACAA

GGCCAGCACC

TCCTACCCC

CTCTCAGAC

GCGATGCC

CACCCCCACC

TCCCCTCAC

CC AAC TC CA

CAACCCATAT

CCTCCCCAC

TGGCCCCTC

CATCCATCAA

ACCCCAACAA

CTTCCACTTC

AAATCCATCA

CCTCTCCCAC

GACTGGCAAG

GCAACCAC

AACCCTCTCC

TCTCATAAAT

CCTCCTCCTT

TTCTACGCCA

TTCCTCCTCA

ACCTCCAC

ACCTCCTCCT

TCCTCCCCCA

TACCCCCTT

CCCCCCACTT

TTTCCCACCA

CCTGCACCCC

ATTATACATC

CCTCAATGCc

CAAACCTCCA

CGTATTGACC

GCCCCACCC

AATTCCGCCA

GAACAACAGT

TCCAATCTCT

CTCCAAACAT

GCTACCCATC

CCTTCCCAC

ACTCTTTACA

GAGAACCTCT

GCTCGCACAC

CCCACCCCCT

TTCCTCTACC

GCGTCCCACC

CC AT CTCCCA

ACCCAGCCTC

ACTTAAACAC

CAACACGTCT

CACCTTCCTA

CAATTCTTCC

TCTCCACATC

AAAACTCACC

ACCTACACCC

ACTATCAACC

CCCTTCTCCT

TCCACACCTT

CCCTCTGCG

CCAACTGACA

CTCCCACCTA

TCTCTCCCCA

CCACCTCCCA

AGCCCTCCT

TTCCACACAC

CCACATCCAA

C CATGCCCCC TAA (SEQ ID NO:103) PMON13 192 WO 97/12985 PCT/US96/1 5774 1 51 101 151 201 251 301 351 401 451 501 551 601 651 701 751 801 851 901

ATGGCTAACT

ACCACCTGCA

CTATCCTGAT

AGGGCTGTCA

TAATCTCCAA

CAATCATCAT

TTCTATCTGG

CGGTGGAGGC

ACAAGCTGTG

ATCCCCTGGG

AGGCTGCTTG

TGCAGGCCCT

CTGCAGCTGG

AGAACTGGGA

CCTTCGCCTC

CATCTGCAGA

CAG C CCACA

TCAAGTCTTT

CAGGAGAAGC

GCTCTATAAT

CCTTTGCTGG

GGACCGAAAC

AGAACTTAGA

CCATGTCTGC

CAAGGCAGGT

TTACCCTTGA

TCCCCGGGTG

CCACCCCGAG

CTCCCCTGAG

AGCCAACTCC

GGAAGGGATA

ACGTCGCCGA

ATGGCCCCTG

TGCTTTCCAG

GCTTCCTGGA

C CAT TGGGCC

AGAGCAAGTG

TGTGTGCCAC

GATCGATGAA

ACCCGAACAA

CTTCGACTTC

AAATGCATCA

CCTCTGCCAC

GACTGGCAAG

GCAAGCGCAG

GTGGTTCTGG

GAGCTGGTGC

CTCCTGCCCC

ATAGCGGCCT

TC CCCCGAGT

CTTTGCCACC

CC CTGCAGC C

CGCCGGGCAG

GGTGTCGTAC

CTGCCAGCTC

AGAAAGATC C

ATTATACATC

CCTCAATGAC

CAAACCTGGA

GGTATTGACG

GGCCGCACCC

AATTCCGGGA

GAACAACAGT

CGGCGGCTCC

TGCTCGGACA

AGCCAGGCCC

TTTCCTCTAC

TG GCTC C CAC

ACCATCTGGC

CACCCAGGGT

GAGGGGTCCT

CGCGTTCTAC

CCTGCCCCAG

ACTTAAAGAG

GAAGACGTCT

GAGCTTCGTA

CAATTCTTCG

TCTCGACATC

AAAACTGACC

ACGTAGAGGG

AACATGGCTT

CTCTCTGGGC

TGCAGCTGGC

CAGGGGCTCC

CTTGGACACA

AGCAGATGGA

GCCATGCCGG

GGTTGCTAGC

GCCACCTTGC

AGCTTCCTGC

CGCAGCGCTC

CTAATAA (SEQ ID NO:104 PMON13193 1 51 101 151 201 251 301 351 401 451 501 551 601 651 701 751 801 851 901 951

ATGGCTAACT

ACCACCTGCA

CTATCCTGAT

AGGGCTGTCA

TAATCTCCAA

CAATCATCAT

TTCTATCTGG

CGGTGGAGGC

CGTCTCCTCC

CTGTGCCACC

CTGGGCTCCC

GCTTGAGCCA

GCCCTGGAAG

GCTGGACGTC

TGGGAATGGC

GCCTCTGCTT

GCAGAGCTTC

CCACACCATT

TCTTTAGAGC

GAAGCTGTGT

GCTCTATAAT

CCTTTGCTGG

GGACCGAAAC

AGAACTTAGA

CCATGTCTGC

CAAGGCAGGT

TTACCCTTGA

TCCCCGGGTG

GTCTAAAGAA

CCGAGGAGCT

CTGAGCTCCT

ACTCCATAGC

GGATATCCCC

GCCGACTTTG

CCCTGCCCTG

TCCAGCGCCG

CTGGAGGTGT

GGGCCCTGCC

AAGTGAGAAA

GCCACCTAAT

GATCGATGAA

AC CCGAACAA

CTTCGACTTC

AAATGCATCA

CCTCTGCCAC

GACTGGCAAG

GCAAGCGCAG

AACCGTCTGG

TCTCATAAAT

GGTGCTGCTC

GCCCCAGCCA

GGCCTTTTCC

CGAGTTGGGT

CCACCACCAT

CAGCCCACCC

GGCAGGAGGG

CGTACCGCGT

AGCTCCCTGC

GATCCAGGGC

AA (SEQ ID

ATTATACATC

CCTCAATGAC

CAAACCTGGA

GGTATTGAGG

GGCCGCACCC

AATTCCGGGA

GAACAACAGT

TCCAATCTCT

CTCCAAACAT

GGACACTCTC

GGCCCTGCAG

TCTACCAGGG

CCCACCTTGG

CTGGCAGCAG

AGGGTGCCAT

GTCCTGGTTG

TCTACGCCAC

CCCAGAGCTT

GATGGCGCAG

NO: 105)

ACTTAAAGAG

GAAGACGTCT

GAGCTTCGTA

CAATTCTTCG

TCTCGACATC

AAAACTGACG

ACGTAGAGGG

ACTATCAACC

GGCTTACAAG

TGGGCATCCC

CTGGCAGGCT

GCTCCTGCAG

ACACACTGCA

ATGGAAGAAC

GCCGGCCTTC

CTAGCCATCT

CTTGCGCAGC

C CTCTCAAG

CGCTCCAGGA

pM0N25190 1 51 101 151

ATGGCTAACT

ACCACCTGCA

CTATCCTGAT

AGGGCTGTCA

GCTCTATAAT

CCTTTGCTGG

GGACCGAAAC

AGAACTTAGA

GATCGATGAA

AC CCGAACAA

CTTCGACTTC

AAATGCATCA

ATTATACATC

CCTCAATGAC

CAAACCTGGA

GGTATTGAGG

ACTTAAAGAG

GAAGACGTCT

GAGCTTCGTA

CAATTCTTCG

WO 97/12985 PCTIUS96/15774 201 251 301 351 401 451 501 551 601 651 701 751 801 851 901

TAATCTCCAA

CAATCATCAT

TTCTATC

TG

CGGTGGAGGC

CCGAGTTGGG

GCCAC'CACCA

GCAGCCCACC

GCAGGAGG

TCGTACCCG

CAGCTCCCTG

AGATOCAGG

AAG C TCTGC C

CCCCTGGGCT

GCTGCTTGAG

CAGGCCCTGG

CCATGTCTGC

CAAGGCAGGT

TTACCCTTGA

TCCCCGGGTG

TCCCACCTTG

TCTGGCAGCA

CAGGGTGCCA

GGTCCTGGTT

TTCTACGCCA

CCCCAGAGCT

CGATGGCGCA

ACCCCGAGGA

CCCCTGAGCT

C CAAC TC CAT

AAGGGATATC

CCTCTGCCAC

GACTGGCAAG

GCAAGCGCAG

GTGGTTCTGG

GACACACTGC

GATGGAAGAA

TGCCGGCCTT

GCTAGCCATC

CCTTGCGCAG

TCCTGCTCAA

GC GCTCCAGG

GCTGGTGCTG

CCTGCCCCAG

GGCCGCACCC

AATTCCGGGA

GAACAACAGT

CGGCGGCTCC

AG C T GAC T

CTGGGAATGG

CCCCTCTGCT

TCCAGAGCTT

CCCACACCAT

GTCTTTAGAG

ACAAGCTGTG

CTCGCACACT

CCAGGCCCTC

TCTCGACATC

AAAACTGACC

ACGTAGAGGG

AACATGGCTC

CCC GAC TTT

CCCCTGCCCT

TTCCAGCGCC

CCTGGAGGTC

TGGGCCCTGC

CAAGTGAGAJA

TGCCACCTAC

CTCTGGCCAT

CAGCTCGCAC

GGCGCTCCTG

CTAATAA (SEQ ID NO:106 pMON2 5191 1 51 101 151 201 251 301 351 401 451 501 551 601 651 701 751 801 851 901 951

ATGGCTAACT

ACCACCTGCA

CTATCCTGAT

AGGGCTGTCA

TAATCTCCAA

CAATCATCAT

TTCTATCTGG

CGGTGGAGC

CGTCTCCTCC

TTCGGTCCCA

CACCATCTGG

CCACCCAGGG

GGAGCGGTCC

CCGCGTTCTA

CCCTGCCCCA

CAGGGCGATC

CTGCCACCCC

GGCCTCCCCT

TTGAGCCAAC

CCTGGAAGGG

GCTCTATAAT

CCTTTGCTGG

CGACCGAAAC

AGAACTTAGA

CCATGTCTC

CAAGGCAGCT

TTACCCTTGA

TCCCCGGGTG

GTCTAAAGAA

C CTTCGACAC

CACCACATGG

TGCCATGCCG

TGGTTGCTAG

CGCCACCTTG

GAGCTTCCTG

GCGCAGCGCT

CAGGAGCTGG

GAGCTCCTC

TCCATAGCGG

ATATCCTAAT

GATCGATGAA

ACCCGAACAA

CTTCCACTTC

AAATGCATCA

CCTCTGCCAC

GACTGGCAAC

GCAACCGCAG

AACCGTCTCG

TCTCATAAAT

ACTGCAGCTG

AAGAACTCGGG

GCCTTCGCCT

C CAT CTG CAG

CCCAGCCCAC

CTCAAGTCTT

CCAGGAGAAG

TGCTGCTCCG

CCCACCCAGG

CCTTTTCCTC

AA (SEQ ID

ATTATACATC

CCTCAATGAC

CAAACCTCGA

GGTATTGAGG

GCCGCACCC

AATTCCCGGA

GAACAACAGT

TCCAATCTCT

CTCCAAACAT

GACCTCGCCG

AATGGCCCCT

CTGCTTTCCA

AGCTTCCTCG

ACCATTGGGC

TAGAGCAAGT

CTGTCTGCCA

ACAC TC TC TG CCC TGCAGCT

TACCAGGGGC

NO: 107) ACTTAAAGAG

I

CAAGACGTCT

GAGCTTCGTA

CAATTCTTCC

TCTCCACATC

AAAACTGACG

ACGTAGAGGG

ACTATCAACC

CGCTCCCGAG

ACTTTCCCAC

GCCCTGCAC

GCGCCGGGCA

ACCTGTCGTA

CCTGCCAGCT

GAGAAAGATC

CCTACAAGCT

G CAT CC CC T

GCCAGGCTGC

TCCTGCAGGC

PMON13194 1 51 101 151 201 251 301 351 401

ATGGCTAACT

ACCACCTGCA

CTATCCTGAT

AGGGCTGTCA

TAATCTCCAA

CAATCATCAT

TTCTATCTGG

CCCTGGAGGC

TGGCCCCTGC

GCTCTATAAT

CCTTTGCTGG

GGACCGAAAC

AGAACTTAGA

CCATGTCTGC

CAAGGCAGGT

TTACCCTTGA

TCCCCGGGTG

C CTGCAG CCC

GATCGATCAA

ACCCGAACAA

CTTCGACTTC

AAATGCATCA

CCTCTCCCAC

GACTGGCAAG

GCAAGCGCAG

GTGGTTCTGG

ACCCAGGGTG

ATTATACATC

CCTCAATGAC

CAAACCTGGA

CCTATTGACG

GCCCGCACCC

AATTCCGGGA

GAACAACAGT

CGCCCCTCC

CCATGCCGGC

ACTTAAAGAG

GAAGACGTCT

GACCTTCGTA

CAATTCTTCG

TCTCGACATC

AAAACTGACG

ACGTAGACGC

AACATGGCTA

CTTCGCCTCT

WO 97/12985 PCTIUJS96/1 5774 451 501 551 601 651 701 751 801 851 901

GCTTTCCAGC

CTTCCTGGAG

CATTGGCCCC

GAGCAAGTGA

C TG T GCCAC C

ACTCTCTGCG

CTCCAGCTGG

C CAGGGCC

CCTTGGACAC

CAGCAGATGG

GCCGGGCAGG

GTGTCCTACC

TGCCAGCTCC

GAAAGATCCA

TACAAGCTGT

C AT CCC CTGG

CAGGCTGCTT

C TGCAGCCC

ACTGCAGCTG

AACAACTGCG

ACGGGTCCTC

CCGTTCTACC

CTCCCCCAGA

GGGCGATGC

CCCACCCCGA

GCTCCCCTGA

GACCCAACTC

TGGAAGGGAT

GACGTCGCCG

GTTGCTACC

CCACCTTGCC

GCTTCCTGCT

CCAGCGCTCC

CGACCTCCTG

GCTCCTCCCC

CATAGCGCC

ATC CC C CGAG

ATICTGCAGAG

CAGCCCACAC

CAAGTCTTTA

AGGAGAACCT

CTCCTCGCAC

CAGCCAGCC

TTTTCCTCTA

TTCGCTCCCA

CACCATCTGC

ATAATAA (SEQ ID NO:108 PMON13 195 1 51 101 151 201 251 301 351 401 451 501 551 601 651 701 751 801 851 901 951

ATGGCTAACT

ACCAC'CTGCA

CTATCCTGAT

AGGGCTGTCA

TAAT C T CCAA

CAATCATCAT

TTCTATCTGG

CGCTGGAGGC

CGTCTCCTCC

CCTGCCCTGC

CCAGCGCCGG

TGGAGGTCTC

GGCCCTCCCA

AGTGAGAAAG

CCACCTACAA

CTGGGCATCC

GCTGGCAGGC

GGCTCCTGCA

GACACACTGC

GATGGAAGAA

GCTCTATAAT

CCTTTCCTGG

GGACCCAAAC

AGAACTTAGA

CCATGTCTC

CAAGGCAGGT

TTACCCTTGA

TCCCCGGGTG

GTCTAAAGAA

AGCCCACCCA

GCAGGAGCGGG

GTACCGCGTT

GCTCCCTGCC

ATCCAGGGCG

CCTGTGCCAC

CCTGGGCTCC

TGCTTGAGCC

GGCCCTGGAA

AGCTGGACGT

CTGGGATAAT

GATCGATGAA

AC CC GAACAA

CTTCGACTTC

AAATGCATC

A

CCTCTGCCAC

GACTGGCAAG

GCAAGCGCAG

AACCGTCTGG

TCTCATAAAT

GG GTCCCAT

C

TCCTGGTTGC

CTACGCCACC

CCAGAGCTTC

ATGGCCCAC

CCCGAGGAGC

CCTGAGCTCC

AACTCCATAG

GGGATATCCC

CGCCCACTTT

AA (SEQ ID

ATTATACATC

CCTCAATGAC

CAAACCTGGA

GGTATTGAGC

GGCCr.CACCC

AATTCCCGGA

GAACAACAGT

TCCAATCTCT

CTCCAAACAT

CCGGCCTTCG

TAGCCATCTG

TTGCCCAGCC

CTGCTCAAGT

GCTCCAGGAG

TGGTGCTGCT

TGCCCCAGCC

CGGCCTTTTC

CCGAGTTGGC

GCCACCACCA

NO: 109)

ACTTAAAGAG

GAAGACGTCT

GAGCTTCGTA

CAATTCTTCG

TCTCGACATC

AAAACTGACG

ACGTAGAGGG

AC TAT CAAC C

GGCTATGGCC

CCTCTGCTTT

CAGAGCTTCC

CACACCATTG

CTTTAGAGCA

AAGCTGTGTG

CGGACACTCT

AGGCCCTGCA

CTCTACCAGG

TCCCACCTTG

TCTGGCAGCA

PMON1319 6 1 51 101 151 201 251 301 351 401 451 501 551 601 651

ATGGCTAACT

ACCACCTGCA

CTATCCTGAT

AGGGCTGTCA

TAATCTCCAA

CAATCATCAT

TTCTATCTGC

CGGTGGAGGC

CCCAGGGTGC

GGGGTCCTGG

C GTTC TAOCC

TGCCCCAGAG

GGCGATGGCG

CCACCCCGAG

GCTCTATAAT

CCTTTGCTGG

GGACCGAAAC

AGAACTTAGA

CCATGTCTGC

CAAGGCAGGT

TTACCCTTGA

TCCCCGGGTG

CATGCCGGCC

TTGCTAGCCA

CACCTTGCGC

CTTCCTGCTC

CAGCGCTCCA

GAGCTGGTGC

GATCGATGAA

AC CC GAACAA CTTC GAOTT C

AAATGCATCA

CCTCTGCCAC

GACTGGCALAG

GCAAGCGCAG

GTGGTTCTGG

TTCGCCTCTG

TCTGCAGAC

AG CCC ACAC C

AAGTCTTTAG

GGAGAAGCTG

TGCTCGGACA

ATTATACATC

CCTCAATGAC

CAAACCTGGA

GGTATTGAGG

GGCCGCACCC

ALATTCCGGGA

GAACAACAGT

CGCCGGCTCC

CTTTCCAGCG

TTCCTGGAGC

ATTGGGCCCT

AGCAAGTGAC

TGTGCCACCT

CTCTCTGGGC

ACTTAAAGAG

GAAGACGTCT

GACCTTCGTA

CALATTCTTCG

TCTCGACATC

AAAACTCACG

ACCTACAGGC

AACATGGCTA

CCCCGC ACCA

TGTCGTACCC

CCAG CTCC C

AAAGATCCAC

ACAAGCTGTG

ATCCCCTGGC

WO 97/12985 PCTIUS96/15774 701 751 801 851 901

CTCCCCTGAG

AGCCAACTCC

GGAAGGGATA

AC GTC GCC GA

ATGGCCCCTG

CTCCTGCCCC

ATAGCGGCCT

TCCCCCGAGT

CTTTGCCACC

CCCTGCAGCC

AGCCAGGCCC TGCAGCTGGC AG GCTGCTTG TTTCCTCTAC CAGGGGCTCC

TGCAGGCCCT

TGGGTCCCAC CTTGGACACA

CTGCAGCTGG

ACCATCTGGC AGCAGATGGA

AGAACTGGGA

CTAATAA (SEQ ID NO:110) PMON13 197 1 51 101 151 201 251 301 351 401 451 501 551 601 651 701 751 801 851 901 951

ATGGCTAACT

ACCACCTGCA

CTATCCTGAT

AGGGCTGTCA

TAATCTCCAJ\

CAATCATCAT

TTCTATCTGG

CGGTGGAGGC

CGTCTCCTCC

GGTGCCATGC

CCTGGTTGCT

TACGCCACCT

CAGAGCTTCC

TGGCGCAGCG

CCGAGGAGCT

CTGACCTCCT

ACTCCATAGC

GGATATCCCC

GCCGACTTTG

CCCTGCCCTG

GCTCTATAAT

CCTTTGCTGG

GGACCGAAAC

AGAACTTAGA

CCATGTCTGC

CAAGGCAGGT

TTACCCTTGA

TCCCCGGGTG

GTCTAAAGAA

CGGCCTTCGC

AGCCATCTGC

TGCGCAGCCC

TGCTCAAGTC

CTCCAGGAGA

GGTGCTGCTC

GCCCCAGCCA

GGCCTTTTCC

CGAGTTGGGT

CCACCACCAT

CAGCCCTAAT

GATCGATGAA

ACCCGAACAA

CTTCGACTTC

AAATGCATCA

CCTCTGCCAC

GACTGGCAAG

GCAAGCGCAG

AACCGTCTGG

TCTCATAAAT

CTCTGCTTTC

AGAGCTTCCT

ACACCATTGG

TTTAGAGCAA

AG CTGT GTG C

GGACACTCTC

GGCCCTGCAG

TCTACCAGGG

CCCACCTTGG

CTGGCAGCAG

AA (SEQ ID

ATTATACATIC

CCTCAATGAC

CAAACCTGGA

GGTATTGAGG

GGCCGCACCC

AATTCCGGGA

GAACAACAGT

TCCAATCTCT

CTCCAAACAT

CAGCGCCGGG

GGAGGTGTCG

GCCCTGCCAG

GTGAGAAAGA

CACCTACAAG

TGGGCATCCC

CTGGCAGGCT

GCTCCTGCAG

ACACACTGCA

ATGGAAGAAC

NO: 111)

ACTTAAAGAG

GAAGACGTCT

GAGCTTCGTA

CAATTCTTCG

TCTCGACATC

AAAACTGACG

ACGTAGAGGG

AC TAT CAAC C

GGCTACCCAG

CAGGAGGGGT

TACCGCGTTC

CTCCCTGCCC

TCCAGGGCGA

CTGTGCCACC

CTGGGCTCCC

GCTTGAGCCA

GCCCTGGAAG

GCTGGACGTC

TGGGAATGGC

PMON13 198 1 51 101 151 201 251 301 351 401 451 501 551 601 651 701 751 801 851 901

ATGGCTAACT

ACCACCTGCA

CTATCCTGAT

AGGGCTGTCA

TAATCTCCAA

CAATCATCAT

TTCTATCTGG

CGGTGGAGGC

CTGCTTTCCA

AGCTTCCTGG

ACCATTGGGC

TAGAGCAAGT

CTGTGTGCCA

ACACTCTCTG

CCC TG CAG CT

TACCAGGGGC

CACCTTGGAC

GGCAGCAGAT

GGTGCCATGC

GCTCTATAAT

CCTTTGCTGG

GGACCGAAAC

AGAACTTAGA

CCATGTCTGC

CAAGGCAGGT

TTACCCTTGA

TCCCCGGGTG

GCGCCGGGCA

AGGTGTCGTA

CCTGCCAGCT

GAGAAAGATC

CCTACAAGCT

GGCATCCCCT

GGCAGGCTGC

TCCTGCAGGC

ACACTGCAGC

GGAAGAACTG

CGGCCTTCGC

GATCGATGAA

ACCCGAACAA

CTTCGACTTC

AAATGCATCA

CCTCTGCCAC

GACTGGCAAG

GCAAGCGCAG

GTGGTTCTGG

GGAGGGGTCC

CCGCGTTCTA

CCCTGCCCCA

CAGGGCGATG

GTGCCACCCC

GGGCTCCCCT

TTGAGCCAAC

CCTGGAAGGG

TGGACGTCGC

ATTATACATC

CCTCAATGAC

CAAACCTGGA

GGTATTGAGG

GGCCGCACCC

AATTCCGGGA

GAACAACAGT

CGGCGGCTCC

TGGTTGCTAG

CGCCACCTTG

GAGCTTCCTG

GCGCAGCGCT

GAGGAGCTGG

GAGCTCCTGC

TCCATAGCGG

ATATCCCCCG

CGACTTTGCC

ACTTAAAGAG

GAAGACGTCT

GAGCTTCGTA

CAATTCTTCG

TCTCGACATC

AAAACTGACG

ACGTAGAGGG

AACATGGCTT

CCATCTGCAG

CGCAGCCCAC

CTCAAGTCTT

CCAGGAGAAG

TGCTGCTCGG

CCCAGCCAGG

CCTTTTCCTC

AGTTGGGTCC

ACCAC CATCT

GCCCACCCAG

CTAATAA (SEQ ID NO:112) WO 97/12985 PCTIUS96/I 5774 PMON13 199 1 51 101 151 201 251 301 351 401 451 501 551 601 651 701 751 801 851 901 951 ATG CC TAAC T

ACCACCTGCA

CTATCCTGAT

AGGGCTGTCA

TAATCTCCAA

CAATCATCAT

TTCTATCTGG

GTCGAGGC

C OTCTOCCTOC TTCCAGCGcc

CCTGGAGGTG

TGGGCCCTGC

CAAGTGAGAA

TGCCACCTAC

CTCTGGGCAT

CAGCTGGCAG

GGGGCTCCTG

TGGACACACT

CAGATGGAAG

CATGCCGGCC

GCTCTATAAT

CCTTTGCTGG

GGACCGAAAC

AGAACTTAGA

CCATGTCTGC

CAAGGCAGGT

T TAC CC T TGA

TCCCCGGGTG

GTCTAAAGAA

GGGCAGGAGG

TCGTACCGCG

C AGCTC C CTG

AGATCCAGGG

AAGCTGTGCC

CCCCTGGGCT

GCTGCTTGAG

CAGGCCCTG

GCAGCTGGAC

AACTGGGAAT

TTCGCCTAAT

GATCCATGAA

ACCCGAACAA

CTTCGACTTC

AAATGCATCA

CCTCTGCCAC

GACTGGCAAG

GCAAGCGCAG

AACCGTCTGG

TCTCATAAAT

GGTCCTGGTT

TTCTACGCCA

CCCCAGAGCT

CGATGGCGCA

ACCCCGAGGA

CCCCTGAGCT

CCAACTCCAT

AAGGGATATC

GTCGCCGACT

GGCCCCTGCC

AA (SEQ ID

ATTATACATC

CCTCAATGAC

CAAACCTGGA

GGTATTGAGG

GGCCGCACCC

AATTCCGGGjA

GAACAACAGT

TCCAATCTCT

CTCCAAACAT

GCTAGCCATC

CCTTGCGCAG

TCCTGCTCA

GCGCTCCAGG

GCTGGTGCTG

CCTGQCCCAG

AGCGGCCTTT

CCCCGAGTTG

TTGCCACCAC

CTGCAGCCCA

NO: 113)

AACTTAAAGAGT

GAGCTTCGTA

CAATTCTTCG

TCTCGACATC

AAAACTGACG

ACGTAGAGGG

ACTATCAACC

GGCTTCTGCT

TGCAGAGCTT

CCCACACCAT

GTCTTTAGAG

AGAAGCTGTG

CTCGGACACT

CCAGGCCCTG

TCCTCTACCA

GCCCCAC

CT

CAT CT CGCAG

CCCAGGGTGC

pMON3 1112 1 51 101 151 201 251 301 351 401 451 501 551 601 651 701 751 801 851 901 951

ATGGCTAACT

GCCACCGCTG

ATATCCTAAT

CGTGCTGTCA

AAATCTCCTG

C AAT C CATAT

TTCTATCTGA

CGGTGGAGGC

CGTCTCCTCC

GGTGCCATGC

CCTGGTTGCT

TACGCCACCT

CTGCTCAAGT

GCTCCAGGAG

TGGTGCTGCT

TGCCCCAGCC

CGGCCTTTTC

CCGAGTTGGG

GCCACCACCA

GCAGCCCTAA

GCTCTAACAT

CCGCTGCTGG

GGACAATAAC

AGTCTCTGCA

CCATGTCTGC

CAAGGACGGT

AAACCTTGGA

TCCCCGGGTG

GTCTAAAGAA

CGGCCTTCGC

AGCCATCTGC

TGCGCAGCCC

CTTTAGACCA

AAGCTGTGTG

CGGACACTCT

AGGCCCTGCA

CTCTACCAGG

TCCCACCTTG

TCTGGCAGCA

GATCGATGAA

ACTTCAACAA

CTTCGTCGTC

GAATGCATCA

CGCTAGCCAC

GACTGGAATG

GAACGCGCAG

AACCGTCTGG

TCTCATAAAT

CTCTGCTTTC

AGAGCTTCCT

TCTGGCGGCT

AGTGAGAAAG

CCACCTACAA

CTGGGCATCC

GCTGGCAGGC

GGCTCCTGCA

GACACACTGC

GATGGAAGAA

ATCATCACCC

CCTCAATGGT

C AAACC TOGA

GCAATTGAGA

GGCCGCACC

AATTCCGTCG

GCTCAACAGT

TCCAATCTCT

CTCCAAACAT

CAGCGCCGGG

GGAGGTGTCG

CTGGCGGCTC

ATCCAGGGCG

GCTGTGCCAC

CCTGGGCTCC

TGCTTGAGCC

GGCCCTGGAA

AGCTGGACGT

CTGGGAATGG

ACCTGAAGCA

GAAGACCAAG

GGCATTCAAC

GCATTCTTAA

ACGCGACATC

TAAACTGACC

ACGTAGAGGG

AC TATCAAC

C

GGCTACCCAG

CAGGAGGGGT

TACCGCGTTC

TCAGAGCTTC

ATGGCGCAGC

CCCGAGGAGC

CCTGAGCTCC

AACTCCATAG

GGGATATCCC

CGCCGACTTT

CCCCTGCCCT

TAA (SEQ ID NO:114) pMON3 1113 ATGGCTAACT GCTCTAACAT GATCGATGAA ATCATCACCC

ACCTGAAGCA

GCCACCGCTG CCGCTGCTGG ACTTCAACAA CCTCAATGGT

GAAGACCAAG

WO 97/12985 WO 97/ 2985PCTIUS96/15774 101 151 201 251 301 351 401 451 501 551 601 651 701 751 801 851 901 951

ATATCCTGAT

CGTGCTCTCA

AAATCTCCTC

CAATCATCAT

TTCTATCTGA

CGGTGGAGC

CGTCTCCTCC

G CTC C ATC

CCTGCTTGCT

TACGCCACCT

CAGAGCTTCC

TGCCAGCG

CCGAGGAGCT

CTGAGCTCCT

ACTCCATAC

GGATATCCCC

GCCCACTTTG

CCCTGCCCTG

GGAAAATAAC

AGTCTCTGCA

C CATGCTC TGC

CCGTGACGGT

AAACCTTGGA

TCCCCGGGTG

GTCTAAAGAA

CGGCCTTCC

ACCCATCTC

TGCGCAGCCC

TCCTCAAGTC

CTCCAGCAGA

GGTGCTGCTC

GCCC CAG CCA

GGCCCTTTTCC

CGACTTGGGT

CCACCACCAT

CAGCCCTAAT

CTTCGTCGTC

GAATGCATC A

CCCTGGCCAC

GACTGGAATG

GAACGCGCAG

AACCCTCTGG

TCTCATAAAT

CTCTGCTTTC

AGAGCTTCCT

AC ACCAT TG C

TTTAGACCAA

AGCTGTGTC

GGACACTCTC

GGCCCTGCAG

TCTACCACGGG

CC CAC CTTG C

CTGGCAGCAG

AA (SEQ ID

CAAACCTCGA

CCAATTGAGA

GGCCGCACCC

AATTCCGTCC

GCTCAACAGT

TCCAATCTCT

CTCCAAACAT

CAGC GCCGCG

GCACGTCTCC

GCCCTGCCAG

CTGAGAAAGA

CACC TACAAC

TGGGCATCCC

CTGGCAGCCT

GCTCCTGCAC

ACACACTGCA

ATGGAAGAAC

NO: 115) GGC ATTCAAC

GCATTCTTA

ACGCGACATC

TAAACTGACC

ACGTAGAGGG

ACTATCAACC

GGCTACCCAG

CAGCAGCGGT

TACCGCCTTC

CTCCCTGCCC

TCCACGCCA

CTGTCCCACC

CTGCGCTCCC

GCTTGAGCCA

GCCCTGGAIAo

GCTGGACGTC

TGGGAATGGC

pMON31114 1 51 101 151 201 251 301 351 401 451 501 551 601 651 701 751 801 851 901 951

ATGGCTAACT

GCCACCGCTG

ATATCCTCAT

CGTGCTGTCA

AAATCTCCTG

CAATCATCAT

TTCTATCTCA

CCC TGGAGGC

CGTCTCCTCC

GGTCCATGC

CCTGGTTCCT

TACCCCACCT

CTCC TC AAGT

CCTCCAGCAG

TGGTGCTGCT

TGCCCCACC

CGGCCTTTTC

CCGACTTGGG

GCCACCACCA

GCACCCCTAA

CCTCTAACAT

CCCCTCCTCC

CCAAAATAAC

ACTCTCTCCA

CCATCTCTC

CCCTCACGCT

AAACCTTCCA

TCCCCCCCTC

CTCTAAACAA

CCCCCTTCC

ACCCATCTC

TCCCACCCC

CTTTACACCA

AAGCTGTCTG

CCCACACTCT

ACCCCCTCCA

CTCTACCACC

TCCCACCTTC

TCTCCCACCA

CATCGATGAA

ACTTCAACAA

CTTCCTCCTC

GAATCCATCA

CCCTCCCCAC

CACTGGAATC

CAACCCCAC

AACCCTCTCC

TCTCATAAAT

CTCTCCTTTC

ACACCTTCCT

TCTGCCCCT

ACTCACAAAC

CCACCTACAA

CTCCCCATCC

CCTCCCAGC

CCCTCCTCCA

CACACACTC

CATGGAACAA

ATCATCACCC

CCTCAATCCT

CAAACCTCGA

GCAATTCAGA

GCCCCACCC

AATTCCCTCG

GCTCAACACT

TCCAATCTCT

CTCCAAACAT

CACCCCCC

CCACCTCTCC

CTGCCCCTC

ATCCACCCCC

CCTCTCCCAC

CCTCCGCTCC

TCCTTGACC

CCCCCTCCAA

ACCTCCACCT

CTCCCAATCC

ACCTCAAGCA

GAACACCAAG

CCCATTCAAC

GCATTCTTAA

ACCACATC

TAAACTCACC

ACCTACACCC

ACTATCAACC

CCCTACCCAG

CACCACCCCT

TACCCTTC

TCACACCTTC

ATGCCCAC

CCCCACAC

CCTCAGCTCC

AACTCCATAG

CCCATATCCC

CCCCACTTT

CCCCTGCCCT

TAA (SEQ ID NO:116) PMON3 1115 1 51 101 151 201 251 301

ATCCCTAACT

CCACCGCTC

ATATCCTAAT

CCTCCTCTCA

AAATCTCCTC

CAATCCATAT

TTCTATCTGA

CCTCTAACAT

CCCCTCCTCC

CCACAATAAC

AGTCTCTCCA

CCATGTCTC

CAACCACGGT

AAACCTTCCA

CATCGATCAA

ACTTCAACAA

CTTCCTCCTC

CAATCCATCA

CCCTACCCAC

CACTCCAATC

CAACC C AC ATCATCAC CC

CCTCAATGGT

CAAACCTCCA

CCAATTCACA

CGCC CCACCC

AATTCCCTCC

CCTCAACAGT

ACCTCAACCA

CAAGACCAAC

CCCATTCAAC

CCATTCTTAA

ACC AC AT C

TAAACTCACC

ACCTAGACCC

WO 97/12985 PCTIUS96/1 5774 351 401 451 501 551 601 651 701 751 801 851 901 951

CGGTGGAGGC

CGTCTCCTCC

GGTGCCATGC

CCTGGTTGCT

TAOCCCAC

CT

CACAGCTTC

TGGCGCAGCG

CCGAGGAGCT

CTGAGCTCCT

ACTCCATAGC

GGATATCCCC

GCCGACTTTG

CCCTGCCCTG

TCCCCGGGTG

GTCTAAAGAA

CGGCCTTCGC

AGCCATCTGC

TGCGCAGCCC

TGCTCAAGTC

CTCCAGGAGA

GGTGCTGCTC

GCCCCAG CCA

GGCCTTTTCC

CGAGTTGGGT

CCACCACCAT

CAGCCCTAAT

AACCGTCTGG

TCTCATAAAT

CTCTGCTTTC

AGAGCTTCCT

AC AC CATTGG

TTTAGAGCAA

AGCTGTGTGC

GGACACTCTC

GGCCCTGCAG

TCTACCAGGG

CCCACCTTGG

CTGGCAGCAG

AA (SEQ ID

TCCAATCTCT

CTCCAAACAT

CAGCGCCGGG

GGAGGTGTCG

GCCCTOCCAG

GTGAGAAAGA

CACCTACAAG

TGGGCATCCC

CTGGCAGGCT

GCTC CTGCAG

ACACACTGCA

ATGGAAGAAC

NO: 117)

A:CTATCAACC

CAGGAGGCGT

TACCGCGTTC

CTCCCTGCCC

TCCAGGGCGA

CTGTGCCACC

CTGGGCTCCC

GCTTGAGCCA

GCCCTGGAAG

GCTGGACGTC

TGGGAATGGC

PMON2 8505

GCTAACTGCTCTATAATGATCGATGATTATACATCACTTAAGAGACCACCGAT

TTGCTGGACCCGAACAACCTCAATGACGAGACGTCTCTATCCTGATGGACGACT

CGACTTCCAAACCTGGAGAGCTTCGTAGGGCTGTCAGAACTTAG~AATGCTAG

ATTGAGGCAATTCTTCGTATCTCCAJCCATGTCTGCCCTCTGCCACGGCCGCCCC

CGCTCACTACAGAGGCTGAGATCGAAATAGT

TATCTGGTTACCCTTGAGCAGCGCAGGAACACAGTACGTAGAGGGCGGTGGGCC

CCGGGTGAACCGTCTGGTCCAATCTCTACTATCAJACC

CGTCTCCTCCGTCTAAAGAJATCT

CATAAATCTCCAAACATGGAGGTTCACCCTTTGCCTACACCTGTCCTGCTGCCTGTG

GACTTTAGCTTGGGAGAJATGGAAAACCCAGATGGAGGAGACCAAGGCACAGGACATTT

GGAGCAGTGACCCTTCTGCTGGAGGGAGTGATGGCAGCACGGGGACAJACTGGGACAT

TGCCTCTCATCCCTCCTGGGGCAGCTTTCTGGACAGGTCCGTCTCCTCCTTGGGGCCT

CAGAGCCTCCTTGGAACCCAGCTTCCTCCACAGGGCAGGACCACAGCTCACAAGGATC

AATGCCATCTTCCTGAGCTTCCAACACCTGCTCCGAGGAAGGTGCGTTTCCTGATGCT

GTAGGAGGGTCCACCCTCTGCGTCAGGGATTCGGCGGCAACATGGCGTCTCCCGCTC

CCTGCTTGTGAC

CTCCGAGTCCTCAGTAAACTGCTTCGTGACTCCCATGTCCTTCACAGC

AGACTGAGCCAGTGCCCA (SEQ ID NO:118) pMON28506

GCTAACTGCTCTATAATGATCGATGAATTATACATCACTTAAJGAGACCACCTGCACCT

TTGCTGGACCCGAACAAC

CTCAATGACGAAGACGTCTCTATCCTGATGGACCGAAACCTT

CGACTTCCAAACCTGGAGAGCTTC

GTAAGGGCTGTCAAGAACTTAGJAJAATGCATCAGGT

ATTGAGGCAATTCTTCGTATCTCCAJACCATGTCTGCCCTCTGCCACGGCCGCACCCTCT

CGCTCACTACAGAGGCGCLGATCGAAATAGT

TATCTGGTTACCCTTGAGCAAGCGCAGGAACACAGTACGTAGAGGGCGGTGGAGGCTCC

CCGGGTGAACCGTCTGGTCCAATCTCTACTATCAACCCGTCTCCTCCGTCTAAGAJATCT

CATAAATCTCCAAACATGTTGCCTACACCTGTCCTGCTGCCTGCTGTGGACTTTAGCTTG

GGAGAATGGAAAACCCAGATGGAGGAGACCAAGGCACAGGACATTCTGGGAGCAGTGACC

CTTCTGCTGGAGGGAGTGATGGCAGCACGGGGACAACTGGGAC

CCACTTGCCTCTCATCC

CTCCTGGGGCAGCTTTCTGGACAGGTCCGTCTCCTCCTTGGGGCCCTGCAGAGCCTCCTT

GGAACCCAGCTTCCTCCACAGGGCAGGACCACAGCTCACALAGGATCCCAATGCCATCTTC

CTGAGCTTCCAACACCTGCTCCGAGGAAGGTGCGTTTCCTGATGCTTGTAGGAGGGTCC

ACCCTCTGCGTCAGGGAJTTCGGCGGCAACATGGCGTCTCCCGCTCCGCCTGCTTGTGAC

CTCCGAGTCCTCAGTAACTGCTTCGTGACTCCCATGTCCTTCACAGCAGACTGAGCCAG

TGCCCAGAGGTTCACCCT (SEQ ID NO:119) WO 97/12985 PCTIUS061, C'T'7A 105 PMON2 8507 GCTAACTGCTCTATAATGATCGATGATTATACATCACTTAGAGAC

CACCTGCACCT

TTGCTGGACCCGAACACCTCATGACGAGACGTCTCTATCCTGATGGACCGAACT

CGACTTCCAACCTGGAGAGCTTCGTAGGGCTGTCAAGACTTAGAATGCATAG

ATTGAGGCATTCTTCGTATCTCCAJACCATGTCTGCCCTCTGCCACGGCCGCACCC

CGCTCACTACAGAGGCTGAGATCGAAATAGT

TACGTACTGGAGGAGACAATCTGGGGTGGCC

CCGGGTGAACCGTCTGGTCCATCTCTACTATCACCCGTCTCCTCCGTCTAAGJ

TC

CATAAATCTCCAAACATGGTCCTGCTGCCTGCTGTGGACTTTAGCTTGGGAGAAGAA

ACCCAGATGGAGGAGACCAAGGCACAGGACATTCTGGGAGCAGTGACCCTTCTGCGA

GGAGTGATGGCAGCACGGGGACAACTGGGACCCACTTGCCTCTCATCCCTCCTGGGA

CTTTCTGGACAGGTCCGTCTCCTCCTTGGGGCCCCTGCAGAGCCTCCTTGACCCGT

CCTCCACAGGGCAGGACCACAGCTCACAJAGGATCCCAATGCCATCTTCCTGAGCTCA

CACCTGCTCCGAGGAAI\GGTGCGTTTCCTGATGCTTGTAGGAGGGTCCACCCTCTCC

AGGGAATTCGGCGGCAACATGGCGTCTCCCGCTCCGCCTGCTTGTGACCTCCGAGCT

AGTAAACTGCTT'CGTGACTCCCATGTCCTTCACAGCAGACTGAGCCAGTGCCCAGGT

CACCCTTTGCCTACACCT (SEQ ID NO:120) pMON28508

GCTAACTGCTCTATAATGATCGATGAATTATACATCACTTAAGAGACCACCTGCCCT

TTGCTGGACCCGAACACCTCAATGACGAGACGTCTCTATCCTGATGGACCGAAACCT

CGACTTCCAACCTGGAGAGCTTCGTAGGGCTTCAAGACTTAGAATGCATCAGG

ATTGAGGCAATTCTTCGTATCTCCACCATGTCTGCCCTCTGCCACGGCCGCACCCTC

CGACATCCAATCATCATCAGGCAGGTGACTGGCGTTCCGGGAACTGACGTTC

TATCTGGTTACCCTTGAGCAAGCGCAGGAACACAGTACGTAGAGGGCGGTGGAGGCTCC

CCGTAACTTGCATTTCATACCTTCCGCAAAAC

CATAAATCTCCAACATGGCTGTGGACTTTAGCTTGGGAGATGGAAACCCAGATGGAG

GAGACCALAGGCACAGGACATTCTGGGAGCAGTGACCCTTCTGCTGGAGGGAGTGATGGCA

GCACGGGGACAACTGGGACCCACTTGCCTCTCATCCCTCCTGGGGCAGCTTTCTGGACAG

GTCCGTCTCCTCCTTGGGGCCCTGCAGAGCCTCCTTGGAACCCAGCTTCCTCCACAGGGC

AGGACCACAGCTCACAJAGGATCCCAATGCCATCTTCCTGAGCTTCCAAkCACCTGCTCCGA

GGAAAGGTGCGTTTCCTGATGCTTGTAGGAGGGTCCACCCTCTGCGTCAGGGAATTCGGC

GGCAACATGGCGTCTCCCGCTCCGCCTGCTTGTGACCTCCGAGTCCTCAGTACTGCTT

CGTGACTCCCATGTCCTTCACAGCAGACTGAGCCAGTGCCCAGAGGTTCACCCTTTGCCT

ACACCTGTCCTGCTGCCT (SEQ ID NO:121) pMON28509

GCTAACTGCTCTATAATGATCGATGAATTATACATCACTTAAAGAGACCACCTGCACCT

TTCGACGAACTATAGAGCTTTTCGTGCGACT

CGCTCACTGGGTCTAGGTTAGATAAATCTAG

ATTGAGGCAATTCTTCGTAATCTCCAACCATGTCTGCCCTCTGCCACGGCCGCACCCTCT

CGACATCCAATCATCATCAGGCAGGTGACTGGCGTTCCGGGACTGACGTTC

TATCTGGTTACCCTTGAGCkJAGCGCAGGAJACCAGTACGTAGAGGGCGGTGGAGGCTCC

CCGTACGCGTCACCATACACGCCTCTTAGAC

CAAACCAAAGATTGTGGAATGAACAAGAGGC

AAGGCACAGGACATTCTGGGAGCAGTGACCCTTCTGCTGGAGGGAGTGATGGCAGCACGG

GGACAACTGGGACCCACTTGCCTCTCATCCCTCCTGGGGCAGCTTTCTGGACAGGTCCGT

CTCCTCCTTGGGGCCCTGCAGAGCCTCCTTGGJACCCAGCTTCCTCCACAGGGCAGGACC

WO 97/1 2985 PC'r/TTQogiic"-y 106 CfcoiA

ACAGCTCACAAGGATCCCATGCCATCTTCCTGAGCTTCCAJACACCTGCTCGGAA

GTGCGTTTCCTGATGCTTGTAGGAGGGTCCACCCTCTGCGTCAGGGAATTCGGGCA

ATGGCGTCTCCCGCTCCGCCTGCTTGTGACCTCCGAGTCCTCAGTAACGTGGC

TCCCATGTCCTTCACAGCAGACTGAGCCAGTGCCCAGAGGTTCACCCTTTGCAAC

GTCCTGCTGCCTGCTGTG (SEQ ID NO:122) pMON2 8510 GCTAAC TGC TCTATAATGATCGATGAAATTATACATCACTTAAAGAGACCACCTGAC

TTCGACGAACTATAGAGCTTTTCGTGCGACT

CGACTTCCAAACCTGGAGAGCTTC GTAAGGGCTGTCAAGACTTAGAAATGCATCAGG3T

ATTGAGGCATTCTTCGTATCTCCAJACCATGTCTGCCCTCTGCCACGGCACTT

CGCTCACTACAGAGGCTGAGATCGAAATAGT

TATGGTACCTTGAGCAAGCGCAGGAJACAJACAGTACGTAGAGGGCGGTGGAGGCTC

CGGGGAACCGTCTGGTCCAATCTCTACTATCAACCCGTCTCCTCCGTCTAAAATCC

TAAACTCCAACATGGAGATGGAACC

CAGATGGAGGAGACCAJAGGCACAGGACATT

CTGGAGCACTGAC

CCTTCTGCTGGAGGGAGTGATGGCAGCACGGGGACAACTGGGACCC

CTTGCTCTCATCCCTCCTGGGGCAGCTTTCTGOACAGGTCCGTCTCCTCCTGGCT

GAGCTCCTTGGAACCCAGCTTCCTCCACAGGGCAGGACCAAGCTCACAAGTC

ATGCATCTTCCTGAGCTTCCACACCTGCTCCGAGGAAJAGGTGCGTTTCCGTTG

TAGGGGGTCCACCCTCTGCGTCAGGGAJATTCGGCGGCAJACATGGCGTCTCGCGC

TGCTTGACTCCAGTCTCAGTAAACTGCTTCGTGACTCCCATGTCCTTCACAGCAGA

CTGACCAGTGCCCAGAGGTTCACCCTTTGCCTACACCTGTCCTGCTGCCTGTTGC

TTAGTTG (SEQ ID NO:123) pMON2 8511

GCTAACTGCTCTATAATGATCGATGAATTATACATCACTTAAAGAGACCACGCT

TTCGACGLCACCAGCAGCTTTTCGTGCGACT

CGCTCACTGGGTCTAGCGCAACTGAATCTAG

ATTGAGGCAATTCTTCGTATCTCCAACCATGTCTGCCCTCTGCCACGGCCGC

CCTCT

CGACATCCAATCATCATCAGGCAGTGACTGGCGTTCCGGGAJCGAGT

TATCTGGTTACCCTTGAGCAAGCGCAGGAJACACAGTACGTAGAGGGCGGTGGAGCC

CCGGGTGAACCGTCTGGTCCAATCTCTACTATCAACCCGTCTCCTCCGTCTAGTC

CATAAATCTCCAAACATGGGACCCACTTGCCTCTCATCCCTCCTGGGGCAGCTTTCCGG

CAGGTCCGTCTCCTCCTTGGGGCCCTGCAGAGCCTCCTTGGAJACCCAGCTTCCTCCACAG

GGCAGGACCACAGCTCACAAGGATCCCAATGCCATCTTCCTGAGCTTCCAACACC

TGCTC

CGAGGAAAGGTGCGTTTCCTGATGCTTGTAGGAGGGTCCACCCTCTGCGTCAGGGAT

GGCGGCAACATGGCGTCTCCCGCTCCGCCTGCTTGTGACCTCCGAGTCCTCAGTAACTG

CTTCGTGACTCCCATGTCCTTCACAGCAGACTGAGCCAGTGCCCAGAGGTTCACCCTTT

CCTACACCTGTC

CTGCTGCCTGCTGTGGACTTTAGCTTGGGAGAATGGAAAACCCAGATG

GAGGAGACCAAGGCACAGGACATTCTGGGAGCAGTGACCCTTCTGCTGGAGGGAGTGAT

GCGAGGGCAT (SEQ ID NO:124) pMON28512 GCTAAC TGCTCTATAATGATCGATGAAATTATACATCACTTAAAGAGAC

CACCTGCACCT

TTCGACGAACTATAGAGCTTTTCGTGCGACT

CGACTTCCAAACCTGGGTCTAGCGCAGATAAATCTAG

ATTGAGGCAATTCTTCGTJATCTCCAACCATGTCTGCCCTCTGCCACGGCCGCACCCT

CGCTCLTACTAGCGTATGAGATCGAAATAGT

TATCTGGTTACCCTTGAGCA3&GCGCAGGAACAACAGTACGTAGAGGGCGGTGGAGGCTCC WO 97/12985 DflIrfyTo WO 9712985107

CCGGGTGAACCGTCTGGTCCATCTCTACTATCAJACCCGTCTCCTCCGTTAGAC

CATAAATCTCCAAIACATGGGAACCCAGCTTCCTCCACAGGGCAGGACCAGCAAG

GATCCCAATGCCATCTTCCTGAGCTTCCACACCTGCTCCGAGGAAAGGGTCT

ATGCTTGTAGGAGGGTCCACCCTCTGCGTCAGGGATTCGGCGGCAACAGCTCC

GCTCCGCCTGCTTGTGACCTCCGAGTCCTCAGTAJAACTGCTTCGTGACTCAGCT

CACAGCAGACTGAGCCAGTGCCCAGAGGTTCACCCTTTGCCTACACCTGTCTTGT

GCTGTGGACTTTAGCTTGGGAGAATGGAAACCCAGATGGAGGAGACCAGCAGC

ATTCTGGGAGCAGTGACC

CTTCTGCTGGAGGGAGTGATGGCAGCACGGGGACAACTGGGA

CCCACTTGCCTCTCATCCCTCCTGGGGCAGCTTTCTGGACAGGTCCGTCTCCTCTG

GCCCTGCACAGCCTCCTT (SEQ ID NO:125) pMON2 8513

GCTAACTGCTCTATAATGATCGATGAATTATACATCACTTAAAGAGACACGAC

TTGCTGGACCCGAACACCTCAATGACGAGACGTCTCTATCCTGATGGCAACT

CGATTCAAACTGGAGAGCTTCGTAAGGGCTGTCAGAACTTAGAAAATGCATCAG

ATTGAGGCAATTCTTCGTAATCTCCACCATGTCTGCCCTCTGCCACGGCACTT

CGACATCCAATCATCATCAAGGCAGGTGACTGGCAAGATTCC

GGGAAAAACTGACGTTC

TATCTGGTTACCCTTGAGCAGCGCAGGAACACAGTACGTAGAGGGCGTAGCC

CCGGGTGAACCGTCTGGTCCAJ\TCTCTACTATCAACCCGTCTCCTCCGTAAGTC

CATAAATCTCCAACATGGGCAGGACCACAGCTCACAGGATCCCAATGCTTCG

AGCTTCCAACACCTGCTC

CGAGGAAAGGTGCGTTTCCTGATGCTTGTAGGAGGGTCCACC

CTCTGCGTCAGGGAATTCGGCGGCJACATGGCGTCTCCCGCTCCGCCTGCTTGGCT

CATCTCAGTAAACTGCTTCGTGACTCCCATGTCCTTCACAGCAGACTGACCAGG

CCAGAGGTTCACCCTTTGCCTACACCTGTCCTGCTGCCTCCTGTGGACTTTACCTTGG

GAATGGAAAACCCAGATGGAGGAGACCAJAGGCACAGGACATTC

TGGGAGCAGTGACCCTT

CTGCTGGAGGGAGTGATGGCAGCACGGGGACJACTGGGACCCACTTGCCTCTC

CCCTC

CTGGGGCAGCTTTCTGGACAGGTC

CGTCTCCTCCTTGGGGCCCTGCAGAGCCTCCTTGGA

ACCCAGCTTCCTCCACAG (SEQ ID NO:126) pMON2 8514

GCTAACTGCTCTATAATGATCGATGAAATTATACATCACTTAAAGAGACCACCGAT

TTGCTGGACCCGAACAJXCCTCAJATGACGAJAGACGTCTCTATCCTGATGGACCGAACT

CGCTCACTGGGTCTAGGTTAGATAAATCTAG

ATTGAGGCAATTCTTCGTATCTCCAACCATGTCTGC CCTCTGCCACGGCCGCAC

CCTCT

CGCTCACTACAGAGGCTGAGATCGAAATAGT

TATCTGGTTACCCTTGAGCAAGCGCAGGACACAGTACGTAGAGGGCGGAGCTC

CCGGGTGAACCGTCTGGTCCAJATCTCTACTATCAACC

CGTCTCCTCCGTCTJAGAATCT

CATAAATCTCCACATGGCTCACAGGATCCCATGCCATCTTCCTGAGCTTCCAAA

CTGCTCCGAGGAAAGGTGCGTTTCCTGATGCTTGTAGGAGGGTCCACCCTCTGCGCG

GAATTCGGCGG.CAACATGGCGTCTCCCGCTCCGCCTGCTTGTGACCTCCGAGTCCAG

AAACTGCTTCGTGACTCCCATGTCCTTCACAGCAGACTGAGCCAGTGCCCAGAGGTTA

CCTTTGCCTACACCTGTCCTGCTGCCTGCTGTGGACTTTAGCTTGGGAGATGGAAJAACC

CAGATGGAGGAGACCAJAGGCACAGGACATTCTGGGAGCAGTGACCCTTCTGCTGGAGG

GTGATGGCAGCACGGGGACAAJCTGGGACCCACTTGCCTCTCATCCCTCCTGGGGCAGCT

TCTGGACAGGTCCGTCTCCTCCTTGGGGCCCTGCAGAGCCTCCTTGGAACCCAGCTTC

CCACAGGGCAGGACCACA (SEQ ID NO:127) pM0N28515 WO 97/12985 PCT/YTQor-/ir 108 GCTAACTGCTCTATAATGATCGATGAATTATACA,

TCACTTAAGGCA:CGAC

TTGCTGGACCCGAACAACCTCAATGACGAAGACGTCTCTATCCTGTGCGACT

CATTACAATTCTGGAGGTTC

GTAGGGCTGTCAAG.AJCTTAGA-ATGCATCAGG

ATTAGGAATCTTGTATCTCAACCATCTCTGCCCTCTGCCACGCCCGCACCCTCT

CGACATCCAATCATCATCAAGGCAGGTGACTGGCAAGATTCCGGGAAJ

CGCGT

CATAATCTCCAACATGGATCCCAJATGCCATCTTCCTGAGCTTCACCTCCG

GGAAAGGTGCGTTTCCTGATGCTTGTAGGAGGGTCCACCCTCTGCGTAGATCG

GGCAACATGGCGTCTCCCGCTCCGCCTGCTTGTGACCTCCGAGCTATACGT

CGTGACTCCCATGTCCTTCACAGCAGACTGAGCCAGTGCCCAGAGTCCCTGC

ACACCTGTCCTGCTGCCTGCTGTGGACTTTAGCTTGGGAGAAGAACCAAGA

GAGACCAAGGCACAGGACATTCTGGGAGCAGTGACCCTTCTGCTGAGATAGC

GCACGGGGACAACTGGGACCCACTTGCCTCTCATCCCTCCTGGCA

TTTGCG

GTCCGTCTCCTCCTTGGGGCCCTGCAGAGCCTCCTTGGAACCCAGTCTCCGG

AGGACCACAGCTCA7AJAC (SEQ ID NO:128) pMON2 8516 GCTAACTGCTCTATAJATGATCGATGAAATTATACATCACTTAA6GCCCTGAC

TTGCTGGACCCGACACCTCATGACGAGACGTCTCTATCCTGTGCGACT

CGACTTCCAAACCTGGAGAGCTTCGTAGGGCTGTCAGACTTAA

ATCCGT

ATTGAGGCAATTCTTCGTAJATCTCCAACCATGTCTGCCCTCTGCCACGCCCCC

CGACATCCAATCATCATCAAGGCAGGTGACTGGCAAGATTCCGGGA

ACTCGC

TATCTGGTTACC'CTTGAGCAGCGCAGGACALCAGTACGTAGAGCGTAGTC

CCGGGTGAACCGTCTGGTCCAJ&TCTCTACTATCAJACCCGTCTCCTCCTAGTT

CATAAATCTCCAAACATGGCCATCTTCCTGAGCTTCCAJACACCTGCTCAGAGG

CGTTTCCTGATGCTTGTAGGAGGGTCCACCCTCTGCGTCAGGGAATGCGACT

GCGTCTCCCGCTCCGCCTGCTTGTGACCTCCGAGTCCTCAGTAAACTCCGATC

CATGTCCTTCACAGCAGACTGAGCCAGTGCCCAGAGGTTCACCCTTTCAACGC

CTGCTGCCTGCTGTGGACTTTAGCTTGGGAGATGGAJAJACCCAGATGGAACA

GCACAGGACATTCTGGGAGCAGTGACCCTTCTGCTGGAGGGAGTGATGACCGG

CAACTGGGACCCACTTGCCTCTCATCCCTCCTGGGGCAGCTTTCTGG

AGCGTCTC

CTCCTTGGGGCCCTGCAGAGCCTCCTTGGAACCCAGC

TTCCTCCACAGGCCAGGACCACA

GCTCACAAGGATCCCAAT (SEQ ID NO:129) pMON2 8519

GCTA-CTGCTCTATAATGATCGATGAATTATACATCACTTAAAGAGACACGAC

TTGCTGGACCCGACACCTCATGACGAGACGTCTCTATCCTGATGCAACT

CGACTTCCAACCTGGAGAGCTTCGTAGGGCTGTCAGCTTAGAATCTAG

ATTGAGGCAJATTCTTCGTAATCTCCAJACCATGTCTGCCCTCTGCCACGCCCCC

CGACATCCAATCATCATCAJAGGCAGGTGACTGGCAGJTTCCGGGAACTCGC

TATCTGGTTACCCTTGAGCAAGCGCAGGACAJCAGTACGTAGAGGGCGTGGCC

CCGGGTGAJACCGTCTGGTCCAJTCTCTACTATCACCCGTCTCCTCCTAGTT

CATAAATCTCCAPJACATGGAGGTTCACCCTTTGCCTACACCTGTCT

TGTCGG

GATTGTGGGAGAACCGAGAGGCAGCCGAATT

GGAGCAGTGACCCTTCTGCTGGAGGGAGTGATGGCAGCACGGGGAC-CGGCCC

TGCCTCTCATCCCTCCTGGGGCAGCTTTCTGGACAGGTCCGTCTCCTCTGGCT

CAGAGCCTCCTTGGAJ&CCCAGCTTCCTCCACAGGGCAGGACCACACAAGATC

AATGCCATCTTCCTGAGCTTCCIACACCTGCTCCGAGAAJAGGTGCGTCTAGT

GTAGGAGGGTCCACCCTCTGCGTCAGGGATTCGGCAACATGGCGTCCGTCCT

WO 97/12985 WO 97/12985PCT/US96/15~7'74 109

GCTTGTGACCTCCGAGTCCTCAGTAAACTGCTTCGTGACTCCCATGTCCTTCACAGCAGA

CTGAGCCAGTGCCCA (SEQ ID NO:130) pMON28520

GCTAACTGCTCTATAATGATCGATGAAATTATACATCACTTAAAGAGACCACCTGCACCT

TTCGACGAACTATAGAGCTTTTCGTGCGACT

CGACTTCCAAAC CTGCAGAGCTTC GTAAGGGCTGTCAAGAACTTAG-AATGCAT

CAGOT

ATTGAGGCAATTCTTCGTAATCTCCAACCATGTCTGCCCTCTGCCACGGCCGCACCCTCT

CGCTCACTACAGAGGCTGAGATCGAAATAGT

TATCTGGTTAC

CCTTGAGCAAGCGCAGGAACAACAGTACGTAGAGGGCGGTGGAGGCTCC

CCGGGTGAACCGTCTGGTCCATCTCTACTATCACCCTCTCCTCCGTCTAAGAATCT

CATAAATCTCCAAACATGTTGCCTACACCTGTCCTGCTGCCTGCTGTGGACTTTAGCTTG

GGAGAATGGAAAACCCAGATGGAGGAGACCAJAGGCACAGGACATTCTGGGAGCAGTGACC

CTTCTGCTGGAGGGAGTGATGGCAGCACGGGGACAAJCTGGGACCCACTTGCCTCTCATCC

CTCCTGGGGCAGCTTTCTGGACAGGTCCGTCTCCTCCTTGGGGCCCTGCAGAGCCTCCTT

GGAACC CAGCTTCCTCCACAGGGCAGGACCACAGCTCACAJGGATCCCAAJTGCCATCTTC

CTGAGCTTCCAACACCTGCTCCGAGGAAAGGTGCGTTTCCTGATGCTTGTAGGAGGGTCC

ACCCTCTGCGTCAGGGAATTCGGCAAJCATGGCGTCTCCCGCTCCGCCTGCTTGTGACCTC

CGAGTCCTCAGTAAACTGCTTCGTGACTCCCATGTCCTTCACAGCAGACTGAGCCAGTGC

CCAGAGGTTCACCCT (SEQ ID NO:131) pMON2 8521

GCTAACTGCTCTATAATGATCGATGATTATACATCACTTAAGAGACCACCTGCACCT

TTGCTGGACCCGAACAAC

CTCAATGACGAAGACGTCTCTATCCTGATGGACCGAAACCTT

CGACTTCCAAAC

CTGGAGAGCTTCGTAAGGGCTGTCAAGAJACTTAGAJATGCATCAGGT

ATTGAGGCAATTCTTCGTAATCTC CAACCATGTCTGCCCTCTGCCACGGCCGCAC

CCTCT

CGACATCCAATCATCATCAGGCAGGTGACTGGCGTTCCGGGAACTGACGTTC

TATCTGGTTACCCTTGAGCAGCGCAGGAAJCAACAGTACGTAGAGGGCGGTGGAGGCTCC

CCGGGTGAACCGTCTGGTCCAATCTCTACTATCAACCCGTCTCCTCCGTCTAAGAATCT

CATAATCTCCAAACATGGTCCTGCTGCCTGCTGTGGACTTTAGCTTGGGAGAATGGAAA

ACCCAGATGGAGGAGACCAAGGCACAGGACATTCTGGGAGCAGTGACCCTTCTGC

TGGAG

GGAGTGATGGCAGCACGGGGACAACTGGGACCCACTTGCCTCTCATCCCTCCTGGGGCAG

CTTTCTGGACAGGTCCGTCTCCTCCTTGGGGCCCTGCAGAGCCTCCTTGGAACCCAGCTT

CCCAAGCGACCGTAAGGTCATCACTCGGTCA

CACCTGCTCCGAGGAAAGGTGCGTTTCCTGATGCTTGTAGGAGGGTCCACCCTCTGCGTC

AGGGAATTCGGCAACATGGCGTCTCCCGCTCCGCCTGCTTGTGACCTCCGAGTCCTCAGT

AAACTGCTTCGTGACTCCCATGTCCTTCACAGCAGACTGAGCCAGTGCCCAGAGGTTCAC

CCTTTGCCTACACCT (SEQ ID NO:132) pMON2 8522, GCTAACTGCTCTATAATGATCGATGAAATTATACATCACTTAAAGAGAC

CACCTGCACCT

TTCGACG.CACCAGCAGCTTTTCGTGCGACT

CGACTTCCAAACCTGGAGAGCTTCGTAAGGGCTGTCAAGAACTTAGAAAATGCATCAGGT

ATTGAGGCAATTCTTCGTAATCTCCAACCATGTCTGCCCTCTGCCACGGCCGCACCCTCT

CGCTCACTACAGAGGCGCAATCGGAAATAGT

TACGTACTGGAGGAGACAATCTGGGGTGGCC

CCGTACGCGTCACCATACACGCCTCTTAGAC

CAAACCAAAGCGGATTACTGAATGAACAAGA

GAGACCAAGGCACAGGACATTCTGGGAGCAGTGACCCTTCTGCTGGAGGGAGTGATGGCA

WO 97/12985 DI-Irfirl 110 001//

GCACGGGGACAACTGGGACCCACTTGCCTCTCATCCCTCCTGGGGCACTTGCG

GTCCGTCTCCTCCTTGGCGCCCCTGCAGAGCCTCCTTGGAACCCAGCTCCAAGC

AGGACCACAGCTCACAAGGATCCCATGCCATCTTCCTGAGCTTCCACCTTCG

GGAAACGTGCGTTTCCTGATGCTTGTAGGAGGGTCCACCCTCTGCGTAGATCC

AACATGGCGTCTCCCCCTCCGCCTGCTTGTGACCTCCGACTCCTCAGTACTTCG

GACTCC CATGTC CTTCACAGCAGACTGAGC CAGTGCC

CAGAGGTTCACCCTTTGCCTACA

CCTGTCCTGCTGCCT (SEQ ID NO:133) pMON2 8523

GCTAACTGCTCTATAATGATCGATGAAATTATACATCACTTAAAGAGACACGAC

TTGCTGGACCCGACACCTCATGACGAGACTCTCTATCCTGATGCGACT

CGACTTCCAAACCTGGAGAGCTTC

GTAAGGGCTGTCAAGAACTTAGAAATGCATCAGGT

ATTGAGGCAATTCTTCGTAJATCTCCAJACCATGTCTGCCCTCTGCCACGGCCCC

CGACATCCAATCATCATCAAGGCAGGTGACTGGCAGAJTTCCGGGAAAATAGT

TATTGGTACCTTGAGCAAGCGCAGGAACACAGTACGTAGAGGGCGGTGGAGCC

CCGGGTGAACCGTCTGGTCCAATCTCTACTATCAACC

CGTCTCCTCCGTCTAAJAGATCT

CATAAATCTCCAA7CATGGACTTTAGCTTGGGAGATGGAAAACCCAAGAGGC

AAGGCACAGGACATTCTGGGAGCAGTGACCCTTCTGCTGGAGCLGAGTAGCCCG

GGACAACTGGGACCCACTTGCCTCTCATCCCTCCTGGGGCAGCTTTCTGAAGCG

CTCCTCCTTGGGGCCCTGCAGAGCCTCCTTGGAACCCAGCTTCCTCCCGGAGC

ACAGCTCACAAGGATCCCATGCCATCTTCCTGAGCTTCCAACACCTCCGGAG

GTGCGTTTCCTGATGCTTGTAGGAGGGTCCACCCTCTGCGTCAGGATCCAAG

GCGTCTCCCGCTCCGCCTGCTTGTGACCTCCGAGTCCTCAGTAAACTGCTTGGCC

CATGTCCTTCACAGCAGACTGAGCCAGTGCCCAGAGGTTCACCCTTTGCTCCTT

CTCCTCCCTGCTGTG (SEQ ID NO:134) pMON2 8524

GCTAACTGCTCTATATGATCGATGAATTATACATCACTTAAGAGACCACCTGAC

TTCGACGAACTATAGAGCTTTTCGTGCGACT

CGCTCACTGGGTCTAGGTTAGATAAATCTAG

ATTGAGGCALTTCTTCGTAATCTC

CAACCATGTCTGCCCTCTGCCACCGCCGCACCCTCT

CGCTCACTACAGAGGCTGAGATCGAAATAGT

TATCTGGTTACCCTTGAGCALGCGCAGGAJACACAGTACGTAGAGGGCGGTGGCC

CCGGGTGAACCGTCTGGTCCAATCTCTACTATCAACC

CGTCTCCTCCGTCTAAAJGAJATCT

CATAAATCTCCAAACATGGGAGAATGGAAACCCAGATGGAGGAGACCAAGGCACGA

ATTCTGGGACCAGTGACCCTTCTGCTGGAGGGAGTGATGGCAGCACGGGGAACGA

CCCACTTGCCTCTCATCCCTCCTGGGGCAGCTTTCTGGACAGGTCGTCCTGG

GCCCTGCAGAGCCTCCTTGGJAACCCAGCTTCCTCCACAGGGCAGGACCACCTCCA

GATCCCAATGCCATCTTCCTGAGCTTCCAJCACCTGCTCCGAGGGGTGGTCT

ATGCTTGTAGGAGGGTCCACCCTCTGCGTCAGGGAATTCGGCAACATGGCGCCCC

CCGCCTGCTTGTGACCTCCGAGTCCTCAGTAAJACTGCTTCGTGACTCCCATTCTA

AGCAGACTGAGCCAGTGCCCAGAGGTTCACCCTTTGCCTACACCTGTCCGTCGT

GTGGACTTTAGCTTG (SEQ ID NO:135) pMON2 8525

GCACGTTTAGTGTAATAAACCTAGGCACGAC

TTCGACGAACTAAGCAGCTTTTCGTGCGACT

CGACTTCCAAAC

CTGGAGAGCTTCGTAAGGGCTGTCAAGAACTTAGAAAATGCATCAGGT

ATTGAGGCAATTCTTCGTATCTCCACCATGTCTGCCCTCTGCCACGGCCGCACCCTCT

WO 97/12985 DrIIrfFTv WO 97/1W2985/14

CCGGGTGACCGTCTGCTCCAATCTCTACTATCACCCGTCTCCGT-AATT

CATAAATCTCCAAACATGGGACCCACTTGCCTCTCATCCCTCCGGACTCGA

CAGGTCCGTCTCCTCCTTGGGGCCCTGCACAGCCTCCTTGGAACACTCCAA

GGCAGGACCACAGCTCACAAGGATCCCATGCCATCTTCCTGAGCTCAACGT

CGAGGAAAGGTGCGTTTCCTGATGCTTGTAGGAGGGTCCACCCTCGGCGGAT

GGCAACATGGCGTCTCCCGCTCCGCCTGCTTGTGACCTCCGAGCTAAATCT

CGTGACTCCCATGTCCTTCACAGCAGACTGAGCCAGTGCCCAGAGTCCCTGC

ACACCTGTCCTGCTGCCTGCTGTGGACTTTAGCTTGGGAGAAGAACCAAGA

GAGACCAAGGCACAGGACATTCTGGGAGCAGTGACCCTTCTGCGAGATAGC

GCACGGGGACAACTG (SEQ ID NO:136) pMON2 8526 TTCTGACCGACAcATCATGA~CGAGACTCTTCTATGCCAAC

CGATTCAAACTGAGACTTGTAAGGGCTGTCAAGAACTTAGAAAATGCATCAGGT

ATTGAGGCAATTCTTCGTAJATCTCCAACCATGTCTCTTGAGCGACTT

COACATCATACTAGCGTATGAGATCGAAAGCTC

TATCTGGTTACCCTTGAGCAGCGCAGGAACACAGTACGTGGCGGAGTC

CCGGGTGACCGTCTGGTCCAATCTCTACTATCACCCGTCTCCTCTTAGAC

CATAAATCTCCAAACATGGACCCAGCTTCCTCCACAGGGCAGCCGTAAA

GATCCCAATGCCATCTTCCTGAGC

TTCCAACACCTGCTCCGAGGAJ.AQGTGCCTTTCCTG

ATGCTTGTAGGAGGGTCCACCCTCTGCGTCAGGGAJATTCGGC;AAGCTCCCC

CCGCCTGCTTGTGACCTCCGAGTCCTCAGTACTGCTTCGTGACCCTTCTA

AGCAGACTGAGCCAGTGCCCAGAGGTTCACCCTTTGCCTACACCTCTGGCGT

GTGCTACTGAATGAACCGTGGAACAGAAGCT

CTGGGAGCAGTGACCCTTCTGCTGGAGGGAGTGATGGCAGCACGGACCTGCC

ACTTGCCTCTCATCCCTCCTGGGGCAGCTTTCTGGACAGGTCCTCTCTGGC

CTGCAGAGCCTCCTT (SEQ ID NO:137) pMON2 8527

GCTAACTGCTCTATAATGATCGATGAATTATACATCACTTAAAGAGCACGAC

TTGCTGGACCCGAACAkC

CTCAATGACGAAGACGTCTCTATCCTGATGGACCGAAACCTT

CGACTTCCAAJC CTGGAGAGCTTCGTAAGGGCTGTCAAGkJACTTAGAAAATGCATCAG ATTGAGGCAATTCTTCGTAATCTCCACCATGTCTGCCCTC

TGCCACOGCCGCACCCTCT

CGACATCCAATCATCATCAGGCAGGTGACTGCJGATTCCGGGAAATAGT

TATCTGGTTACCCTTGAGCAGCGCAGGAACACAGTACGTAGAGGGTGGCC

CCGGGTGAACCGTCTGGTCCAATCTCTACTATCACCCGTCTCCTCCTTAGAC

CATAAATCTCCAAACATGGGCAGGACCACAGCTCACAAGGATCCCAAGCTTCT

AGCTTCCAACACCTGCTCCGAGGAJAAGGTGCGTTTCCTGATGCTTGTGAGTCC

CTCTGCGTCAGGGAJATTCGGCAACATGGCGTCTCCCGCTCCGCCTCGGATCA

GTCCTCAGTAAACTGCTTCGTGACTCCCATGTCCTTCACAGCAGATGCGGCA

GAGGTTCACCCTTTGCCTACACCTGTCCTGCTGCCTGCTGTGGACTTACTGAA

TGGAAAACCCAGATGGAGGAGACCAAGGCACAGGACATTCTGGACTACTCG

CTGGAGGGAGTGATGGCAGCACGGGGACACTGGGAC

CCACTTGCCTCTCATCCCTCCTC

GGGCAGCTTTCTGGACAGGTCCGTCTCCTCCTTGGGGCCCTGCAGGCCTGAC

CAGCTTCCTCCACAG (SEQ ID NO:138) pMON2 8528 WO 97/12985 PrTfrTcn.<i 112 AD~Juiji

TTGCTGGACCCGACAACCTCATGACGAAACGTCTCTATCCTGTACAACT

CGATTCAAACTGAGACTTGTAAGGGCTGTCAAGAJACTTAGAATGCATCAGGT

ATTGAGGCCATTCTTCGTAATCTCCACCATGTCTGCCCTCTGCCACGCCCCC

CGACATCCAATCATCATCAAGGCAGGTGAC

TGGCAAGAATTCCGGGAJAACTGACGTTC

TATCTGGTTACCCTTGAGCAGCGCAGGAACACAGTACGTAGAGCGTAGTC

CCGGGTGAACCGTCTGGTCCAATCTCTACTATCACCCGTCTCCTCCGTTAGAC

CATAAATCTCCAACATGGCTCACAGGATCCCATGCCATCTTCCTGAGTCAAA

CTGCTCCGAGGAAAGGTGCGTTTCCTGATGCTTGTAGGAGGGTCCACCCTGTAG

GAATTCGGCAACATGGCGTCTCCCGCTCCGCCTGCTTGTGACCTCCGAGCTATA

CTGCTTCGTGACTCCCATGTCCTTCACAGCAGACTGAGCCAGTGCCCAGGTCCT

TTGCCTACACCTGTCCTGCTGCCTGCTGTGGACTTTAGCTTGGGAGAAGAAACA

ATGGAGGAGACCAAGGCACAGGACATTCTGGGAGCAGTGACCCTTCTGCGAGAT

ATGGCAGCACGGGGACAJACTGGGACCCACTTGCCTCTCATCCCTCCTGGGACTC

GGACAGGTCCGTCTCCTCCTTGGGGCCCTGCAGAGCCTCCTTGGA\CCCGTCCA

CAGGGCAGGACCACA (SEQ ID NO:139) pMON2 8529

GCTAACTGCTCTATATGATCGATGATTATACATCACTTAGAGCATCCT

TTGCTGGACCCGACACCTCATACGAGACGTCTCTATCCTGATGCGACT

CGACTTCCAAACCTGGAGAGCTTCGTAGGGCTGTCAGACTTAGAATCCGT

ATTGAGGCAATTCTTCGTAATCTCCACCATGTCTGC

CCTCTGCCACGGCCGCACCCTCT

CGCTCACTACAGAGGCTGAGATCGAAATAGT

TATCTGGTTACCCTTGAGCAGCGCAGGAACACAGTACGTAGAGGGCGGTGGCC

CCGGGTGAACCGTCTGGTCCAATCTCTACTATCAAJCCCGTCTCCTCCGTCTAGTC

CATAAATCTCCAACATGGATCCCATGCCATCTTCCTGAGCTTCCAACACTTCG

GGAAAGGTGCGTTTCCTGATGCTTGTAGGAGGGTCCACCCTCTGCGTCAGGATCC

AACATGGCGTCTCCCGCTCCGCCTGCTTGTGACCTCCGAGTCCTCAGTAAJACTCCG

GACTCCCATGTCCTTCACAGCAGACTGAGCCAGTGCCCAGAGGTTCACC

CTTTGCCTACA

CCTGTCCTGCTGCCTGCTGTGGACTTTAGCTTGGAGATGGAACCCAGATGGA

ACCAAGGCACAGGACATTCTGGGAGCAGTGACCCTTCTGCTGGAGGGAGTGTGAC

CGGGGACAACTGGGACCCACTTGCCTCTCATCCCTCCTGGGGCAGCTTTCTGCGC

CGTCTCCTCCTTGGGGCCCTGCAGAGCCTCCTTGGAACCCAGCTTCCTCCACAGGGCG

ACCACAGCTCACAAG (SEQ ID NO:140) pMON2 8530

GCACGTIAATACAGATAAACCTAGGCACGAC

TTCGACGAACTATAGAGCTTTTCGTGCGACT

CGCTCACTGGGTCTAGGTTAGATAAATCTAG

ATTGAGGCAATTCTTCGTATCTCCACCATGTCTGCCCTCTGCCACGGCACTT

CGACATCCAATCATCATCAGGCAGGTGACTGCAAGAATTCCGGGAAAAATCGC

TATCTGGTTACCCTTGAGCAGCGCAGGAACACAGTACGTAGAGGGCGTAGCC

CCGGGTGAACCGTCTGGTCCAATCTCTACTATCACCCGTCTCCTCCGTCTAAGAC

CATAAATCTCCAAACATGGCCATCTTCCTGAGCTTCCAJACACCTGCTCCGAGGAAGT

CGTTTCCTGATGCTTGTAGGAGGGTCCACCCTCTGCGTCAGGQGJATTCGGCAACATGGCG

TCTCCCGCTCCGCCTGCTTGTGACCTCCGAGTCCTCAGTAAACTGCTTCGTACCT

GTCCTTCACAGCAGACTGAGCCAGTGCCCAGAGGTTCACCCTTTGCCTAACGCT

CTGCCTGCTGTGGACTTTAGCTTGGGAGAJATGGAAACCCAGATGGAGGACAGA

CAGGACATTCTGGGAGCAGTGACCCTTCTGCTGGAGGGAGTGATGGCAGAGGAA

WO 97/12985 PrT/IrjQn.<m&-f-FA WO 9 /129 5 PC IIT~ uui 1137

CTGGGACCCACTTGCCTCTCATCCCTCCTGGGGCAGCTTTCTGGACAGGTCCGCCT

CTTGGGGCCCTGCAGAGCCTCCTTGGAJACCCAGCTTC CTCCAC AGGGCACGACCACAGCT CACAAGGATCCCAAT (SEQ ID NO:141) pMON28533

GCTAACTGCTCTATAATGATCGATGATTATACATCACTTAAGAGACCACCTGAC

TTGCTGGACCCGAACAACCTCJATGACGAAGACGTCTCTATCCTGATGGACCGAACT

GATCAACGAACTGAGGCGCAACTGAAGACGT

TGAGGCAATTCTTCCTAATCTCCAACCATGTCTGCCCTCTGCCACGGCCGCACCCTG

CACATACTAGCGTATGCAATCGGAACGCTCA

TGGTTACCCTTGAGCAAkCCGCAGGAAC?3CAGTACGTAGAGGGCGGTGGAGGCTCCG

TAACCGTCTGGTCCATCTCTACTATCAACCCGTCTCCTCCGTCTAAAGPITCTCTA

TCTCCAAACATGGAGGTTCACCCTTTGCCTACACCTGTCCTGCTGCCTGCTGTGGCT

AGTGGGAGAACCGTGGGGCAGCCGAATTGAC

GTGACCCTTCTGCTGGAGGGAGTGATGGCAGCACGGGGACAACTGGGACCCACTTCT

TCATCCCTCCTGGGGCAGCTTTCTGGACAGGTCCGTCTCCTCCTTGGGGCCCTGCGG

CTCCTTGGAACCCAGCTTCCTCCACAGGGCAGGACCACAGCTCACAAGGATCCCATC

ATCTTCCTGAGCTTCCAACACCTGCTCCGAGGAAAGGTGCGTTTCCTGATGCTTGTAG

GGGTCCACCCTCTGCGTCAGGGAATTCGGCGGCAJACGGCGGCAACATGGCGTCCCAG

CCGCCTGCTTGTGACCTCCGAGTCCTCAGTAAACTGCTTCGTGACTCCCATGTCCTTA

AGCAGACTGAGCCAGTGCCCA (SEQ ID NO:142) pMON28534 GCTAACTGCI

TATAATGATCGATGAAATTATACATCACTTAAAGAGACCACCTGCACCT

TTCGACGAACTATAGAGCTTTTCGTGCGACT

CGACTTCCAAACCTGGAGAGCTTC

GTAAGGGCTGTCAAGACTTAGAATGCATCAGGT

ATTGAGGCAATTCTTCGTAJATCTC CAACCATGTCTGC

CCTCTGCCACGGCCGCACCCTCT

CGCTCACTACAGAGGCTGAGATCGAAATAGT

TATCTGGTTACCCTTGAGCAAGCGCAGGACACAGTACGTAGAGGGCGGTGGAGGCTCC

CCGTACGCGTCACCATACACGCCTCTTAGAC

CATAAATCTCCAAACATGTTGCCTACACCTGTCCTGCTGCCTGCTGTGGACTTTAGCTTG

GGAGAATGGAAAACCCAGATGGAGGAGACCAAGGCACAGGACATTCTGGGAGCAGTGACC

CTTCTGCTGGAGGGAGTGATGGCAGCACGGGGACAJACTGGGACCCACTTGCCTCTCATCC

CTCCTGGGGCAGCTTTCTGGACAGGTCCGTCTCCTCCTTGGGGCCCTGCAGAGCCTCCTT

GGACCCAGCTTCCTCCACAGGGCAGGACCACAGCTCACAAGGATCCCATGCCATCTTC

CTGAGCTTCCAACACCTGCTCCGAGGAAAGGTGCGTTTCCTGATGCTTGTAGGAGGGTCC

ACCCTCTGCGTCAGGGAATTCGGCGGCAAJCGGCGGCACATGGCGTCCCCAGCGCCGCCT

GCTTGTGACCTCCGAGTCCTCAGTAAACTGCTTCGTGACTCCCATGTCCTTCACAGCAGA

CTGAGCCAGTGCCCAGAGGTTCACCCT (SEQ ID NO:143) pMON2 8535

GCTACTGCTCTATAATGATCGATGAATTATACATCACTTAAAGAGACCACCTGCACCT

TTCGACGAACTATAGAGCTTTTCGTGCGACT

CGACTTCCAAAC

CTGGAGAGCTTCGTAGGGCTGTCAAGACTTAGAATGCATCAGGT

ATTGAGGCAATTCTTCGTAATCTCCACCATGTCTGCCCTCTGCCACGGCCGCACCCTCT

CGACATCCAATCATCATCAGGCAGGTGACTGGCAGAATTCC

GGGAAAAACTGACGTTC

TATCTGGTTACCCTTGAGCAGCGCAGGAJACACAGTACGTAGAGGGCGGTGGAGGCTCC

CCGGGTGAACCGTCTGGTCCAATCTCTACTATCAACCCGTCTCCTCCGTCTAAAGAATCT

CATAAATCTCCAACATGGTCCTGCTGCCTGCTGTGGACTTTAGCTTGGGAGATGGA

WO 97/12985 PCT/UQQKIlrc 114 ACCCAGATGGAG CAGCGAe CATTCTGGAGCAGTACC~tGT

CTTTCTGGACAGGTCCGTCTCCTCCTTGGGGCCCTGCAGAGCCTCCTGACCGT

CCTCCACAGGGCAGGACCACAGCTCACAAGGATCCCAATGCCATCTTCGGTCA

CACCTGCTCCGAGGAAAGGTGCCTTTCCTGATGCTTGTAGGAGGGTCCACTTCT

AGGGAATTCGGCGGCAACGGCGGCAJACATGGCGTCCCCAGCGCCCCTGTGGCT

CGAGTCCTCAGTAAACTGCTTCGTGACTCCCATGTCCTTCACAGCAGACTGGCGG

CCAGAGGTTCACCCTTTGCCTACACCT (SEQ ID NO:144) pMON28536

GCTAACTGCTCTATAATGATCGATGAAJATTATACATCACTTAAAGAGCACGAC

TTGCTGGACCCG

AACAACCTCAATGACGAAGACGTCTCTATCCTGATGCGACT

CGATTCAAACTGAGACTTGTAAGGGCTGTCAAGAACTTAGAJAATGCATCAGGT

ATTGAGGCAATTCTTCGTAATCTCCACCATGTCTGCCCTCTGCCACGCCCCC

CGACATCCAATCATCATCAAGGCAGGTGACTGGCACATTCCGGGAACTCGC

TATTGGTACCTTGAGCAAGCGCAGGAACACAGTACGTAGAGGGCGGTGGGCC

CCGGGTGAACCGTCTGGTCCAATCTCTACTATCAJACCCGTCTCCTCCTTAGTT

CATAAATCTCCA1\ACATGGCTGTGGACTTTAGCTTGGGAGAATGGAAACAAGA

GAGACCAAGGCACAGGACATTCTGGGAGCAGTGACCCTTCTGCTGGAGGTTGC

GCACGGGGACAJCTGGGACCCACTTGCCTCTCATCCC

TCCTGGGGCAGCTTTCTGGACAC

GTCCGTCTCCTCCTTGGGGCCCTGCAGAGCCTCCTTGGAACCCAGCTCCAAGC

AGGACCACAGCTCACAAGGATCCCAATGCCATCTTCCTGAGCTTCCAAACGCCG

GGAAAGGTGCGTTTCCTGATGCTTGTAGGAGGGTCCACCCTCTGCGTAGATCC

GGCAACGGCGGCAACATGGCGTCCCCAGCGCCGCCTGCTTGTGACCTCCATCCG

AAACTGCTTCGTGACTCCCATGTCCTTCACAGCAGACTGAGCCAGTGCCAAGTA

CCTTTGCCTACACCTGTCCTGCTGCCT (SEQ ID NO:145) pMON2 8537

GCTAACTGCTCTATATGATCGATGAAATTATACATCACTTAAAGAGACACGAC

TTGCTGGACCCGAACAACCTCAATGACGAGACGTCTCTATCCTGATGGCGACT

CGACTTCCACCTGGAGAGCTTCGTAGGGCTGTCAAGACTTAGAA&TGACAG

ATTGAGGCAATTCTTCGTAJATCTCCAACCATGTCTGCCCTCTGCCACGGCCCCCC

CGCTCACTACAGAGGCGCAATCGGAAATAGT

TATCTGGTTACCCTTGAGCAAGCGCAGGAJACACAGTACGTAGAGGGCGGTGGCC

CCGGGTGAACCGTCTGGTCCATCTCTACTATCAJACCCGTCTCCTCCGTCTAGTC

CATAAATCTCCAAACATGGACTTTAGCTTGGGAGATGGAAAACCCAGATGAAAC

AAGGCACAGGACATTCTGGGAGCAGTGACCCTTCTGCTGGAGGGAGTGATGCGAG

GGACAACTGGGACCCACTTGCCTCTCATCCCTCCTGGGGCAGCTTTCTGGACAGGCT

CTCCTCCTTGGGGCCCTGCAGAGCCTCCTTGGAACCCAGCTTCCTCCACAGGAGC

ACAGCTCACAAGGATCCCAATGCCATCTTCCTGAGCTTCCAACACCTCCGGAG

GTGCGTTTCCTGATGCTTGTAGGAGGGTCCACCCTCTGCGTCAGGGAJATTCGGCGCA

GGCGGCAACATGGCGTCCCCAGCGCCGCCTGCTTGTGACCTCCGAGTCCTCGAAT

CTTCGTGACTCCCATGTCCTTCACAGCAGACTGAGCCAGTGCCCAGAGGTACTG

CCTACACCTGTCCTGCTGCCTCCTGTC (SEQ ID NO:146) pMON2 8538

GCTAACTGCTCTATAATGATCGATGAAATTATACATCACTTAAAGAGCATCCT

TTCGACGAACTATAGAAGCCACTAGACACT

CGCTCACTGGGTCTAGGTTAGATAAATCTAG

WO 97/12985 PCT/U,4ZQA/ICP7'7A

ATTGAGGCAATTCTTCGTATCTCCAJACCATGTCTGCCCTCTGCCACGGCCCCCCC

CGACATCCAATCATCATCAGGCAGGTGACTGGCAGAATTCC

GGGAAAAACTGACGTTC

TATCTGGTTACC

CTTGAGCAAGCGCAGGAACAACAGTACGTAGAGGGCGGTGGAGGCTC

CCGGGTGAACCGTCTGGTCCAATCTCTACTATCACCCGTCTCCTCCGTCTAGTC

CAAACCAAAGGGAGAAACAAGAGGCAGCCGA

ATTCTGGGAGCAGTGACCCTTCTGCTGGAGGGAGTGATGGCAGCACGGGGACACGA

CCCACTTGCCTCTCATCCCTCCTGGGGCAGCTTTCTGGACAGGTCCGTCTCCTCGG

CCCTGCAGAGCCTCCTTGGAACCCAGCTTCCTCCACAGGGCAGGACCACAGCCCA

GATCCCAATGCCATCTTCCTGAGCTTCCACACCTGCTCCGAGGAGGTGGTCT

ATGCTTGTAGGAGGGTCCACCCTCTGCGTCAGGGATTCGGCGGCAACGCGGAC

GCGTCCCCAGCGCCGCCTGCTTGTGACCTCCGAGTCCTCATAJAACTGCTTGACC

CATGTC CTTCACAGCAGACTGAGCCAGTGC CCAGAGGTTCACCCTTTGC

CTACACCTGTC

CTGCTGCCTGCTGTGGACTTTAGCTTG (SEQ ID NO:147) pMON28539

GCTAACTGCTCTATAATGATCGATGAAATTATACATCACTTAOAGACCACGCT

TTGCTGGACCCGACACCTCATGACGAGACGTCTCTATCCTGATGGCCGACT

CGACTTCCAAACCTGGAGAGCTTC

GTAAGGGCTGTCAAGAACTTAGAATGCATCAGGT

ATTGAGGCAATTCTTCGTA1ATCTCCAACCATGTCTGCCCTCTGCCACGGCCGCACCC

CGCTCACTACAGAGGCTGAGATCGAAATAGT

TATCTGGTTACC

CTTGAGCAAGCGCAGGZAJCJCAGTACTAGAGGGCGGTGGAGGCTCC

CCGGGTGAACCGTCTGGTCCAATCTCTACTATCAACC

CGTCTCCTCCGTCTAAAJGAATCT

CATAAATCTCCAAACATGGGACCCACTTGCCTCTCATCCCTCCTGGGGCAGCTCGA

CAGGTCCGTCTCCTCCTTGGGGCCCTGCAGAGCCTCCTTGGAACCCAGCTTCCCAG

GGAGCAACCCAGTCATGCTTCTACTCAACGT

CGAGGAAAGGTGCGTTTCCTGATGCTTGTAGGAGGGTCCACCCTCTGCGTCAGGGAT

GGCGGCAACGGCGGCAJ&CATGGCGTCCCCAGCGCCGCCTGCTTGTGACCTCCGAGTCT

AGTAAACTGCTTCGTGACTCCCATGTCCTTCACAGCAGACTGAGCCAGTGCCCAGAGT

CACCCTTTGCCTACACCTGTCCTGCTGCCTGCTGTGGACTTTAGCTTGGGAGATGGAAAJ

ACCCAGATGGAGGAGACCAAGGCACAGGACATTCTGGGAGCAGTGACCCTTCTGCTGGA

GGAGTGATGGCAGCACGGGGACAACTG (SEQ ID NO:148) pMON2 3540

GCTACTGCTCTATAATGATCGATGAATTATACATCACTTAAJAGAGACCACCTGCACCT

TTCGACGAACTATAGAGCTTTTCGTGCGACT

CGACTTCCAAACCTGGAGAGCTTCGTAGGGCTGTCAAGAACTTAGAAAATCCAG

ATTGAGGCAJATTCTTCGTAJATCTCCACCATGTCTGCCCTCTGCCACGGCCGCACCCTC

CGCTCACTACAGAGGCGCAATCGGAAATAGT

TATCTGGTTACCCTTGAGCAJAGCGCAGGAACA3&CAGTACGTAGAGGGCGGTGGAGGCTC

CCGTACGCGTCACCATACACGCCTCTTAGAC

CATAAATCTCCAAACATGGGALCCCAGCTTCCTCCACAGGGCAGGACCACAGCTCACAA

GATCCCAATGCCATCTTCCTGAGCTTCCALACACCTGC

TCCGAGGAAAGGTGCGTTTCCTG

ATGCTTGTAGGAGGGTCCACCCTCTGCGTCAGGGATTCGGCGCLCGGCGGCAACATG

GCGTCC CCAGCGCCGCCTGCTTGTGACCTCCGAGTCCTCAGTAAACTGCTTCGTGACTCC

CATGTCCTTCACAGCAGACTGAGCCAGTGCCCAGAGGTTCACCCTTTGCCTACACCTGTC

CTGCTGCCTGCTGTGGACTTTAGCTTGGGAGJATGOAACCCAGATGGAGGAGACCAAG

GCACAGGACATTCTGGGAGCAGTGACCCTTCTGCTGGAGGGAGTGATGGCAGCACGGGGA

CAACTGGGACCCACTTGCCTCTCATCCCTCCTGGGCCAGCTTTCTGGACAGGTCCGTCTC

CTCCTTGGGGCCCTGCAGAGCCTCCTT (SEQ ID NO:149) WO 97/12985 Vi-lrin pMON283541

GCTAACTGCTCTATATGATCGATGAATTATACATCACTTAAGGACCTGAC

TTGCTGGACCCGAACAIACCTCAATGACGkJAGACGTCTCTATCCTGTGCGACT

CGACTTCCAAACCTGGAGAGCTTCGTAAGGGCTGTCAAGAACTAAAGCCGT

ATTGAGGCAATTCTTCGTAATCTCCACCATGTCTGCCCTCTGCCGCCCCC

CGACATCCAATCATCATCAGGCAGGTGACTGGCAGATTCCGAACTCTC

TATCTGGTTACCCTTGAGCAGCGCAGGAACACAGTACGTAGAC

CGGGGCC

CCGGGTGAACCGTCTGGTCCAATCTCTACTATCACCCGTCTCCTCTTAGAC

CATAAATCTCCAAACATGGGCAGGACCACAGCTCACAAGGATCCCAGCTTCT

AGCTTCCAACACCTGCTCCGAGGAAAGGTGCGTTTCCTGATGCTTTGAGTCC

TTCTCCGATCTCAGTTACGCTCGTACCTCTAAGCAGACT

AGCCAGTGCCCAGAGGTTCACCCTTTGCCTACACCTGTCCTGCGTCGGATT

AGCTTGCGAGAATGGAAAACCCAGATGGAGGAGACCAAGGCACAGAATTGAC

GTGACCCTTCTGCTGGAGGGAGTGATGGCAGCACGGGGACAACTGGCCCTC

TCATCCCTCCTGGGGCAGCTTTCTGGACAGGTCCGTCTCCTCCTTGGCTCGG

CTCCTTGGAACCCAGCTTCCTCCACAG (SEQ ID NO:150) pMON28542

GCTAACTGCTCTATAATGATCGATGAAATTATACATCACTTAGGCACGAC

TTGCGGACCGACAACTCAATGACGAAGACGTCTCTATCCTGATGGACCGAJAACCT

CGACTTCCAAAC

CTGGAGAGCTTCGTAAGGGCTGTCAAGAACTTAGAAAATGCATAG

ATTGAGGCAATTCTTCGTAJATCTCCAACCATGTCTGCCCTCTGCCACGGCCCCC

CGACATCCAJATCATCATCAAGGCAGGTGACTGGCAJAGAATTCCGGAAATAGT

TATCTGGTTACCCTTGAGCAGCGCAGGAACACAGTACGTAGAGGGGTGGCC

CCGGGTGAACCGTCTGGTCCAATCTCTACTATCACCCGTCTCCTCCAAGTT

CATAAATCTCCAA3ACATGGCTCACAAGGATCCCAATGCCATCTTCTATCACC

CTGCTCCGAGGAAAGGTGCGTTTCCTGATGCTTGTAGGAGGGTCCCTTGTAG

GAATTCGGCGGCAACGGCGGCAACATGGCGTCCCCAGCGCCGCCTGCTTACCG

GTCCTCAGTA3AACTGCTTCGTGACTCCCATGTCCTTCACAGCAGATACATCC

GAGGTTCACCCTTTGCCTACACCTGTCCTGCTGCCTGCTGTGGACTTACGGGA

TGGAAAACCCAGATGGAGGAGACCJAGGCACAGGACATTCTGGGAGCGACTCG

CTGGAGGGAGTGATGGCAGCACGGGGCAACTGGGACCCACTTGCCTTACCCT

GGGCAGCTTTCTGGACAGGTCCGTCTCCTCCTTGGGGCCCTGCAGCTCTGAC

CAGCTTCCTCCACAGGGCAGGACCACA (SEQ ID NO:151) pMON2 8543

GCTAACTGCTCTATAJATGATCGATGAAATTATACATCACTTAAAGAGACCACCTGAC

CGACTTCCAAACCTGGGTCTAGCGCAGATAAATCTAG

ATTGAGGCATTCTTCGTAJATCTCCAACCATGTCTGCCCTCTGCCACGGACTT

CGACATCCAATCATCATCAGGCAGGTGACTGGCAGATTCCGGG-ACTCTC

TATCTGGTTACCCTTGAGCAAGCGCAGGACAJCAGTACGTAGAGGGTGGCC

CCGGGTGAACCGTCTGGTCCATCTCTACTATCAJACC

CGTCTCCTCCGTCTAAAGAJATCT

CATAAATCTCCAAAJCATGGATCCCAATGCCATCTTCCTGAGCTTCCACCTCCG

GGAAAGGTGCGTTTCCTCGATGCTTGTAGGAGGGTCCACCCTCTGCGTCAGGATCC

GGCAACGGCGGCACATGGCGTCCCCAGCGCCGCCTGCTTGTGACTCATCCG

AAACTGCTTCGTGACTCCCATGTC

CTTCACAGCAGACTGAGCCAGTCCCAGAGGTTCAC

CCTTTGCCTACACCTGTCCTGCTGCCTGCTGTGGACTTTAGCTTGGACTGAAC

WO 97/12985 PCTIUS06/1-7-YA WO 9/1295 PCII Tot~i1177 CAGATGGAGGAGAC

CAAGGCACAGGACATTCTGGGAGCAGTGACCCTTCTGCTGCAGGGA

GTGATGGCAGCACGGGGACAJ\CTGGGACCCACTTGCCTCTCATCCCTCCTGCGGGCGT

TCTGGACAGGTCCGTCTCCTCCTTGGGGCCCTGCAGAGCCTCCTTGGAACCCAGCTTC

CCACAGGGCAGGACCACAGCTCACJAG (SEQ ID NO:152) pMON2 8544

CGACTTCCAAACCTGGAGAGCTTCGTAAGGGCTGTCAGACTTAGAAATGCATCAGGT

ATTGAGGCAATTCTTCGTAATCTCCACCATGTCTGCCCTCTGCCACGGCCGCACCCT

CGCTCACTACAGAGGATGAGATCGAAATAGTTC

TATCTGGTTACCCTTGAGCAAGCGCAGGAJACACAGTACGTAGAGGGCGGTGGAGGCTC

CCGGGTGAACCGTCTGGTCCAATCTCTACTATCAACCCGTCTCCTCCGTCTAAAGAAC

CATAAATCTCCAAACATGGCCATCTTCCTGAGCTTCCA\CACCTGCTCCGAGGAAAGGTG

CGTTTCCTGATGCTTGTAGGAGGGTCCACCCTCTGCGTCAGGGAATTCGGCGGCAACGGC

GGCAACATGGCGTCCCCAGCGCCGCCTGCTTGTGACCTCCGAGTCCTCAGTAAACTGCT

CGTGACTCCCATGTCCTTCACAGCAGACTGAGCCAGTGCCCAGAGGTTCACCCTTTGCCT

ACACCTGTCCT(CTGCCTGCTGTGGACTTTAGCTTGGGAGATQGAAACCCAGATGGAG

GAGACCAAGGCACAGGACATTCTGGGAGCAGTGACCCTTCTGCTGGAGGGAGTGATGGCA

GCACGGGGACAACTGGGACCCACTTGCCTCTCATCCCTCCTGGGGCAGCTTTCTGGACAG

GTCCGTCTCCTCCTTGGGGCCCTGCAGAGCCTCCTTGGAACCCAGCTTCCTCCACAGGGC

AGGACCACAGCTCACAAGGATCCCAAT (SEQ ID NO:153) pMON28545 GCTAACTGCTCTATAATGATCGATGAAATTATACATC ACTTAAAGAGAC

CACCTGCACCT

TTGCTGGACCCGAACAAC

CTCAATGACGAAGACGTCTCTATCCTGATGGACCGAAACCTT

CGACTTCCAAACCTGGAGAGCTTCGTAGCGCAACTAAATCTAG

ATTGAGGCAATTCTTCGTAATCTCCAACCATGTCTGCCCTCTGCCACGGCCGCACCCTCT

CGCTCACTACLGCGTATGAGATCGAAATAGT

TATCTGGTTACCCTTGAGCAGCGCAGGAJACACAGTACGTAGAGGGCGGTGGAGGCTCC

CCGTACGCGTCACCATACACGCCTCTTAGAC

CAAACCAAAGACCAGCACTCGGTCACCTCCG

GGAAAGGTGCGTTTCCTGATGCTTGTAGGAGGGTCCACCCTCTGCGTCAGGGAATTCGGC

GGCAACATGGCGTCTCCCGCTCCGCCTGCTTGTGACCTCCGAGTCCTCAGTAAACTGCTT

CGTGACTCCCATGTCCTTCACAGCAGACTGAGCCAGTGCCCAGAGGTTCACCCTTTGCCT

ACCTTCGTCTCGGATTACTGAATGAACAAGA

GAGACCAAGGCACAGGACATTCTGGGAGCAGTGACCCTTCTGCTGGAGGGAGTGATGGCA

GCACGGGGACAACTGGGACCCACTTGCCTCTCATCCCTCCTGGGGCAGCTTTCTGGACAC

GTCCGTCTCCTC

CTTGGGGCCCTCCAGAGCCTCCTTGGAACCCAGGGCAGGACCACAGCT

CACAAG (SEQ ID NO:154) pMON15981 1 ATGGCTAACT GCTCTATAAT GATCGATGAA ATTATACATC

ACTTAAAGAG

51 ACCACCTGCA CCTTTGCTGG ACCCGAACAA CCTCAATGAC

GAAGACGTCT

101 CTATCCTGAT GGATCGAAAC CTTCGACTTC CAAACCTGGA

GAGCTTCGTA

151 AGGGCTGTCA AGAACTTAGA AAATGCATCA GGTATTGAGG

CAATTCTTCG

201 TAATCTCCAA CCATGTCTGC CCTCTGCCAC GGCCGCACCC

TCTCGACATC

251 CALATCATCAT CAAGGCAGGT GACTGGCAAG AATTCCGGGA

AAAACTGACG

WO 97/12985 PCT/US96/1 5774 301 351 401 451 501 551 601 651 701 751 801 851 901 951 TTCTATC TGG

CGGTGGAGGC

CGTCTCCTCC

C TGTGuCACC CTGGGCTcC

GCTTGAGCCA

GCCCTGGAAG

GCTGGACGTC

TGGGAATGGC

GCCTCTGCTT

GCAGAGCTTC

CCGGCGGCGG

CCCCAGAGCT

CGATGGCGCA

TTACCCTTGA

TCCCCGGGTG

GTCTAAAGAA

CCGAGGAGCT

CTGAGCTCCT

ACTCCATAGC

GGATATCCCC

GCCGACTTTG

CCCTGCCCTG

TCCAGCGCCG

CTGGAGGTGT

CTCTGACATG

TCCTGCTCAA

GCGCTCCAGG

GCAAGCGCAG

AACCGTCTGG

TCTCATAAAT

GGTGCTGCTC

GCCCCAGCCA

GGCCTTTTCC

CGAGTTGGGT

CCACCACCAT

CAGCCCACCC

GGCAGGAGGG

CGTACCGCGT

GCTACACCAT

GTCTTTAGAG

AGAAGCTGTG

GAACAACAGT

TCCAATCTCT

CTCCAAACAT

GGACACTCTC

GCCCTGCAG

TCTACCAGGG

CCCACCTTCG

CTGGCAGCAG

AGGGTGCCAT

GTC CT GGTrG TCTACGCCAc

TAGGCCCTGC

CAAGTGAGGA

TGCCACCTAJA

AC GTAGAGGG ACTATCAAC

C

GTCTTAC7AG

TGGGCATCCC

CTGGCAGGCT

GCTCCTGCAG

ACACACTGCA

ATGGAAGA.C

GCCGGCCTTC

CTAGCCATCT

CTTGCGCAC

CAGCTCCCTG

AGATCCAGGG

TAA;

(SEQ ID NO:155) PMON15982 1 51 101 151 201 251 301 351 401 451 501 551 601 651 701 751 801 851 901 951

ATGGCTAACT

ACCACCTGCA

CTATCCTGAT

AGGGCTGTCA

TAATCTCCAA

CAATCATCAT

TTCTATCTGG

CGGTGGAGC

CGTCTCCTCC

TTGGGTCCCA

CACCATCTGG

CCACCCAGGG

GGAGGGGTCC

CCGCGTTCTA

CACCATTAGG

TTAGAGCAAG

GCTGTGTGCC

GACACTCTCT

GCCCTGCAGC

CTACCAGGGG

GCTCTATAAT

CCTTTGCTGG

GGATCGAAAC

AGAACTTAGA

CCATGTCTGC

CAAGGCAGGT

TTACCCTTGA

TCCCCGGGTG

GTCTAAAGAA

CCTTGGACAC

CAGCAGATGG

TGCCATGCCG

TGGTTGCTAG

CCCCAC CTTG

CCCTGCCAGC

TGAGGAAGAT

ACCTACAAGC

GGGCATCCCC

TGGCAGGCTG

CTCCTGCAGG

GATCGATGAA

ACCCGAACAA

CTTCGACTTC

AAATGCATCA

CCTCTGCCAC

GACTGGCAA3

GCAAGCGCAG

AACCGTCTGG

TCTCATAAAT

ACTGCAGCTG

AAGAACTGGG

GCCTTCGCCT

CCATCTGCAG

CGCAGCCCGG

TCCCTGCCCC

CCAGGGCGAT

TGTGCCACCC

TGGGCTCCCC

CTTGAGCCAA

CCCTGGAAGG

ATTATACATC

CCTCAATGAC

CAAACCTGGA

GGTATTGAGG

GGCCGCACCC

AATTCCGGGA

GAACAACAGT

TCCAATCTCT

CTCCAAACAT

GACGTCGCCG

AATGCC CC T

CTGCTTTCCA

AGCTTCCTGG

CGGCGGCTCT

AGAGCTTCCT

GGCGCAGCGC

CGAGGAGCTG

TGAGCTCCTG

CTCCATAGCG

GATATCCTAI\

ACTTAAAGAG

GAAGACGTCT

GAGCTTCGTA

CAATTCTTCG

TCTCGACATC

AAAACTGACG

ACGTAGAGGG

ACTATCAACC

GTCTCCCGAG

ACTTTGCCAC

GCCCTGCAGC

GCGCCGGGCA

AGGTGTCGTA

GACATGGCTA

GCTCAAGTCT

TCCAGGAGAA

GTGCTGCTCG

CC CC AC CAG

GCCTTTTCCT

TAA;

(SEQ ID NO:156) PM0N15965 1 51 101 151 201 251 301 351 401 451

ATGGCTAACT

ACCACCTGCA

CTATCCTGAT

AGGGCTGTCA

TAATCTCCAA~

CAATCATCAT

TTCTATCTGG

CGGTGGAGGC

CGTCTCCTCC

TTCCAGC GCC

GCTCTATAAT

CCTTTGCTGG

GGATCGAAAC

AGAACTTAGA

CCATGTCTGC

CAAGGCAGGT

TTACCCTTGA

TCCCCGGGTG

GTCTAAAGAA

GGGCAGGAGG

GATCGATGAA

AC C CGAAC AA

CTTCGACTTC

AAATGCATCA

CCTCTGCCAC

GACTGGCAAG

GCAAGCGCAG

AACCGTCTGG

TCTCATAAAT

GGTCCTGGTT

ATTATACATC

CCTCAATGAC

CAAACCTGGA

GGTATTGAGG

GGCCGCACCC

AATTCCGGGA

GAACAACAGT

TCCAATCTCT

CTCCAAACAT

GCTAGCCATC

ACTTAAAGAG

GAAGACGTCT

GAGCTTCGTA

CAATTCTTCG

TCTCGACATC

AAAACTGACG

ACGTAGAGGG

AC TAT CAAC C

GTCTTCTGCT

TGCAGAGCTT

WO 97/1 2985 PCTIUS96/1 5774 501 551 601 651 701 751 801 851 901 951

CCTGGAGGTG

GCTCTGACAT

TTCCTGCTCA

AOCGCTCCAG

AGCTGGTGCT

TCCTGCCCCA

TAGCGGCCTT

CCCCCGAGTT

TTTGCCACCA

C CT GCAO CCC

TCGTACCGCG

GOCTACACCA

AGTCTTTAGA

GAGAAGCTGT

GCTCGGACAC

GCCAGGCCCT

TTCCTCTACC

GGGTCCCACC

CCATCTGGCA

ACCCAGGGTG

TTCTACGCCA

TTAGOCCCTG

GCAAGTGAGG

GTGCCACCTA

TCTCTGGGCA

GCAGCTGGCA

AGGGGCTCCT

TTGGACACAC

GCAGATGGAA

CCATGCCGGC

CCTTGCGCAG

CCAGCTCCCT

AAGATCCAGG

CAAOCTGTGC

TCCCCTGGGC

GGCTGCTTGA

GCAGGCCCTG

TGCAGCTGGA

GAACTGOGAA

CTTCGCCTAAk CCtGGCGGCG

GCCCCAGAGC

GCGATGGCGC

CACCCCGAGG

TCCCCTOAGC

GCCAACTCCA

GAAGGGATAT

CGTCGCCGAC

TGGCCCCTGC

TAA (SEQ ID NO:157) PMON15966 1 51 101 151 201 251 301 351 401 451 501 551 601 651 701 751 801 851 901 951

ATGGCTAACT

ACCACCTGCA

CTATCCTGAT

AGGGCTGTCA

TAATCTCCAA

CAATCATCAT

TTCTATCTGG

CGT GAGGC

CGTCTCCTCC

CCTGCCCTGC

CCAGCGCCGG

TGGAGGTGTC

TCTGACATGG

CCTGCTCAAG

CGCTCCAGGA

CTGGTGCTGC

C TGCCCC AG C

GCGGCCTTTT

CCCGAGTTGG

T GC CAC CAC C

GCTCTATAAT

CCTTTGCTGG

GGATCGAAAC

AGAACTTAGA

CCATOTCTGC

CAAGGCAGGT

TTACCCTTGA

TCCCCGGGTG

GTCTAAAGAA

AGCCCACCCA

GCAGGAGGGO

GTACCGCOTT

CTACACCATT

TCTTTAGAGC

GAAGCTGTGT

TCGGACACTC

CAGGCCCTGC

CCTCTACCAG

GTCCCACCTT

ATCTGGCAGC

GATCGATGAA

ACCCGAACAA

CTTCOACTTC

AAATGCATCA

CCTCTGCCAC

GACTGGCAAG

GCAAGCGCAG

AACCGTCTGG

TCTCATAAAT

GGGTGCCATO

TCCTOGTTGC

CTACGCCACC

AGGCCCTGCC

AAGTGAGGAA

GCCACCTACA

TCTGGGCATC

AGCTGGCAGG

GGGCTCCTGC

GGACACACTG

AGATGGAAGA

ATTATACATC

CCTCAATGAC

C AAAC C TGA

GGTATTGAGG

GGCCGCACCC

AATTCCOGGA

GAACAACAGT

TCCAATCTCT

CTCCAAACAT

CCGGCCTTCG

TAGCCATCTG

TTGCOCAGCC

AGCTCCCTGC

OATCCAGOOC

AOCTGTOCCA

CCCTOGGCTC

CTGCTTGAGC

AGGCCC TOGA

CAOCTOGACG

ACTGGGATAA

ACTTAAAGAG

GAAGACOTCT

OAGCTTCGTA

CAATTCTTCO

TCTCOACATC

AAAACTGACG

ACGTAGAGGG

ACTATCAACC

OTCTATGOCC

CCTCTOCTTT

CAGAGCTTCC

CGGCGOCOOC

CCCAOAGCTT

GATGGCOCAG

CCCCGAGOAG

CCCTGAGCTC

CAACTCCATA

AGGGATATCC

TCGCCOACTT

TAA

(SEQ ID NO:158) pMON15967 1 51 101 151 201 251 301 351 401 451 501 551 601 651

ATGOCTAACT

ACCACCTGCA

CTATCCTGAT

AGGGCTGTCA

TAATCTCCAA

CAATCATCAT

T TCTATCTOG

CGGTOGAGOC

CGTCTCCTCC

GOTOCCATGC

CCTGGTTGCT

TACGCCACCT

GGCCCTGCCA

AGTGAGGAAG

GCTCTATAAT

CCTTTOCTOO

GOATCGAAAC

AGAACTTAGA

CCATGTCTGC

CAAOOCAGGT

TTACCCTTGA

TCCCCGOOTG

GTCTAAAGAA

CGGCCTTCGC

AOCCATCTGC

TGCGCAGCCC

GCTCCCTGCC

ATCCAGGGCG

OATCGATGAA

ACCCOAACAA

CTTCGACTTC

AAATOCATCA

CCTCTOCCAC

GACTGGCAAG

GCAAGCGCAG

AACCOTCTGG

TCTCATAAAT

CTCTGCTTTC

AOAGCTTCCT

GOCGGCOOCT

CCAOAGCTTC

ATGGCOCAGC

ATTATACATC

CCTCAATGAC

CAAACCTGGA

GGTATTGAGG

GGCCGCACCC

AATTCCGGGA

GAACAACAGT

TCCAATCTCT

CTCCAAACAT

CAGCOCC 000

GGAOGTGTCG

CTGACATGGC

CTGCTCAAGTr

GCTCCAGGAG

ACTTAAAGAG

OAAGACOTCT

GAGCTTCc3TA

CAATTCTTCG

TCTCGACATC

AAAACTOACG

ACGTAGAGGO

ACTATCAACC

GTCTACCCAG

CAGGAGGOT

TACCGCGTTC

TACAC CAT TA

CTTTAGAGCA

AAGCTGTGTG

WO 97/1 2985 PCTIUS96/'15774 701 751 801 851 901 951

CCACCTACAA

CTGGGCATCC

GCTGGCAGGC

GGCTCCTGCA

GACACACTGC

GATGGAAGAA

GCTGTGCCAC

CCTGGGCTCC

TGCTTGAGCC

GGCCCTGGAA

AGCTGGACGT

CTGGGAATGG

CCC GAGGAGO

CCTGAGCTCC

AACTCCATAG

GGGATATCCC

CGCCGACTTT

CCCCTGCCCT

TGGTGCTGCT

TGCCCCAGCC

CGGCCTTTTC

CC GAG TTGGG

GCCACCACCA

GCAGCCCTAA

CGOGACACTCT AGGCCC

TCA

CTCTAC

CAGG

TCCCACCTTG

TCTGGCAGCA

TAA

(SEQ ID NO:159) pMON15960 1 51 101 151 201 251 301 351 401 451 501 551 601 651 701 751 801 851 901 1001 1051

ATGGCTACAC

CAAGTCTTTA

AGGAGAAGCT

CTGCTCGGAC

CAGCCAGGCC

TTTTCCTCTA

TTGGGTCCCA

CAC CAT CTG C CAC CCAG GO

GGAGGGGTCC

CCGCGTTCTA

CAC CAT TOGO

TTAGAGCAAG

GCTGTGTGCC

GACACTCTCT

GCCCTGCAGC

CTACCAGOO

CCACCTTGGA

TGOCAGCAOA

TCCTGGTTOC

OTACOC CACC

CATTGOGCCC

GAOCAAGTGA

OTOTGCCACC

ACTCTCTOGGG

CTGCAOCTG

CCAGGGGCTC

CCTTGGACAC

CAOCAOATG

TOCCATGCCG

TOOTTOCTAG

CGCCACCTTO

CCCTGCCAGC

TGAGGAAGAT

ACCTACAAGC

OGGCATCCCC

TOOCAGOCTO

CTCCTGCAGO

CACACTOCAG

TGGAAGAACT

TAGCCATCTG

TTGCOCAGCC

TOCCAOCTCC

GGAAGATCCA

TACAAGCTGT

CATCCCCTG

CAOOCTGCTT

CTOC AGC C C

ACTOCAOCTO

AAGAACTGGG

GCCTTCOCCT

CCATCTGCAO

CGCAOCCCGO

TCCCTGCCCC

CCAGOGCGAT

TGTOCCACCC

TOGGCTCCCC

CTTGAGCCAA

CCCTGGAAGG

CTGGACGTCO

GGGAATGGCC

CTGCCCCAGA

GOCOATOOC

GCCACCCCOA

OCTCCCCTOA

GAGCCAACTC

TGGAAGGGAT

GACOTCOCCO

AATG OCCCCT

CTGQTTTCCA

AOCTTCCTGO

CGGCGGCTCT

AOAOCTTCCT

OGCOCAOCGC

CGAGOAOCTO

TGAGCTCCTO

CTCCATAOCO

OATATCCCCC

CCGACTTTGC

CCTGCCCTGC

OCTTCCTOCT

OCAOCOCTCC

GGAGC TOT 0

GCTCCTOCCC

CATAOCGOCC

ATCCCCCGAG

ACTTTGCCAC

GCCCTOCAGC

GCOCCGOCA

AGGTGTCGTA

GACATOOCTA

OCTCAAOTCT

TCCAGGAGAA

OTOCTGCTCG

CCCCAOCCAG

GCCTTTTCCT

OAGTTGOGTC

CACCACCATC

AGCCCACCCA

OTACCOCOTT

CTGATAA (SEQ ID NO:16C PMON3 2132

TCTCCCOCTCCGCCTGCTTGTGACCTCCGAGTCCTCAGTAAACTGCTTCGTGACTCCCAT

GTCCTTCACAGCAGACTGAOCCAGTGCCCAGAGGTTCACCCTTTGCCTACACCTGTCCTO

CTGCCTGCTGTGGACTTTAGCTTGGGAGAATGGAAAACCCAGATGGAGGAGACCAAGGC

CAGGACATTCTGGGAGCAGTGACCCTTCTGCTGGAGGGAGTGATGGCAGCACGGGGACAA

CTOOGACCCACTTGCCTCTCATCCCTCCTGGGGCAOCTTTCTGGACAGOTCCGTCTCCTC

CTTGGGGCCCTGCAGAGCCTCCTTGGJJCCCAGCTTCCTCCACAGGGCAGGACCACAGCT

CACAAGGATCCCAJATGCCATCTTC

CTGAGCTTCCAACACCTGCTCCGAGGIAJAGGTGCGT

TTCCTGATGCTTGTAOOAGGGTCCACCCTCTOCGTCAOO (SEQ ID NO: 249) PMON3 2133

TCTCCCGCTCCGCCTGCTTGTGACCTCCGAGTCCTCAGTAAACTGCTTCGTGACTCCCAT

GTCCTTCACAGCAGACTGAGCCAGTGCCCAGAGGTTCACCCTTTGCCTACACCTGTCCTG

CTGCCTGCTGTGGACTTTAGCTTGGGAGATGGAACCCAGATGGAGGAGACCAAGGCA

CAOGACATTCTOGGAGCAGTGACCCTTCTGCTGGAGGGAGTGATGGCAGCACGGGGACAA

CTGOOACCCACTTOCCTCTCATCCCTCCTGGGOCAOCTTTCTGOACAOOTCCOTCTCCTC

CTTGGOGCCCTGCAOAOC CTCCTTGG7 4

CCCAGGGCAGGACCACAGCTCACAAGGATCCC

WO 97/12985 PrTlITCO'cl-jr.? 121

AATGCCATCTTCCTGAGCTTCCAACACCTGCTCCGACGGAAAGTGCTT(TAGT

CTAGGAOGGTCCACCCTCTGCOTCAGG (SEQ ID NO:250) pM0N32134

TCCCCAGCGCCGCCTGCTTGTGACCTCCGAGTCCTCAGTAAACTGCTCGACCT

GTCCTTCACAGCAGACTGAGCCAGTGCCCAGAGGTTCACCCTTTGCCTAACGCT

CTGCCTGCTGTGGACTTTAGCTTGGGAGATGGAAAACCCAGATGGAGACAGA

CAGGACATTCTGGGAGCAGTGACCCTTCTGCTGGAGGGAGTGATGGCAGAGGAA

CTGGGACCCACTTGCCTCTCATCCCTCCTGGGGCAGCTTTCTGGACA(

GTCGCC

CTTGGGGCCCTGCAGAGCCTCCTTGGAACCCAGCTTCCTCCACAGGGAACCGT

CACAAGGATCCCAATGCCATCTTCCTGAGCTTCCAACACCTGCTCCGGAGTCT

TTCCTGATGCTTGTAGGAGGGTCCACCCTCTGCGTCAOG (SEQ ID NO: 251) Pmonl3l8.

1 51 101 151 201 251 301 351 401 451

CCATGGCTAA

AGACCACCTG

C TC TAT CCTG

TAAGGGCTGT

CGTAATCTCC

TCCAATCATC

CGTTCTATCT

ggcggtggag

CCCGTCTCCT

CCGCATGCAA

CTGCTCTATA

ATGATCGATG

CACCTTTGCT

GGACCCGAAC

ATGGATCGAjA

ACCTTCGACT

CAAGAACTTA

GAAAATGCAT

AACCATGTCT

OCCCTCTGCC

ATCAAGGCAG

GTGACTGGCA

GOTTACCCTT

GAGCAAGCGC

gctcCCCGGG

TGAACCGTCT

CCGTCTAAAG

AATCTCATAA

GCTT (SEQ ID NO:257)

AAATTATACA

AACCTCAATG

TCCAAACCTG

CAGGTATTGA

ACGGCCGCAC

AGAATTCCOG

AGGAACAACA

GGTCCAATCT

ATCTCCAAAC

TCACTTAAAG

ACGAAGACGT

GAGAGCTTCG

GGCAATTCTT

CCTCTCGACA

GAAAAACTGA

GTACGTAgag

CTACTATCAA

ATGTAAGGTA

Pmonl3 180 .Seg 1 51 101 151 201 251 301 351 401 CCATGGCTAA CTGCTCTATA ATGATCGATG AAATTATACA

TCACTTAAAG

AGACCACCTG CACCTTTGCT GGACCCGAAC AACCTCAATG

ACGAAGACGT

CTCTATCCTG ATGGATCGAA ACCTTCGACT TCCAAACCTG

GAGAGCTTCG

TAAGGGCTGT CAAGAACTTA GA.AAATGCAT CAGGTATTGA

GOCAATTCTT

CGTAATCTCC AACCATGTCT GCCCTCTGCC ACGGCCGCAC

CCTCTCGACA

TCCAATCATC ATCAAGCAG GTGACTGGCA AGAATTCCGG

GAAAAACTGA

CGTTCTATCT GGTTACCCTT GAGCAAGCGC AGGAACAACA GTACGTAgag ggcggtggag gctcCCCGGG TGGTGGTTCT GGCCOCGGCT

CCAACATGTA

AGGTACCGCA TGCAAGCTT (SEQ ID NO:258) WO 97/12985 PCT11URGAIIC-YPYA 122- TABLE 3 PROTEIN SEQUENCES pM0N26458pep ValLeuHisSerArLeuSerGnCysProGuVaHProQProh~o~le L euProAiaValAspPheS erLeuGlyG luTrpLysThrGlnMetGluG luThrLysAl a PheLeuMetLeuValGlyGlyS erThrLeuCysVa1ArgGluPhe (SEQ ID NO:161) pM0N28548pep SerProAlaProProAlaCysAspLeu~rgValLeuS erLysLeuLeuArgAsps erHi s LeuPro aviAsp Ser~u heseurpLshrly~e~l~l~h 1 1 LeuGlyProThrCysLeuSerSerLeuLeuGlyGlnLeuSerGlGlVl~r~ue LeuGlyAlaLeuGinS erLeuLeuGlyThrGlnLeuProProG lnGlyArgThrThrAla HisLysAspProAsnAaIePheLeuSer heGn nH±SeLeu eUA~lLy al~ Ph~ue~ua~l~ye re~s~lr~uh~ylyAsivetAla SerProAlaProProAlaCysAspLeuArgValLeuS erLysLeuLeuArgAspSer~is Va~ui~rr~ue~ny~o~ua~sr~ur~rr~le LeuProAlaValAspPheSerLeuGyGuTrpLysThrG1etGluGluThrLysAla GlnAspIleLeuGlyAlaValThrLeuLeuLeuGluGlyValMetAlaAlaArgGll LulAlaL eul reue~yh~l~yr h~rl~ sLysAspPro AsnAlal lePheLeuSerPheGn~isLeuLeuArgGlyy l~gh~e~te ValGlyGlyserThrLeuCysValArg (SEQ ID NO:162) pMON2 8500 LeuProAlaValAspPheSerLeuGlyuTrpLysThr GlueGl ThLla GlnAsplleLeuGlyAlaValThrLeuLeuLeuGluGlyValMetAlaAlaArgGlyGln LeuGlyProThrCysLeuSerS erLeuLeuGlyGlnL euS erGlyGlnvalArgL euLeu LeuGlyAlaLeuGlnS erLeuLeuGlyThrGlnLeuProProG lnGlyArgThrThrAla HisLysAspProAsnAlallePheLeuSerPheGlnHisLeuLeuArgGlyLysValArg Ph~ue~ua~yl~rh~uy~lr~uh~ysie~ae Pr~ar~ol~ss~ur~a ue~se~ur~pe~ sVal Le~se~ge~rl~sr~u~li~oe~oh~oa~ue ProAlaValAspPheS erLeuGlyGluTrpLysThrG lrMetG luG luThrLysAlaGln AsplleLeuGlyAlaValThrLeuLeuLeuGluGlyValMetAlaAlAGlGlnL GlyProThrCysLeuSerSerLeuLeuGl lnL eu~eGlyGal VLLLe GlyAlaLeuGlnSerLeuLeuGlyThrGlnLeuProProGlnGlrThThAlaH WO 97/12985 lDt-'rffTc!n 123 LeuMetLeuValclyGlySerThrLeuCysValArg (SEQ ID NO: 163) pMON2 8501 SerProAlaProProA icysAspLeuArg va~e~e LySe~e~g~peri LeuProAiaValAspPheS erLeuGlyGluTrpLysThrGl1etGluG iuThrLysAla GlnAspIleLeuGlyAla valThrLeuLeuLeuV~ltlaAlarlyl Hi sLysAspProAsnAialePheLeuSerPheolnHi sLeuLeuArgoiyLysValArg PheLeuMtLealeuvleryhLeysaAGlhellysmta LeuProAiaValAspPheSerLeuGlyGuTrpLysThrG1ri~tGiul~r~sl GinAspIleLeuGiyAlaValThrLeuLeuLeuGiuGiyValMetAlaAlaArgGiydln LeuGlyProThrCysLeuSerSerLeuLeuGiyGlnLeuSerGlydlnvalArgL euLeu HisbysAspProAsnAlalePheLeuSerPheGnHisLeuLAGiyy~lr PheLeuMetLeuVaiGiyGiySerThrLeuCysValArg (SEQ ID NO: 164) pMON2 8502 LeuProAiaV& iAspPheSerLeuGyGluTrLsThrGlietlluhysa LeuGiyProThrCysLeuSerSerLeuLeuGiyGinLeuSerdiyGlnVaiArg~euLeu LeuGlyAaLeuGnSerLeuLeuGlyThlnLn eoPro riGlrghr~r AsniMetAlaS erProAlaProProAiaCysAspLeuArgValL euSerLysLeuLeuArg ProValLeuLeuProAlaVaAspPheSerLeuGlyGluTrLThrGlrie~u ThrLysAlaGlnAspIl1eLeuGlyAiavalThrLeuL euLeuG iuGiyValMetAlaAla Ar~ue~ul~l el~re~u~yh~ne~oriGlynaig (SEQ ID NO:165) 13182 .Pept Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg Pro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Giu Asp Val Ser Ile Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Giu Ser Phe Val Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly Ile Glu Ala Ile Leu Arg Asn Leu Gin Pro Cys Leu Pro Ser Ala Thr Ala Ala Pro Ser Arg His Pro Ile Ile Ile Lys Ala Gly Asp Trp Gin Glu Phe Arg Giu Lys Leu Thr Phe Tyr Leu Val Thr Leu Giu Gin Ala Gin Giu Gin Gin Tyr Val Giu Gly Gly Gly Gly Ser Pro WO 97/12985 PCTIUS96/15 7 74 124 Gly Gly Gly Ser Gly Gly His Pro Giu Giu Leu Val Trp Ala Pro Leu Ser Ser Gly Cys Leu Ser Gin Leu Leu Leu Gin Ala Leu Glu Leu Asp Thr Leu Gin Leu Trp Gin Gin Met Giu Glu Thr Gin Gly Ala Met Pro Ala Gly Gly Val Leu Val Val Ser Tyr Arg Val Leu Ser Gly Gly Ser Gin Ser Arg Lys Ile Gin Gly Asp Ala Thr (SEQ ID NO:166) Gly Leu Cys His Gly Asp Leu Ala Ala Arg Phe Gly Ser Leu Pro Ser Ile Val Gly Phe Ser His Leu Ala Asn Met Gly His Ser Gin Gly Leu Ser Pro Ala Asp Met Ala Ala Ser His Leu Leu Ala Leu Lys Ala Leu Ala Ser Ala Phe Giu Phe Pro Ala Gin Gin Ser Gin Tyr Ly: Leu Leu Gly Ile Leu Gin Leu Leu Tyr Gin Leu Gly Pro Ala Thr Thr Ala Leu Gin Phe Gin Arg Ser Phe Leu PrcG Ser Gly Leu Glu Gin Giu Lys Leu Cys Pro Ala Gly Thr Ile Pro Arg Giu Gly Val Cys 13183 Pept Asn Cys Pro Pro Val Ser Ser Phe Giu Ala Ala Ala Gin Glu Gin Ala Gly Glu Ser Lys His Pro Trp Ala Gly Cys Leu Leu Leu Asp Trp Gin Thr Gin Ala Gly Val Ser Ser Gly Arg Lys Ala Thr Ser Ile Met Ile Ala Pro Leu Leu Ile Leu Met Asp Val Arg Ala Val Ile Leu Arg Asn Pro Ser Arg His Phe Arg Giu Lys Gin Giu Gin Gin Pro Ser Gly Pro Glu Ser His Lys Giu Giu Leu Val Pro Leu Ser Ser Leu Ser Gin Leu Gin Ala Leu Glu Thr Leu Gin Leu Gin Met Giu Giu Gly Ala Met Pro Giy Val Leu Val Tyr Arg Val Leu Gly Ser Gin Ser Ile Gin Gly Asp (SEQ ID NO:167) Asp Glu Asp Pro Arg Asn Lys Asn Leu Gin Pro Ile Leu Thr Tyr Val Ile Ser Ser Pro Leu Leu Cys Pro His Ser Gly Ile Asp Val Leu Gly Ala Phe Ala Ser Arg His Phe Leu Gly Ala Ile Ile Asn Asn Leu Arg Leu Giu Pro Cys Ile Ile Phe Tyr Giu Gly Thr Ile Asn Met Gly His Ser Gin Gly Leu Ser Pro Ala Asp Met Ala Ala Ser His Leu Leu Ala Leu Lys Ala Leu His Letq Leu Asn L eu Lys Leu Gly Asn Ala Ser Ala Phe Giu Phe Pro Ala Gin Gin Ser Gin his Asn Pro Ala Pro Ala Val Gly Pro Tyr Leu Leu Leu Leu Ala Ala Phe Ser Pro Leu Glu L eu Asp Asn Ser Ser Gly Thr Gly Ser Lys Gly Gin Tyr G ly Thr L eu Gin Phe S er Giu Lys Lys Giu Leu Gly Ala Asp Leu Ser Pro Leu Ile Leu Gin Pro Thr Gin Arg Leu Gly Gin Leu Arg Asp Giu Ile Thr Trp Giu Pro Pro Cys Pro Ala Gly Thr Ile Pro Arg Giu Gly Val Cys 13 184. Pept Asn Cys Ser Pro Pro Ala Val Ser Ile Ser Phe Val Giu Ala Ile Ala Ala Pro Gin Giu Phe Gin Ala Gin Giy Gly Gly Ile Met Ile Asp Glu Pro Leu Leu Asp Pro Leu Met Asp Arg Asn Arg Ala Val Lys Asn Leu Arg Asn Leu Gin Ser A rg His Pro Ile Arg Giu Lys Leu Thr Giu Gin Gin Tyr Vai Ser Gly Gly Gly Ser Ile Ile His His Asn Asn Leu Asn Leu Arg Leu Pro Leu Giu Asn Ala Pro Cys Leu Pro Ile Ile Lys Ala Phe Tyr Leu Val Giu Gly Gly Giy Asn Met Ala Pro L eu Asp Asn S er S er Giy Thr Gly Giu Lys Giu Leu Gly Ala Asp Leu Ser Leu Arg Asp Giu Ile Thr Trp Giu Pro Gly WO 97/12985 PCTIUS96/1 5774 Pro Thr Gin Arg Leu Gly Gin Leu Leu Pro Ser I I e Thr Ile Pro Arg Giu Giy Val Cys Gly Ser Gly .q r LeU Asp Trp Gin Thr Gin Ala Gly Val Ser Ser Gly Arg Lys Ala Thr His Ser Gin Ala Leu Phe (SEQ ID Thr Leu Gin Met Gly Ala Gly Val Tyr Arg Gly Ser Ile Gin Tyr Lys Leu Gly Leu Gin Leu Tyr NO: 168) Gin Giu Met Leu Val Gin Gly Leu Ile L eu Gin Leu Asp Giu Leu Pro Ala Val Ala Leu Arg Ser Phe Asp Gly Cys His Pro Trp Ala Gly Gly Leu Vai Gly Phe S er His L eu Ala Pro Ala Cys L eu Ala Met Ala His Leu Leu Ala Giu Pro L eu Gin Asp Phe Ala Ala Pro Ala Ser Ala Phe Leu Gin Ser Ala Gin Pro Lys Ser Leu Leu Gin Giu Giu Leu Val Leu Ser Ser Ser Gin Leu Aia Leu Glu Thr Leu Gin Phe Ser Giu Lys Leu Cys His Gly l 3 Asn Cys Ser Ile Met Ile Pro Pro Ala Pro Leu Leu Val Ser Ile Leu Met Asp Ser Phe Val Arg Ala Val Giu Ala Ile Leu Arg Asn Ala Ala Pro Ser Arg His Gin Giu Phe Arg Glu Lys Gin Ala Gin Giu Gin Gin Gly Giu Pro Ser Gly Pro Ser Lys Giu Ser His Lys Pro Thr Leu Asp Thr Leu Thr Ile Trp Gin Gin Met Gin Pro Thr Gin Gly Ala Arg Arg Ala Gly Gly Val Leu Giu Val Ser Tyr Arg Gly Gly Ser Giy Gly Ser Gin Val Arg Lys Ile Gin Leu Cys Ala Thr Tyr Lys Leu Giy His Ser Leu Gly Pro Ser Gin Ala Leu Gin Ser Gly Leu Phe Leu Tyr Ile Ser (SEQ ID NO:i69) Asp Giu Asp Pro Arg Asn Lys Asn Leu Gin Pro Ile Leu Thr Tyr Val Ile Ser Ser Pro Gin Leu Giu Giu Met Pro Leu Val Val Leu Gin Ser Gly Asp Leu Cys Ile Pro Leu Ala Gin Gly Ile Asn Leu Leu Pro Ile Phe Glu Thr Asn Asp Leu Ala Ala Arg Phe Gly His Trp Gly Leu Ile Asn Arg Giu Cys Ile Tyr Gly Ile Met Val Gly Phe S er His L eu Aia Pro Ala Cys L eu His His Leu Leu Asn Asp Leu.Pro Asn Asn Ala Ser Leu Pro Ser Lys Ala Giy Leu Val Thr Gly Gly Gly Asn Pro Ser Ala Pro Glu Ala Asp Phe Met Ala Pro Ala Ser Ala His Leu Gin Leu Ala Gin Leu Lys Ser Ala Leu Gin Giu Giu Leu Pro Leu Ser Leu Ser Gin Gin Ala Leu Lys Giu Leu Gly Ala Asp Leu Ser Pro Leu Ala Ala Phe Ser Pro Leu Giu Val Ser Leu Giu Arg Asp Glu Ile Thr Trp Giu Pro Pro Gly Thr Leu Gin Phe Ser Giu Lys Leu Cys His G ly 13 186. Pept Asn Cys, Ser Ile Met Pro Pro Ala Pro Leu Val Ser Ile Leu Met Ser Phe Vai Arg Ala Giu Ala Ile Leu Arg Ala Ala Pro Ser Arg Gin Giu Phe Arg Giu Gin Ala Gin Giu Gin Gly Gly Gly Ser Gly Leu Gin Pro Thr Gin Ile Leu Asp Val Asn His Lys Gin Gly Gly Asp Asp Arg Lys L eu Pro Leu Tyr Gly Ala Giu Ile Ile His His Leu Lys Pro Asn Asn Leu Asn Asp Glu Asn Leu Arg Leu Pro Asn Leu Asn Leu Giu Asn Ala Ser Gly Gin Pro Cys Leu Pro Ser Ala Ile Ile Ile Lys Ala Gly Asp Thr Phe Tyr Leu Val Thr Leu Vai Giu Gly Giy Gly Gly Ser Ser Asn Met Ala Met Ala Pro Met Pro Ala Phe Ala Ser Ala Arg Asp Glu Ile Thr Trp Glu Pro Aia Phe WO 97/12985 126 PCTIUS96/1 5774 Gin Phe Ser Glu Lys Leu Cys His Gly Asp Leu Arg Leu Gly Gin Leu Leu Pro Ser Ile Val Gly Arg Ala Glu Val Gly Ser Val Arg Cys Ala Gly His Ser Gin Gi" Leu Ser Pro Ala Asp (SEQ ID Gly Gly Ser Tyr Gly Gly Lys Ile Thr Tyr Ser Leu Ala Leu Phe Leu Glu Leu Phe Ala NO:170) Val Arg Ser Gin Lys Gly Gin Tyr Gly Thr Leu Val Gin Gly Leu Ile Leu Gin Pro Thr Val Leu Ser Asp Cys Pro Ala Gly Thr Ile Ala Arg Phe Gly His Trp Gly Leu Leu Trp Ser His Led His Leu Ala Leu Leu Lys Ala Ala Leu Pro Giu Glu Ala Pro Leu Cys Leu Ser Leu Gin Ala Asp Thr Leu Gin GirT Met Gin Gin Ser Gin Leu Ser Gin Leu Gin Glu Ser Pro Leu Glu Val Ser Leu Glu Leu Glu 13187. Pept Asn Cys Pro Pro Val Ser Ser Phe Giu Ala Ala Ala Gin Giu Gin Ala Gly Glu Ser Lys Leu Gin Gin Arg Phe Leu Ser Gly Glu Gin Lys Leu Leu Leu Cys Pro His Ser Gly Ile Asp Val Leu Gly Ser Ile Ala Pro Ile Leu Val Arg Ile Leu Pro Ser Phe Arg Gin Glu Pro Ser Glu Ser Pro Thr Arg Ala Glu Val Gly Ser Val Arg Cys Ala Gly His Ser Gin Gly Leu Ser Pro Ala Asp (SEQ ID Met Ile Leu Leu Met Asp Ala Val Arg Asn Arg His Glu Lys Gin Gin Gly Pro His Lys Gin Gly Gly Gly Ser Tyr Gly Gly Lys Ile Thr Tyr Ser Leu Ala Leu Phe Leu Glu Leu Phe Ala NO: 171) Asp Giu Ile Ile His His Leu Asp Pro Asn Asn Leu Asn Asp Arg Asn Leu Arg Leu Pro Asn Lys Asn Leu Giu As4 Ala Ser Leu Gin Pro Cys Leu Pro Ser Pro Ile Ile Ile Lys Ala Gly Leu Thr Phe Tyr Leu Val Thr Tyr Vai Giu Gly Gly Gly Gly Ile Ser Thr Ile ASn Pro Ser Ser Pro Asn Met Ala Met Ala Ala Met Pro Ala Phe Ala Ser Val Leu Val Ala Sex His Leu Arg Val Leu Arg His Leu Ala Ser Gin Ser Phe Leu Leu Lys Gin Gly Asp Gly Ala Ala Leu Lys Leu Cys His Pro Giu Glu Gly Ile Pro Trp Ala Pro Leu Gin Leu Ala Gly Cys Leu Ser Tyr Gin Gly Leu Leu Gin Ala Gly Pro Thr Leu Asp Thr Leu Thr Thr Ile Trp Gin Gin Met Lys Glu Leu Gly Ala Asp Leu Ser Pro Pro Ala Gin Gin Ser Gin Leu Ser Gin Leu Gin Glu Arg Asp Glu Ile Thr Trp Glu Pro Pro Ala Phe Ser Pro Leu Glu Val Ser Leu Glu Leu Giu 13188.Pept Asn Pro Val Ser Glu Ala Gin Gin Gly Met Leu Cys Ser Pro Ala Ser Ile Phe Vai Ala Ile Ala Pro Glu Phe Ala Gin Gly Gly Pro Ala Val Ala Ile Pro Leu Arg Leu Ser Arg Giu Ser Phe Ser Met Leu Met Ala Arg Arg Glu Gin Gly Ala His Ile Leu Asp Val Asn His Lys Gin Gly Ser Leu Asp Glu Asp Pro Arg Asn Lys Asn Leu Gin Pro Ile Leu Thr Tyr Val Gly Ser Ala Phe Gin Ser Ile Ile Asn Asn Leu Arg Leu Glu Pro Cys Ile Ile Phe Tyr Glu Gly Asn Met Gin Arg Phe Leu His His Leu Asn Leu Pro Asn Ala Leu Pro Lys Ala Leu Val Gly Gly Ala Thr Arg Ala Glu Val Leu Asp Asn Ser Ser Gly Thr Gly Gin Gly Ser Lys Glu Leu Gly Ala Asp Leu Ser Gly Gly Tyr Arg Asp Glu Ile Thr Trp Glu Pro Ala Val Arg WO 97/12985 PCT/US96/15774 Val Gin Gly Leu Ile Leu Gin Pro Thr Gin Leu Ser Asp Cys Pro Ala Gly Thr Ile Pro Arg His Phe Leu Gly Ala His Pro Trp Ala Gly Cys Leu Leu Leu Asp Trp Gin (SEQ ID Leu Ala Leu Lys Ala Leu Glu Glu Pro Leu Leu Ser Gin Ala Thr Leu Gin Met NO:172) Gin Pro Ser Leu Gin Glu Leu Val Ser Ser Gin Leu Leu Glu Gin Leu Glu Glu Ser Gly Glu Gin Lys Leu Leu Leu Cys Pro His Ser Gly Ile Asp Val Leu Gly Gly Val Cys Gly Ser Gly Ser Ala Met Ser Arg Ala His Gin Leu Pro Asp Ala Gly Lys Thr Ser Ala Phe Glu Phe Pro Gly Ile Tyr Leu Leu Leu Leu Ala Ala Ser Gin Lys Gly Gin Tyr Gly Thr Leu 13189.Pept Asn Pro Val Ser Glu Ala Gin Gin Gly Ser Met Leu Val Gin Gly Leu Ile Leu Gin Pro Thr Gin Cys Ser Ile Pro Ala Pro Ser Ile Leu Phe Val Arg Ala Il- Leu Ala Pro Ser Glu Phe Arg Ala Gin Glu Glu Pro Ser Lys Glu Ser Pro Ala Phe Val Ala Ser Leu Arg His Ser Phe Leu Asp Gly Ala Cys His Pro Pro Trp Ala Ala Gly Cys Gly Leu Leu Thr Leu Asp Ile Trp Gin Pro (SEQ ID Met Ile Leu Leu Met Asp Ala Val Arg Asn Arg His Glu Lys Gin Gin Gly Pro His Lys Ala Ser His Leu Leu Ala Leu Lys Ala Leu Glu Glu Pro Leu Leu Ser Gin Ala Thr Leu Gin Met NO:173) Asp Glu Ile Ile His His Leu Asp Pro Asn Asn Leu Asn Asp Arg Asn Leu Arg Leu Pro Asn Lys Asn Leu Glu Asn Ala Ser Leu Gin Pro Cys Leu pro Ser Pro Ile Ile Ile Lys Ala Gly Leu Thr Phe Tyr Leu Val Thr Tyr Val Glu Gly Gly Gly Gly Ile Ser Thr Ile Asn Pro Ser Ser Pro Asn Met Ala Thr Gin Ala Phe Gin Arg Arg Ala Gly Gin Ser Phe Leu Glu Val Ser Gin Pro Ser Gly Gly Ser Gly Ser Leu Glu Gin Val Arg Lys Gin Glu Lys Leu Cys Ala Thr Leu Val Leu Leu Gly His Ser Ser Ser Cys Pro Ser Gin Ala Gin Leu His Ser Gly Leu Phe Leu Glu Gly Ile Ser Pro Glu Gin Leu Asp Val Ala Asp Phe Glu Glu Leu Gly Met Ala Pro Lys Glu Leu Gly Ala Asp Leu Ser Pro Gly Gly Tyr Gly Ile Tyr Leu Leu Leu Leu Ala Ala Arg Asp Glu lle Thr Trp Glu Pro Pro Ala Val Arg Ser Gin Lys Gly Gin Tyr Gly Thr Leu 13190.Pept Asn Pro Val Ser Glu Ala Gin Gin Gly Arg Leu Gly Cys Ser Pro Ala Ser Ile Phe Val Ala Ile Ala Pro Glu Phe Ala Gin Gly Gly Arg Ala Glu Val Gly Ser Ile Met Pro Leu Leu Met Arg Ala Leu Arg Ser Arg Arg Glu Glu Gin Ser Gly Gly Gly Ser Tyr Gly Gly Ile Asp Glu Leu Asp Pro Asp Arg Asn Val Lys Asn Asn Leu Gin His Pro Ile Lys Leu Thr Gin Tyr Val Gly Gly Ser Val Leu Val Arg Val Leu Ser Gin Ser Ile Ile His His Leu Lys Asn Asn Leu Asn Asp Glu Leu Arg Leu Pro Asn Leu Leu Glu Asn Ala Ser Gly Pro Cys Leu Pro Ser Ala Ile Ile Lys Ala Gly Asp Phe Tyr Leu Val Thr Leu Glu Gly Gly Gly Gly Ser Asn Met Ala Ser Ala Phe Ala Ser His Leu Gin Ser Arg His Leu Ala Gin Pro Phe Leu Leu Lys Ser Leu Arg Asp Glu Ile Thr Trp Glu Pro Gin Phe Ser Glu WO 97/12985 PCTIUS96/t1 5 7 7 4 Gin Val Leu Cys Leu Gly Pro Ser Ser Gly Ile Ser Val Ala Gly Met Phe Ala Arg Lys Ile Gin Ala Thr Tyr Lys His Ser Leu Gly Gin Ala Leu Gin Lei, Phe Leu Tyr Pro Giu Leu Gly Asp Phe Ala Thr Ala Pro Ala- Leu (SEQ ID NO:174) Gly Leu Ile Leu Gin Pro Thr Gin Asp Cy s Pro Ala Giy Thr Ile Pro Gly His Trp Gly Leu Leu Trp Thr Ala Pro Ala Cys L eu Asp Gin Gin Ala Leu Giu Giu Pro Leu Leu Ser Gin Ala Thr Leu Gin Met Gly Ala Gin- Giu Leu Val Ser Ser Gin Leu Leu Giu Gin Leu Giu Giu Met Pro Lys Leu Cys His Gly Asp Leu Ala 131 9 1i.Pept Asn Cys Pro Pro Val Ser Ser Phe Giu Ala Ala Ala Gin Giu Gin Ala Gly Giu Ser Lys Arg Arg Leu Giu Gly Gly Gin Val Leu Cys Leu Gly Pro Ser Ser Gly Ile Ser Val Ala Gly Met Phe Ala Ser Ile met Ile Ala Pro Leu Leu Ile Leu Met Asp Val Arg Ala Val Ile Leu Arg Asn Pro Ser Arg His Phe Arg Glu Lys Gin Giu Gin Gin Pro Ser Gly Pro Giu Ser His Lys Ala Gly Gly Val Val Ser Tyr Arg Ser Giy Gly Ser Arq Lys Ile Gin Ai Thr Tyr Lys His Ser Leu Gly Gin Ala Leu Gin Leu Phe Leu Tyr Pro Giu Leu Gly Asp Phe Ala Thr Ala Pro Ala Leu (SEQ ID NO:i75) Asp Glu Asp Pro Arg Asn Lys Asn Leu Gin Pro Ile Leu Thr Tyr Val Ile Ser Ser Pro Leu Val Vai Leu Gin Ser Gly Asp Leu Cys Ile Pro Leu Ala Gin Gly Pro Thr Thr Ile Gin Pro Ile Asn L eu L eu Pro Ile Phe Glu Thr Asn Ala Arg Phe Gly His Trp Gly Leu L eu Trp Thr Ile Asn Arg Giu Cys Ile Tyr Gly Ile Met S er His L eu Ala Pro Ala Cys Leu Asp Gin Gin His Leu Leu Asn Leu Lys Leu Gly Asn Ala His Leu Leu Ala Giu Pro Leu Gin Thr Gin Gly His Asn Pro Ala Pro .Ala Val Gly Pro Ser Leu Ala Lys Leu Giu Leu Ser Ala Leu Met Ala L eu Asp Asn S er Ser Gly Thr G ly Ser Ala Gin Gin Ser Gin Leu S er Gin Leu Gin G iu Met Ly s Giu Leu Gly Ala Asp Leu Ser Pro Phe Ser Pro Leu Giu Val Ser Leu Giu Leu Giu Pro Arg Asp Giu Ile Thr Trp Giu Pro Pro Gin Phe Ser Giu Lys Leu Cys His Giy Asp Leu Ala 13 192. Pept Asn Cys Pro Pro Val Ser Ser Phe Giu Ala Ala Ala Gin Giu Gin Ala Giy Gly His Pro Trp Ala Gly Cys Leu Leu Ser Ala Ile Vai Ile Pro Phe Gin Gly Giu Pro Leu Gin Ile Pro Leu Arg Leu Ser Arg Giu Ser Giu Leu Ser Ala Met Ile Leu Leu Met Asp Ala Val Arg Asn Arg His Giu Lys Gin Gin Gly Gly Leu Val Ser Ser Gin Leu Leu Giu Asp Asp Arg Lys Leu Pro Leu Tyr Gly Leu Cys His Gly Giu Ile Ile Pro Asn Asn Asn Leu Arg Asn Leu Giu Gin Pro Cys Ile Ile Ile Thr Phe Tyr Val Giu Giy Ser Asn Met Leu Gly His Pro Ser Gin Ser Gly Leu Ile Ser Pro His Leu Leu Asn Leu Lys Leu Gly Ala Ser Ala Phe Glu His Asn Pro Ala Pro Ala Val Gly Tyr Leu Leu Leu Leu Leu Asp Asn Ser S er Gly Thr Gly Lys G ly Gin Tyr Gly Lys Giu Leu Gly Ala Asp Leu Ser Leu Ile L eu Gin Pro Arg Asp Giu Ile Thr Trp Giu Pro Cys Pro Ala Gly Thr WO 97/12985 PCT/US96/15774 Leu Trp Thr Ala Val Gly Glu Lys Asp Thr Gin Gin Gin Gly Gly Gly Ser Tyr Pro Ala Gin Val Leu Cys Leu Gin Met Glu Ala Met Val Leu Arg Val Ser Ser Arg Lys Ala Thr Leu Asp Val Ala Glu Leu Gly Met Pro Ala Phe Ala Val Ala Ser His Leu Arg His Leu Leu Pro Gin Ser Ile Gin Gly Asp (SEQ ID NO:176) Asp Ala Ser Leu Ala Phe Gly Phe Ala Thr Thr Pro Ala Leu Gin Ala Phe Gin Arg Gin Ser Phe Leu Gin Pro Thr Pro Leu Leu Lys Ser Ala Ala Leu Gin lie Pro Arg Glu Leu Leu Glu 13193.Pept Asn Cys Pro Pro Val Ser Ser Phe Glu Ala Ala Ala Gin Glu Gin Ala Gly Glu Ser Lys His Pro Trp Ala Gly Cys Leu Leu Leu Asp Trp Gin Thr Gin Ala Gly Val Ser Gly Pro Glu Gin Lys Leu Ser Ala Ile Val Ile Pro Phe Gin Pro Glu Glu Pro Leu Gin Thr Gin Gly Gly Tyr Ala Val Cys Ile Met Ile Asp Glu Ile Pro Leu Leu Asp Pro Asn Leu Met Asp Arg Asn Leu Arg Ala Val Lys Asn Leu Leu Arg Asn Leu Gin Pro Ser Arg His Pro Ile Ile Arg Glu Lys Leu Thr Phe Glu Gin Gin Tyr Val Glu Ser Gly Pro Ile Ser Thr Ser His Lys Ser Pro Asn Glu Leu Val Leu Leu Gly Leu Ser Ser Cys Pro Ser Ser Gin Leu His Ser Gly Ala Leu Glu Gly Ile Ser Leu Gin Leu Asp Val Ala Met Glu Glu Leu Gly Met Ala Met Pro Ala Phe Ala Val Leu Val Ala Ser His Arg Val Leu Arg His Leu Ser Ser Leu Pro Gin Ser Arg Lys Ile Gin Gly Asp Ala Thr (SEQ ID NO:177) Ile His His Asn Leu Asn Arg Leu Pro Glu Asn Ala Cys Leu Pro Ile Lys Ala Tyr Leu.Val Gly Gly Gly Ile Asn Pro Met Ala Tyr His Ser Leu Gin Ala Leu Leu Phe Leu Pro Glu Leu Asp Phe Ala Ala Pro Ala Ser Ala Phe Leu Gin Ser Ala Gin Pro Phe Leu Leu Gly Ala Ala Leu Asp Asn Ser Ser Gly Thr Gly Ser Lys Gly Gin Tyr Gly Thr Leu Gin Phe Thr Lys Leu Lys Glu Leu Gly Ala Asp Leu Ser Pro Leu Ile Leu Gin Pro Thr Gin Arg Leu Pro Ser Gin Arg Asp Glu Ile Thr Trp Glu Pro Pro Cys Pro Ala Gly Thr Ile Pro Arg Glu Leu Leu Glu 25190.Pept Asn Cys Pro Pro Val Ser Ser Phe Glu Ala Ala Ala Gin Glu Gin Ala Gly Gly Pro Thr Thr Ile Gin Pro Arg Arg Leu Glu Ser Ala Ile Val Ile Pro Phe Gin Gly Leu Trp Thr Ala Val Ile Met Ile Asp Pro Leu Leu Asp Leu Met Asp Arg Arg Ala Val Lys Leu Arg Asn Leu Ser Arg His Pro Arg Glu Lys Leu Glu Gin Gin Tyr Ser Gly Gly Gly Asp Thr Leu Gin Gin Gin Met Glu Gin Gly Ala Met Gly Gly Val Leu Ser Tyr Arg Val Glu Ile Ile His Pro Asn Asn Leu Asn Leu Arg Leu Asn Leu Glu Asn Gin Pro Cys Leu Ile Ile Ile Lys Thr Phe Tyr Leu Val Glu Gly Gly Ser Asn Met Ala Leu Asp Val Ala Glu Leu Gly Met Pro Ala Phe Ala Val Ala Ser His Leu Arg His Leu His Leu Asn Asp Pro Asn Ala Ser Pro Ser Ala Gly Val Thr Gly Gly Pro Glu Asp Phe Ala Pro Ser Ala Leu Gin Ala Gin Lys Glu Leu Gly Ala Asp Leu Ser Leu Ala Ala Phe Ser Pro Arg Asp Glu Ile Thr Trp Glu Pro Gly Thr Leu Gin Phe Thr WO 97/12985 PCTIUS96/1 5774 Pro Ser Gin Leu Ser Gin Leu Leu Gi1- Leu Giu GiU Lys Val Leu Ser Cys Leu His Giu Gly Pro Gin Leu Leu Pro S er Ile Ala Ser Ser Val Arg Lys Cys Ala Thr Gly His Ser Ser Gin Ala Gly Leu Phe Ser (SEQ ID Leu Pro Gin Ile Gin Gly Tyr Lys Leu Leu Giy Ile Leu Gin Leu Leu Tyr Gin NO:i78) Ser Phe Asp Gly Cys His Pro Trp Aia Giy Giy Leu Aia Pro Ala Cys Leu Leu Lys Ala Leu Giu Giu Pro Leu Leu Ser Gin Ala PMON25191.Pep Asn Cys Pro Pro Val Ser Ser Phe Giu Ala Ala Ala Gin Glu Gin Ala Gly Giu Ser Lys Pro Thr Thr Ile Gin Pro Arg Arg Leu Glu Pro Leu Ser Leu Gin Giu Leu Val Ser Ser Gin Leu Leu Glu S er Ala Ile Val Ile Pro Phe Gin Pro Glu L eu Trp Thy Ala Val Gly Giu Lys Leu Cys His Gly Ile Met Ile Asp Glu Ile Ile His Pro Leu Leu Asp Pro Asn Asn Leu Leu Met Asp Arg Asn Leu Arg Leu Arg Ala Val Lys Asn Leu Giu Asn Leu Arg Asn Leu Gin Pro Cys Leu Ser Arg His Pro Ile Ile Ile Lys Arg Giu Lys Leu Thr Phe Tyr Leu Giu Gin Gin Tyr Val Giu Gly Giy.

Ser Gly Pro Ile Ser Thr Ile Asn Ser His Lys Ser Pro Asn Met Ala Asp Thr Leu Gin Leu Asp Vai Ala Gin Gin Met Glu Giu Leu Gly Met Gin Gly Ala Met Pro Ala Phe Ala Giy Gly Val Leu Val Ala Ser His Ser Tyr Arg Val Leu Arg His Leu Pro Ala Ser Ser Leu Pro Gin Ser Gin Val Arg Lys Ile Gin Gly Asp Leu Cys Ala Thr Tyr Lys Leu Cys Leu Gly His Ser Leu Gly Ile Pro Pro Ser Gin Ala Leu Gin Leu Ala Ser Gly Leu Phe Leu Tyr Gin Gly Ile Ser (SEQ ID NO:l79) His Leu Asn Asp Pro Asn Ala Ser Pro Ser Ala Gly Val Thr Giy Gly Pro Ser Pro Giu Asp Phe Ala Pro Ser Ala Leu Gin Ala Gin Phe Leu Gly Ala His Pro TrP Ala Gly Cys Leu Leu Lys Giu Leu G ly Ala Asp Leu S er Pro Leu Ala Ala Phe Ser Pro Leu Ala Giu Pro Leu Gin Arg Asp Giu Ile Thr Trp Giu Pro Pro Gly Thr Leu Gin Phe Thr Lys Leu Giu Leu Ser Ala 13194. Pept Asn Pro Val Ser Giu Ala Gin Gin Gly Leu Gin Phe Thr Lys Leu Cy s Pro Ser Phe Ala Ala Giu Ala Gly Gin Arg Leu Pro Ser Gin Ser Ala Ile Val Ile Pro Phe Gin G ly Pro Arg Giu L eu Leu Glu Ile met Pro Leu Leu Met Arg Ala Leu Arg Ser Arg Arg Giu Giu Gin Ser Gly Thr Gin Ala Gly Val Ser Gly Pro Giu Gin Lys Leu Ile Asp Giu Ile Ile Leu Asp Pro Asn Asn Asp Arg Asn Leu Arg Val Lys Asn Leu Giu Asn Leu Gin Pro Cys His Pro Ile Ile Ile Lys Leu Thr Phe Tyr Gin Tyr Val Giu Giy Gly Gly Ser Asn Met Giy Ala Met Pro Ala Giy Val Leu Val Ala Tyr Arg Val Leu Arg Ala Ser Ser Leu Pro Val Arg Lys Ile Gin Cys Ala Thr Tyr Lys His His Leu Asn Leu Pro Asn Ala Leu Pro Lys Ala Leu Vai Gly Gly Ala Met Phe Ala Ser His His Leu Gin Ser Gly Asp Leu Cys Leu Lys Asp Glu Asn Leu Ser Gly Ser Ala Gly Asp Thr Leu Gly Ser Ala Pro Ser Ala Leu Gin Ala Gin Phe Leu Gly Ala His Pro Arg Asp Giu Ile Thr Trp Glu Pro Ala Phe Ser Pro Leu Ala Giu WO 97/12985 PCT/US9615774 Glu Leu Ser Ala Leu Met Leu Val Ser Ser Gin Leu Leu Glu Gin Leu Giu Glu Leu Leu Cys Pro His Ser Gly Ie Asp Val Leu Giy Gly His Ser Gin Gly Leu Ser Pro Ala Asp (SEQ ID Ser Leu Ala Leu Phe Leu Glu Leu Phe Ala NO: 180) Gly Gin Tyr Gly Thr Ile Pro Leu Ala Gin Gly Pro Thr Thr Ile Trp Ala Pro Gly Cys Leu Leu Leu Gin Leu Asp Thr Trp Gin Gin 13 19 5. Pept Asn Cys Pro Pro Val Ser Ser Phe Giu Ala Ala Ala Gin Giu Gin Ala Gly Glu Ser Lys Leu Gin Gin Arg Phe Leu Thr Pro Lys Ser Leu Gin Giu Leu Leu Ser Ser Gin Ala Leu Leu Gin Met Glu S er Ala Ile Val Ile Pro Phe Gin Pro Glu Pro Arg Giu Leu Leu Giu Val Ser Leu Giu L eu Giu Ile met Pro Leu Leu Met Arg Ala Leu Arg Ser Arg Arg Giu Giu Gin Ser Gly Ser His Thr Gin Ala Gly Val Ser Gly Pro Giu Gin Lys Leu Leu Leu Cys Pro His Ser Gly Ile Asp Vai Leu Gly Ile Asp Leu Asp Asp Arg Val Lys Asn Leu His Pro Lys Leu Gin Tyr Pro Ile Lys Ser Giy Ala Gly Val Tyr Arg Ala Ser Val Arg Cys Ala Gly His Ser Gin Giy Leu Ser Pro Ala Asp (SEQ ID Gil Pro Asr Asn Gin Ile Thr Val Ser Pro Met Leu Val Ser Lys Thr Ser Ala Phe Giu Phe

NO:

Ile Asn Leu Leu Pro Ile Phe Giu Thr Asn Pro Val Leu Leu Ile Tyr Leu Leu Leu Leu Ala 181) Ile Asn Arg Glu Cys Ile Tyr Giy Ile Met Ala Ala Arg Pro Gin Lys Gly Gin Tyr Gly Thr His His Leu Asn Leu Pro Asn Ala Leu Pro Lys Ala Leu Val Gly Gly Asn -pro Ala Met Phe Ala Ser His His Leu Gin Ser Gly Asp Leu Cys Ile Pro Leu Ala Gin Gly Pro Thr Thr Ile Leu Asp Asn S er S er Giy Thr G ly Ser Ala S er Leu Ala Phe G ly His Trp G ly Leu Leu Trp Lys Glu Leu G ly Ala Asp Leu Ser Pro Pro Ala Gin Gin Leu Ala Pro Ala Cys Leu Asp Gin Arg Asp Giu TIe Thr Trp Glu Pro Pro Ala Phe Ser Pro Leu Ala Glu Pro Leu Gin Thr Gin 13 19 6.Pept Asn Cys Pro Pro Val Ser Ser Phe Giu Ala Ala Ala Gin Giu Gin Ala Giy Gly Met Pro Leu Val Val Leu Ser Leu Lys Ile Thr Tyr Ser Leu Ser Ala Ile Val Ile Pro Phe Gin Gly Ala Ala Arg Pro Gin Lys Gly Ile Met Ile Asp Pro Leu Leu Asp Leu Met Asp Arg Arg Ala Val Lys Leu Arg Asn Leu Ser Arg His Pro Arg Giu Lys Leu Glu Gin Gin Tyr Ser Gly Gly Gly Phe Ala Ser Ala Ser His Leu Gin His Leu Ala Gin Gin Ser Phe Leu Gly Asp Giy Ala Leu Cys His Pro Ile Pro Trp Ala Glu Ile Ile Pro Asn Asn Asn Leu Arg Asn Leu Giu Gin Pro Cys Ile Ile Ile Thr Phe Tyr Val Glu Gly Ser Asn Met Phe Gin Arg Ser Phe Leu Pro Thr Pro Leu Lys Ser Aia Leu Gin Giu Giu Leu Pro Leu Ser His Leu Leu As n Leu Lys Leu Gly Ala Arg Giu Leu Leu Giu Val Ser His Asn Pro Ala Pro Ala Val Gly Thr Ala Val Gly Glu Lys Leu Cy s Leu Asp Asn Ser S er Gly Thr Gly Gin Gly Ser Pro Gin Leu Leu Pro Lys Giu Leu Gly Ala Asp Leu Ser Gly Gly Tyr Ala Val Cys Gly Ser Arg Asp Glu Ile Thr Trp Glu Pro Ala Val Arg Ser Arg Ala His Gin WO 97/12985 PCTIUS96/1 5 7 7 4 Ala Leu Gin Phe Leu Tyr Giu Leu Gly Phe Ala Thr Pro Ala Leu Leu Gin Pro Thr Gin Ala Gly Thr Ile Pro Gly Cys Leu Ser Gin Leu His Sez, Gly Leu Leu Gin Ala Leu Glu Gly Ile Ser Leu Asp Thr Leu Gin Leu Asp Val Ala Trp Gin Gin Met Giu Giu Leu Gly Met (SEQ ID NO:182) Leu Pro Asp Ala 13197 Pept Asn Cys Pro Pro Val Ser Ser Phe Giu Ala Ala Ala Gin Glu Gin Ala Gly Giu Ser Lys Met Pro Leu Val Val Leu Ser Leu Lys Ile Thr Tyr Ser Leu Ala Leu Phe Leu Giu Leu Phe Ala Pro Ala Ser Ile Met Ala Pro Leu Ile Leu Met Val Arg Ala Ile Leu Arg Pro Ser Arg Phe Arg Giu Gin Glu Gin Pro Ser Gly Glu Ser His Ala Phe Ala Ala Ser His Arg His Leu Pro Gin Ser Gin Gly Asp Lys Leu Cys Gly Ile Pro Gin Leu Ala Tyr Gin Gly Gly Pro Thr Thr Thr Ile Leu Gin Pro Ile Asp Leu Asp Asp Arg Val Lys Asn Leu His Pro Lys Leu Gin Tyr Pro Ile Lys Ser Ser Ala Leu Gin Ala Gin Phe Leu Gly Aia His Pro Trp Ala Gly Cys Leu Leu Leu Asp Trp Gin (SEQ ID Giu Ile Pro Asn Asn Leu Asn Leu Gin Pro Ile Ile Thr Phe Val Giu Ser Thr Pro Asn Phe Gin Ser Phe Pro Thr Leu Lys Ala Leu Giu Giu Pro Leu Leu Ser Gin Ala Thr Leu Gin Met NO: 183) Ile His Asn Leu Arg Leu Giu Asn Cys Leu Ile Lys Tyr Leu Gly Gly Ile Asn Met Ala.

Arg Arg Leu Giu Pro Leu Ser Leu Gin Giu Leu Val Ser Ser Gin Leu Leu Giu Gin Leu Glu Giu His- Leu Asn Asp Pro Asn Ala Ser Pro Ser Ala Giy Val Thr Gly Giy Pro Ser Thr Gin Ala Gly Val Ser Gly Pro Giu Gin Lys Leu Leu Leu Cys Pro His Ser Gly Ile Asp Val Leu Gly Lys Giu Leu Gly Ala Asp Leu Ser Pro Giy Gly Tyr Aia Val Cys Gly Ser Giy Ser Ala Met Arg Asp Glu Ile Thr Trp Giu Pro Pro Ala Val Arg Ser Arg Ala His Gin Leu Pro Asp Ala 1319 8. Pept Asn Pro Val S er Giu Ala Gin Gin Gly Arg Leu Pro Ser Gin Leu Ser Gin Cy s Pro Ser Phe Ala Ala Giu Ala Giy Arg Giu Leu Leu Glu Val Ser Leu Ser Ala Ile Val Ile Pro Phe Gin Gly Ala Vai Gly Giu Lys Leu Cys His Ile Pro Leu Arg Leu Ser Arg Giu Ser Gly Ser Pro Gin Leu Leu Pro Ser Met Leu Met Ala Arg Arg Giu Gin Gly Gly Tyr Ala Val Cys Gly Ser Gly Ile Leu Asp Vai Asn His Lys Gin Gly Val Arg Ser Arg Ala His Gin Leu Asp Asp Arg Lys Leu Pro Leu Tyr Gly Leu Val Ser Lys Thr Ser Ala Phe Giu Pro Asn Asn Gin Ile Thr Val Ser Vai Leu Leu Ile Tyr Leu Leu Leu Ile Asn Leu Leu Pro Ile Phe G iu Asn Ala Arg Pro Gin Lys Gly Gin Tyr Ile Asn Arg Giu Cys Ile Tyr Gly Met Ser His Gin Gly Leu Ile Leu Gin H is Hiss Leu Leu Pro Asn Asn Ala Ser Leu Pro Ser Lys Ala Gly Leu Val Thr Gly Gly Gly Ala Ser Ala His Leu Gin LeU Ala Gin Ser Phe Leu Asp Gly Ala Cys His Pro Pro Trp Ala Ala Gly Cys Gly Leu Leu Lys Glu Leu Gly Ala Asp Leu Ser Phe Ser Pro Leu Ala Giu Pro Leu Gin Arg Asp Giu Ile Thr Trp Giu Pro Gin Phe Thr Lys Leu Giu Leu Ser Ala WO 97/12985 Leu Glu Gly Gin Leu Asp Glu Glu Leu Met Pro Ala 133 Ile Ser Pro Glu Leu Gly Pro Thr Leu Val Ala Asp Phe Ala Thr Thr Ile Trp Gly Met Ala Pro Ala Leu Gin Pro Thr Phe Ala (SEQ ID NO:184) PCT/US96/15774 Asp Thr Leu Gln Gin Met Gin Gly Ala 13199.Pept Asn Cys Ser Pro Pro Ala Val Ser Ile Ser Phe Val Glu Ala Ile Ala Ala Pro Gin Glu Phe Gin Ala Gin Gly Glu Pro Ser Lys Glu Arg Arg Ala Leu Glu Val Pro Leu Gly Ser Leu Glu Gin Glu Lys Leu Val Leu Ser Ser Cys Gin Leu His Leu Glu Gly Gin Leu Asp Glu Glu Leu Met Pro Ala Ile Met Pro Leu Leu Met Arg Ala Leu Arg Ser Arg Arg Glu Glu Gin Ser Gly Ser His Gly Gly Ser Tyr Pro Ala Gin Val Leu Cys Leu Gly Pro Ser Ser Gly Ile Ser Val Ala Gly Met Phe Ala Ile Asp Glu Ile Ile Leu Asp Pro Asn Asn Asp Arg Asn Leu Arg Val Lys Asn Leu Glu Asn Leu Gin Pro Cys His Pro Ile Ile Ile Lys Leu Thr Phe Tyr Gin Tyr Val Glu Gly Pro Ile Ser Thr Ile Lys Ser Pro Asn Met Val Leu Val Ala Ser Arg Val Leu Arg His Ser Ser Leu Pro Gin Arg Lys Ile Gin Gly Ala Thr Tyr Lys Leu His Ser Leu Gly Ile Gin Ala Leu Gin Leu Leu Phe Leu Tyr Gin Pro Glu Leu Gly Pro Asp Phe Ala Thr Thr Ala Pro Ala Leu Gin (SEQ ID NO:185) His His Leu Asn Leu Pro Asn Ala Leu Pro Lys Ala Leu Val Gly Gly Asn Pro Ala Ser His Leu Leu Ala Ser Phe Asp Gly Cys His Pro Trp Ala Gly Gly Leu Thr Leu Ile Trp Pro Thr Leu Asp Asn Ser Ser Gly Thr Gly Ser Ala Gin Gin Leu Ala Pro Ala Cys Leu Asp Gin Gin Lys Glu Leu Gly Ala Asp Leu Ser Pro Phe Ser Pro Leu Ala Glu Pro Leu Gin Thr Gin Gly Arg Asp Glu Ile Thr Trp Glu Pro Pro Gin Phe Thr Lys Leu Glu Leu Ser Ala Leu Met Ala 31104.Pep Leu Asp Asp Arg Val Lys Asn Leu His Pro Lys Leu Gin Gly His His Gly Gly Pro Ser Thr Gin Ala Gly Val Ser Ser Gly Arg Lys Ala Thr His Ser Pro Asn Asn Gin Ile Thr Gly Leu Ser Pro Gly Gly Tyr Gly Ile Tyr Leu Asn Asn Leu Asn Asp Glu Leu Arg Leu Pro Asn Leu Leu Glu Asn Ala Ser Gly Pro Cys Leu Pro Ser Ala Ile Ile Lys Ala Gly Asp Phe Tyr Leu Val Thr Leu Gly Ser Asn Cys Ser Ile Lys Arg Pro Pro Ala Pro Pro Gly Glu Pro Ser Gly Pro Ser Lys Glu Ser His Ala Met Pro Ala Phe Ala Val Leu Val Ala Ser His Arg Val Leu Arg His Leu Ser Gin Ser Phe Leu Leu Gin Gly Asp Gly Ala Ala Lys Leu Cys His Pro Glu Gly Ile Pro Trp Ala Pro Asp Val Ser Ile Glu Ser Phe Val Ile Glu Ala Ile Thr Ala Ala Pro Trp Gin Glu Phe Glu Gin Ala Gin Met Ile Asp Glu Leu Tyr Val Glu Pro Ile Ser Thr Lys Ser Pro Asn Ser Ala Phe Gin Leu Gin Ser Phe Ala Gin Pro Ser Lys Ser Leu Glu Leu Gin Glu Lys Glu Leu Val Leu Leu Ser Ser Cys Leu Met Arg Ala Leu Arg Ser Arg Arg Glu Glu Gin Ile Ile Gly Gly Ile Asn Met Ala Arg Arg Leu Glu Gly Gly Gin Val Leu Cys Leu Gly Pro Ser WO 97/12985 PCT/US96/15774 Gin Leu Pro Asp Ala Ala Phe Glu Phe Pro Leu Leu Leu Ala Ala Gin Leu Ala Gly Cys Leu Ser Gin Tyr Gin Gly Leu Leu Gin Ala Leu Gly Pro Thr Leu Asp Thr Leu Gin Thr Thr Ile Trp Gin Gin Met Glu Leu Gin Pro (SEQ ID NO:186) Leu His Ser Glu Gly Ile Leu Asp Val Glu Leu Gly Gly Ser Ala Met 31105.Pep Asn Leu Lys Leu Asn Pro Val Ser Gly Pro Thr Ala Val Ser Arg Ala His Gin Leu Pro Asp Ala Ala Pro Ala Val Cys Pro Ser Phe Gly Ser Gin Gly Ser Gly Lys Thr Ser Ala Phe Glu Phe Pro Ser Ser Gly Thr Ser Ala Ile Val Ser Pro Gly Gly Tyr Gly Ile Tyr Leu Leu Leu Leu Ala Ala Gly Ile Ala Thr Asp Trp Leu Glu Ile Met Pro Leu Leu Met Arg Ala Pro Gly Pro Ser Ala Met Val Leu Arg Val Ser Gin Gin Gly Lys Leu Gly Ile Gin Leu Tyr Gin Gly Pro Thr Thr Leu Gin Glu Ala Gin Gin Ile Leu Asp Val Glu Lys Pro Val Leu Ser Asp Cys Pro Ala Gly Thr Ile Pro Ala Ile Ala Pro Glu Phe Ala Gin Asp Glu Asp Pro Arg Asn Lys Asn Pro Ser Glu Ser Ala Phe Ala Ser Arg His Phe Leu Gly Ala His Pro Trp Ala Gly Cys Leu Leu Leu Asp Trp Gin Leu Ser Arg Glu Ile Asn Leu Leu Gly His Ala His Leu Leu Ala Glu Pro Leu Gin Thr Gin Arg Arg Glu Gin Ile Asn Arg Glu Pro Lys Ser Leu Ala Lys Leu Glu Leu Ser Ala Leu Met Asn Leu His Pro Lys Leu Gin Gly His His Leu Asn Leu Pro Tyr Val Ile Ser Sec -Pro Ala Phe Gin Ser Gin Pro Ser Leu Gin Glu Leu Val Ser Ser Gin Leu Leu Glu Gin Leu Glu Glu Gin Pro Cys Ile Ile Ile Thr Phe Tyr Gly Gly Ser Leu Lys Arg Asp Glu Asp Asn Leu Glu Glu Gly Gly Thr Ile Asn Asn Met Ala Gin Arg Arg Phe Leu Glu Ser Gly Gly Glu Gin Val Lys Leu Cys Leu Leu Gly Cys Pro Ser His Ser Gly Gly Ile Ser Asp Val Ala Leu Gly Met (SEQ ID NO:187) 3 1106.Pep Ala Glu Ala Asp Asp Arg Lys Leu Gly Pro Thr Ala Val Ser Arg Ala His Pro Ser Phe Arg Gin Glu Glu Ile Pro Asn Asn Leu Asn Leu Gin Pro Gly Ser Ser Pro Gin Gly Gly Gly Ser Tyr Gly Gly Lys Ile Thr Tyr Ser Leu Arg Glu Gin Ile Asn Arg Glu Cys Pro Pro Ala Val Arg Ser Gin Lys Gly His Pro Lys Leu Gin Gly His His Leu Asn Leu Pro Asn Ala Leu Pro Gly Glu Ser Lys Met Pro Leu Val Val Leu Gin Ser Gly Asp Leu Cys Ile Pro Ile Thr Gly Leu Asp Asn Ser Ser Pro Glu Ala Ala Arg Phe Gly His Trp Ile Phe Gly Lys Glu Leu Gly Ala Ser Ser Phe Ser His Leu Ala Pro Ala Ile Tyr Ser Arg Asp Glu Ile Thr Gly His Ala His Leu Leu Ala Glu Pro Lys Leu Asn Pro Val Ser Glu Ala Pro Lys Ser Leu Ala Lys Leu Glu Leu Ala Gly Asp Val Thr Leu Cys Ser Ile Pro Ala Pro Ser Ile Leu Phe Val Arg Ala Ile Leu Tyr Val Glu Ile Ser Thr Ser Pro Asn Ala Phe Gin Gin Ser Phe Gin Pro Ser Ser Leu Glu Gin Glu Lys Leu Val Leu Ser Ser Cys Trp Glu Met Leu Met Ala Arg Gly Ile Met Arg Leu Gly Gin Leu Leu Pro Gin Gin Ile Leu Asp Val Asn Gly Asn Ala Arg Glu Gly Val Cys Gly Ser WO 97/12985 135 PCT/US96/15774 Gin Ala Leu Gin Leu Ala Gly Cys Leu Ser Gin Leu Phe Leu Tyr Gin Gly Leu Leu Gin Ala Leu Pro Glu Leu Gly Pro Thr Leu Asp Thr Leu Gin Asp Phe Ala Thr Thr Ile Trp Gin Gin Met Glu Ala Pro Ala Leu Gin Pro (SEQ ID NO:188) Leu His Ser Glu Gly Ile Leu Asp Val Glu Leu Gly Gly Ser Ala Met 31107.Pep Ala Val Cys Pro Ser Phe Ala Ala Gly Pro Thr Ala Val Ser Arg Ala His Gin Leu Pro Asp Ala Gly Thr Ser Ala Ile Val Ile Pro Gly Ser Gin Gly Ser Gly Lys Thr Ser Ala Phe Glu Phe Pro Asp Trp Leu Glu Ile Met Pro Leu Leu Met Arg Ala Leu Arg Ser Arg Ser Pro Pro Pro Gly Ala Gly Val Tyr Arg Gly Ser Ile Gin Tyr Lys Leu Gly Leu Gin Leu Tyr Leu Gly Ala Thr Ala Leu Gin Gin Ile Leu Asp Val Asn His Gly Ser Met Leu Val Gin Gly Leu Ile Leu Gin Pro Thr Gin Glu Ala Asp Asp Arg Lys Leu Pro Glu Lys Pro Val Leu Ser Asp Cys Pro Ala Gly Thr Ile Pro Phe Arg Glu Lys Gin Glu Gin Gin Glu Ile Ile His Pro Asn Asn Leu Asn Leu Arg Leu Asn Leu Glu Asn Gin Pro Cys Leu Ile Ile Ile Lys Pro Ser Gly Pro Glu Ser His Lys Ala Phe Ala Ser Ala Ser His Leu Arg His Leu Ala Phe Leu Leu Lys Gly Ala Ala Leu His Pro Glu Glu Trp Ala Pro Leu Gly Cys Leu Ser Leu Leu Gin Ala Leu Asp Thr Leu Trp Gin Gin Met (SEQ ID NO:189) Leu Thr'Phe Gly Gly Gly His Leu Lys Asn Asp Glu Pro Asn Leu Ala Ser Gly Pro Ser Ala Tyr Val Glu Ile Ser Thr Ser.Pro Asn Ala Phe Gin Gin Ser Phe Gin Pro Ser Ser Leu Glu Gin Glu Lys Leu Val Leu Ser Ser Cys Gin Leu His Leu Glu Gly Gin Leu Asp Glu Glu Leu Tyr Ser Arg Asp Glu Ile Thr Gly Ile Met Arg Leu Gly Gin Leu Leu Pro Ser Ile Val Gly Leu Asn Pro Val Ser Glu Ala Gly Asn Ala Arg Glu Gly Val Cys Gly Ser Gly Ser Ala Met 31108.Pep Leu Asp Pro Asp Arg Asn Val Lys Asn Asn Leu Gin His Pro Ile Lys Leu Thr Gin Gly Gly Ser Ile Met Ala Pro Leu Ser Gly Pro Ser His Lys Phe Ala Ser Ser His Leu His Leu Ala Leu Leu Lys Ala Ala Leu Pro Glu Glu Asn Asn Leu Arg Leu Glu Pro Cys Ile Ile Phe Tyr Gly Ser Ile Asp Tyr Val Ile Ser Ser Pro Ala Phe Gin Ser Gin Pro Ser Leu Gin Glu Leu Val Leu Leu Asn Leu Lys Leu Gly Glu Glu Thr Asn Gin Phe Ser Glu Lys Leu Asn Pro Ala Pro Ala Val Gly Ile Gly Ile Met Arg Leu Gly Gin Leu Leu Asp Asn Ser Ser Gly Thr Gly Ile Gly Asn Ala Arg Glu Gly Val Cys Gly Glu Asp Leu Glu Gly Ile Ala Thr Asp Trp Leu Glu Ser Gly His His Gly Gly Pro Ser Thr Gin Ala Gly Val Ser Ser Gly Arg Lys Ala Thr His Ser Val Ser Glu Ala Gin Gin Gly Leu Ser Pro Gly Gly Tyr Gly Ile Tyr Leu Ser Phe Ala Ala Glu Ala Gly Lys Pro Pro Ala Val Arg Ser Gin Lys Gly Ile Val Ile Pro Phe Gin Ser Arg Gly Ser Met Leu Val Gin Gly Leu Ile Leu Met Arg Ala Leu Arg Ser Arg Arg Glu Glu Gin Asn Cys Pro Pro Glu Pro Lys Glu Pro Ala Val Ala Leu Arg Ser Phe Asp Gly Cys His Pro Trp WO 97/12985 PCTIUS96/15 7 7 4 Ala Pro Leu Ser Ser Cys Leu Ser Gin Leu Leu Gin Ala Leu Glu Asp Thr Leu Gin Leu Gin Gin Met Giu Glu (SEQ ID NO:190) Cys His Gly Asp Leu Pro Ser Gin Ala Leu Ser Gly Leu Phe Leu Ile Ser Pro Giu Leu Val Ala Asp Phe Ala Giy Met Ala Pro Ala Gin Leu Ala Tyr Gin Gly Gly Pro Thr Thr Thr Ile Leu Gin Pro Gly Leu Leu Trp 31109 Pep Asn Ala Ser Leu Pro Ser Lys Ala Gly Leu Val Thr Gly Gly Gly Gu Ile Ile Pro Asn Asn Asn Leu Arg Asn Leu Giu Ser Gly Pro Ser His Lys Phe Ala Ser Ser His Leu His Leu Ala Leu Leu Lys Ala Ala Leu Pro Glu Giu Ala Pro Leu Cys Leu Ser Leu Gin Ala Asp Thr Leu Gln Gin Met (SEQ ID NO: Gly Ala Asp Leu Ser His Leu Leu Tyr Ile Ser Ala Gin Gin Ser Gin Leu Ser Gin Leu Gin Giu 191) Ile Thr Trp Giu Gly His Asn Pro Val Ser Pro Phe Ser Pro Leu Glu Val Ser Leu Glu Leu Glu Giu Ala Gin Gin Gly Leu Asp Asn Giu Thr Asn Gin Phe Ser Giu Lys Leu Cys His Gly Asp Leu Ala Ile Leu Ala Pro Ser Giu Phe Arg Ala Gin Giu Gly Ser Asn Lys Arg Pro Giu Asp Val Leu Giu Ser Gly Gly Gly Ile Asn Pro Met Ala Thr Arg Arg Ala Leu Glu Val Gly Gly Ser Gin Val Arg Leu Cys Ala Leu Gly His Pro Ser Gin Ser Gly Leu Ile Ser Pro Val Ala Asp Giy Met Ala Arg Arg Giu Gin Cys Pro S er Phe Gly Ser Gin G ly S er Gly Lys Thr S er Ala Phe G iu Phe Pro Asn Leu-Gln His Pro Lys Leu Gin Gly *Ser Ile Ala Pro Ile Leu Val Arg Ser Pro Pro_ Pro Giy Ala Gly Val Tyr Arg Gly Ser Ile Gin Tyr Lys Leu Gly Leu Gin Leu Tyr Leu Gly Ala Thr Ala Leu Ile Thr Gly Met L eu Met Ala Gly Ser Met Leu Val Gin Gly Leu Ile Leu Gin Pro Thr Gin Pro Ile Phe Gly Ile Leu Asp Val Glu Lys Pro Val Leu Ser Asp Cys Pro Ala Gly Thr Ile Pro Cys Ilie Tyr Ser Asp Asp Arg Lys Pro Glu Ala Ala Arg Phe Gly His Trp Giy Leu Leu Trp 31110. Pep Ala Glu Ala Gly Lys Glu L eu Gly Ala Ser Ser Phe Ser His Leu Ala Pro Pro Phe Gin Ser Arg Asp Giu Ile Thr Gly His Ala His Leu Leu Ala Giu Ser Arg Giu Asn Pro Val Ser Glu Ala Pro Lys Ser L eu Ala Lys Leu Giu Arg Giu Gin Cys Pro Ser Phe Ala Tyr Ile Ser Ala Gin Gin Ser Gin Leu His Lys Gin Ser Ala Ile Val Ile Val Ser Pro Phe Ser Pro Leu Giu Val Pro Leu Gly Ile Pro Leu Arg Leu Giu Thr Asn Gin Phe Ser Giu Lys Leu Ile Thr Gly Met Leu Met Ala Arg G ly Ile Met Arg Leu Gly Gin Leu Leu Ile Phe Gly Ile Leu Asp Val Asn Gly Asn Ala Arg Giu Gly Val Cys Gly Ile Tyr Ser Asp Asp Arg Lys, Leu Gly Pro Thr Ala Val Ser Arg Ala His Lys L eu Gly Glu Pro Asn Asn Gin Gly S er Gin G ly S er Gly Lys Thr Ser Ala Val Gly Ile Asn Leu Leu Pro Ser Pro Gly Gly Tyr Gly Ile Tyr Leu Gly Thr Gly Ile Asn Arg Giu Cys Pro Pro Ala Val Arg Ser Gin Lys Gly Asp Leu Ser His Leu Leu Asn L eu Gly Ser Met L eu Val Gin Gly L eu Ile Trp Glu Gly His Asn Pro Ala Pro Giu Lys Pro Val Leu Ser Asp Cys Pro Gin Gin Gly Leu Asp Asn Ser Ser Pro Giu Ala Ala Arg Phe Gly His Trp WO 97/12985 PCTJUS96,1 5774 Ala Pro Leu Ser Ser Cys Leu Ser Gin Leu Leu Gin Ala Leu Glu Asp Thr Leu Gin Leu Gin Gin Met Glu Glu (SEQ ID NO:192) Cys His Gly Asp Leu Pro Ser Gin Ala Ser Gly Leu Phe Ile Ser Pro Giu Val Ala Asp Phe Gly Met Ala Pro Leu Gin Leu Tyr Leu Gly Ala Thr Ala Leu Leu Gl1a Gly Pro Thr Leu Thr Ile Trp Gin Pro 311il.Pep Ala Gly Val Thr Gly Gly Ile Ile Asn Asn Leu Arg Leu Giu Pro Cys Ile Ile Ser Gly Ser His Phe Ala Ser His His Leu Leu Leu Ala Ala Pro Giu Ala Pro Cys Leu Leu Gin Asp Thr Gin Gin Asp Leu Ser His Leu Leu Asn Leu Lys Pro Lys S er L eu Ala Lyz,: Leu Giu Leu Ser Ala Leu Met Trp Glu Gly His Asn Pro Ala Pro Ile Ser Ala Gin Gin Ser Gin Leu Ser Gin Leu Gin Gin Gin Gly Leu Asp As n Ser Ser Val Ser Pro Phe Ser Pro Leu Glu Val Ser Leu Giu Leu Giu Giu Ala Gly Lys Giu Leu G ly Ala Giu Thr Asn Gin Phe Ser Glu Lys Leu Cys His G ly Asp L eu Phe Arg Gin Giu Ser Asn Arg Pro Asp Val Glu Ser Ile Giu Thr Ala Gly Gly Ile Asn Met Ala Arg Arg Leu Giu Giy Gly Gin Val Leu Cys Leu Gly Pro Ser Ser Gly Ile Ser Vai Ala Giy met Giu Gin Cys Pro Ser Phe Ala Ala Gly Pro Thr Ala Val Ser Arg Ala His Gin Leu Pro Asp Ala Lys Gin Ser Ala Ile Vai Ile Pro Gly S er Gin G ly S er G ly Lys Thr S er Ala Phe Giu Phe Pro Leu Giy Ile Pro Leu Arg Leu Ser Ser Pro G ly G ly Tyr Gly Ile Tyr Leu Leu Leu Leu Ala Ala Thr-Phe Tyr Gly Gly Ser Met Ile Asp Leu Leu Asp Met Asp Arg Ala Val Lys Arg Asn Leu Arg His Pro Pro Gly Giu _Pro Ser Lys Aia Met Pro Val Leu Val Arg Vai Leu Ser Gin Ser Gin Gly Asp Lys Leu Cys Gly Ile Pro Gin Leu Ala Tyr Gin Gly Gly Pro Thr Thr Thr Ile Leu Gin Pro Leu Gly Giu Pro Asn Asn Gin Ile Pro Giu Ala Ala Arg Phe Gly His Trp Gly Leu Leu Trp (SEQ ID NO:193) 981 ProLeuLeuAspProAsnAsnLeu~sAspGluAspValSerI ieLeuMetAspArgAsn erPheVaiArgAiaVaiLysAsn~~eu luAsnAlaS er GiyIieGiuAiaIieLeuArgAsnLeuGlnProCys~euPrQ erAiaThrAiaAiaPro PheTyrLeuVaiThrLeuGiuGinAiaGinoiuGinG inTyrVaiGiuGiyGiyGiyGiy SerProGlyGiuProSerGiyPro IleSerThrleAsnProSerProProSerLysGiu GlyHisSerLeuGlylieProTrpAlaProLeuSerS erCysProSerGinAlaLeuGin LeuAaGlyCysLeuSerGnLeuHisSerGlyLeuPLeu euT~lGiyLuli AiaLeuGuGyleSerr~lroGileuroyhro~sThrLeu~slL~i~li AiaAspPheAiaThrThrlieTrpGinGliMetGiuGluLeuGiyMetAiaProAiaLeu GinProThrG inGiyAiaMet ProAiaPheAlaserAiaPheGinArgArgAiaGlyGiy VaiLeuVaiAiaSerHisLeuGinSerPheLeuGiuVaiSerTyrArgVaiLeArgHi LeuAlaGnProGyGyGySerAspMetAiarr~u~roiAiSeru ProGinSerPheLeuLeuLysS erLeuGiuGinVaiArgLysIieGinGlyAspGlyAia AlabeuGinGiuLysLeuCysAiaThr (SEQ ID NO:i94) WO 97/12985 Prr1yjva4,, 138 TI cn lE pMON15982 MetAlaAsnCysSerIleMetIleAspGlu~leIleHSHiSLeUy~gr~o ProLeuLeuAspProAsnAsnLeuAsnAspGluAspVa1SerIleLeuetASpArgAsn PheTyrLeuValThrLeuGluGlnAlaGlnGu~lGlnTVall~yl~yl SerProGlyG'i ProSerGlyProIleSerThrIleAsnProSerPPSeysl AspValAlaAspPheAlaThrThrIeTrpGnG1etGluGluelytlar AlaLeuGlnProThrGlnGlyAlaMetProAlaPheaeAlalhe~nr~g GlyGlyValLeuValAlaSer~iisLeuGlnSerPheLeuGluValSerTyrArgValLeu Ar~se~a~nr~yl~ye~pe~ah~oe~yr~ae SerLeuProGlnSerPheLeuLeuLysSerLeuGlGlVlArg 1 ~eGlnGlyAsp GlyAlaAlaLeuGlnGluLysLeuCysAlaThr~yrLysLeuCE S~ProGluG luLeu ValLeuLeuGyHisSerLe uGylIe~ro r aPrLSreY' o~r LeuLeuGlnAlaLeuGluGlyIleSer (SEQ ID NO:195) pMON15965 ProLeuLeuAspProAsDAsnLeuAsnAspGuAspValSIleuetsrgn er h~lr~aa~s~ne~us~ae PheTyrLuvar1ThlulneucinuGnflTVll~yl~y ProGlyGlyGlySerAspMetAaThrProLeuG1yProAlSSeeurlnr GlyCysLeuSerGlnLeu~isSerlyeulyeLeu eurln~ yrLeuGl~laLe .GluGlyIleSerProGluLeuGlyp~roe~sThr enLep~hrL l~las PheAlaThrThrl leTrpGlnGlniMetGluGluLeuG lyMetAlaProAlaLeuGlnPro 'ThrGlnGlyAlaMetProAlaPheAla (SEQ ID NO:196) pMON15966 MetAlaAsnCysSerIleMetIleAspGluIleIleHisHis~euLysArgProProAla ProLeuLeuAspProAsnAsnLeuAsspGuAspValSI leLeuMetASpArgAsn PheTyrLeuValThrLeuGluGlnAlaGlnGluGllG lnTyrValGluGlyGlyGlyGly SerProGlyGluPro serGly proIle serThrIleAsnProSslu SerHisLysSerProAsnMetAa~etAaProAaLeuGlPThr 111~~e Pr~ah~ae~ah~nr~g~al~ya~ua~ae~se WO 97/12985 139- AlaThrTyrLysLeuCys~isProGuGuLeuVaeLeuGl.se~e~y ProTrpAlaProLeuSerSerCysProSerGlnAlaLeu 011l~y~seue GlnLeuHisSerGye~e~uy~ nGlyer0 uJLGllaeluyler IleTrpGlnGlnMetGluoluLeuGly (SEQ ID NO:197) pMON15967 ProLeuLeuAspProAsnAsnLeu~sASspCuAValSerleLeul~etAspArgAsn erPheVa1ArgAlaValLysAsfLeu~ 0 luAsnAlaSer PheTyrLeuVaThrLeuGuGnAaGnGluGlnyrVllu y lyGly SerPro~lyGluProSerGlyPro IleSerThrlleAsnProSerProProSerLysGlu SerHisLysSerProAsnMetAaThrGnGyA etPAahe~ae~a IleGlnGlyAspGlyAaAaLeuGnGuLysLeuCysAaTh~ry~e~s ProGluGluLeuValLeuLeuGlyHisSerLeuGlyI leProTrpAlaProLeuS erSer CysProSerGlnAaLeuG1euAlaGyCysLeuSer~lLeHisey~u LeuTyrGlnGlyLeuLeuGlnAlaLeuGluGlyIleS erProGluLeuclyProThrLeu AspThrLeuGlnLeuAspValAlaAspPheAlaThrThrIleTrpGlriG nMeto luGlu LeuGlyMetAlaProAlaLeuGlnPro (SEQ ID NO:198) pMON3 1112 .pep MetAlaAsnCysSerAsniMetIleAspGluIleIleThisLeuy~nr~oe ProLeuLeuAspPheAsnAsnLeuAsnGYG1uAspGlAIleuetssnn LeuArArgProAsnLeuo1UAlaph~l~a~s re~l~n~ae ThrArgHisPro IleHis l~ss~ys~ps~l~er~gy~uh PheTyrLeuLysmhrLeuGuAsnAaGnAaGnGlnyVlGluGlyllyy SerProGlyGluProSerGlyProleTle shr roeePrPoe~sl SerHisLysSerProAsetAaThrGnG ya~etPAlPhlaelah Gl~gr~alyl~le llae~se~nerPheLeuGluValSer TyrArgValLeuArgisLeuAal~oflr 05 ly 0 y 01 r~yly 0 j 0 1 5 j r LysLeuCysAlaThrrLysLeuCysYs~rS~lG1uG1u~ LeLul.se LeuGlyl leProTrpAlaProLeuSerSerCysProS erGlnAlaLeuc~lnLeuAlaoly CysLeuSerGlnLeuHisSerGlyLeuPeuylyLeu urLeGlnlaLeu (SEQ ID NO:199) WO 97/12985 Pl-'r/TTQo,</li 140 Z 1 pMON3 1113 .pep MetAlaAsnCysSerAsrietIleAspGluIleIieThr iLeU~~nr~O ProLeuLeuAspPheAsnAsnLeuAsnGlyGuAspGlApleLeul~etGluAsnAsfl Le~gr~os~ul~ah~n~gl~ly~re~ns~ae Ala~e~l~erleLeuLysAsnLeuLeuProCysLeuProLeUAlaThrAlaAlar Th~gi~ol~el~gs~y~pr~nl~er~gy~uh PheTyrLeuLysThrLeuGluAsnAlaGlnAlaGlnGlnTyrVaGl~yl~yl SerProGlyGluproS erGlyProI leSerThrl leAsnProS erProProSerLysGlu SerHisLysSerProAsnmetAlaThrGlnGlyAlaMetPAlPhAlaelah Gl~gr~al~ya~ua~a~ri~ul~rh~ul~le Ty~ga~ur~i~ul nr~r~oe~yr~aerS erLeuPro GlnSerPheLeuLeuLysSerLeuGluGlnValArgLysl leGlnGlyAspGlyAlaAla LeuGln~GluLysLeuCysAlaThrTyrLysLeuCysHisPr GiGiue~l~ue GlyHisSerLeueiyIleProTrpAiaProLeuSerSerCysProSeGlleun LeuAlaGlyCysLeuSerGlnLeuHisSerGlyLeuPhebeuTyGl~ye~ul AlaLeuGiuGyIeSerProGuLeucyProThrLeuAsThLul~u~pa AlaAspPheAlaThrThrleTrpGnGnMetGlueuGMlarla GiriPro (SEQ ID NO:200) pMON3 1114 .pep MetAlaAsnCysSerAsnMetleAspGullelThrHiLsbi oe ProLeuLeuAspPheAsnAsnLeuAsnGyGuAspGlsIieLeetlsn Le~gr~osne~ul esnr~aa~serLeuGinAsn~iaSer Ala~leGiuSerIeLeuLysAsnLeuLeuPrysLeuProLAThla~ar Th~giP-.l~el~gs~y~pr~nl~er~gy~uh PheTyrLeuLysThrLeuGluAsnAanlanlanGlnrVlGlGlly~y SerProGiyGluProSerGyProIeSerThrIeAsnoeProePrPSeysl SerHisLysSerProAsietAlaThrGlnGlyAaetProAlaPheAl~rlah Gl~gr~al~ya~ua~a~ri~ul~rh~ul~le Ty~ga~u~gi ul~l~oe~ylySerGiyGiySerGlnSerPhe Le~uy~re~ul~lr~s~el~ys~yl~ae~nl LysLeuCysAlaThrTyrLysLeuCysHisProGuGluLeuVeLuGl.se LeuGlyl leProTrpAlaProLeuSerS erCysProS erGirIAlaLeuGinLeuAlaGly CysLeuSerGlnLeuHisSerGlyLeuPheLeuTyrGlnGiyLeuLeuGinAlaLeuGlu GlyleSerProGluLeuGlyProThrLeuAspThrLeuG inLe aAlAlhe AlaThrThrI leTrpelnGlniMetGiuGiuLeuGlyMetAiaProAiaLeuGlnPro (SEQ ID NO:201) pMON3 1115 .pep MetAiaAsnCysSerAsetIeAspGulIleThrHiLLGlnrroe ProLeuLeuAspPheAsnAsnLeuAsnGlyGluAspGlnspT leLeuMetAspASriAsn Le~gr~osne~ul esnr~aa~serLeuGlnAsnAlaSer Alal eGiuS er IieLeuLysAsnLeuLeuProCysLeuProLeuAiaThrAlaAlaPro ThrArg-is Pro IleHis IleLysAspGlyAspTrpAsnGluPheArgArgLySLeuThr PheTyrLeuLysThrLeuGuAsnAaGnAaGnGTyrVlGiGliGlyGly SerProGlycluProSerGlyProlleSerThrl leAsnProSerProProSerLysGlu SerHi sLysSerProAsnimetAlaThrGlnGlyAaMetProAlaPheAiaserAlPhe WO 97/12985 PCTITTOZOr./l C77A 141 erHisLeuGinS erPheLeucd1uValSer GlnserPheLeuLeuLysSerLeuGluclnValArgLys TleG lrGlyAspGlyAlaAia LeuGlnGluLysLeuCysAiaThrTyrLysLeuCysHi sProG luGluLeuValLeULeu GlyHisSerLeuGlyIleProTrpAlaProLeuSerSerCysProSerGlnAlaLeuGln LeuAlaGlyCysLeuSerGlnLeuHi sSerGlyLeuPheLeuTyrGlnGlyLeuLeuGln AlaLeuGluGlyIleSerProGluLeuGlyProThrLeuAspThrLeuGlnLe spa AlaAspPheAlaThrThrTleTrpGnG1ietGuGuLeuGyMetAlPAlae GinPro (SEQ ID NO:202) pMON2 8505 AlaAsnCysSerlleMet l~pl~el~si~e~sr~or~ar LeuLeuAspProAsnAsnLeuAsnAspGluAspValSerIleLeu~etASpArgAsnLeu TyrLeuValThrLeuGluGlnAlaGlnGluGlnGlnTyrValGlu~lyGlyGlyGlySer ProGlyGluProSerGlyProIleSerThrIleAsnProSerProProSeLGlue Hi sLysSerProAsnMetGuValHisProLeuProThrProValLLeuePrAlVl AspPheSerLeuGlycfluTrpLysThrGlnMeGluGluThrLysAaGlnAI leLeu Gl~aa~re~ue~ul~l~tl~ar~yl~ul~oh CysLeuSerSere ul~ne~rl~n~lr~ue~ul~ae GlnSerLeuLeuGlyThrGlnLeuProProGlnGlyArgThrThrAlaHis~ys~spPro AsnAlal ePheLeuSerPheGinHis ue~gl~salr~eemte VaiGlyGlyS erThrLeuCysValArgGluPheG lyG lyAsniMetAlaS erProAlapro Pr~ay~pe~ga~ue~s~ue~gs~ri~le~se ArgLeuSerGlnCysPro (SEQ ID NO:203) pMON28506 Al~ny~rl~tl~pl~e~ei~se~sr~or~ar LeuLeuAspProAsnAsnLeuAsnAspGluAspValS er leLeuMetAspArgAsnLeu Ar~ur~ne~ue~ea~g~aa~ss~ul~nl~rl Il~ul~ee~gs~ul~o~se~oe~ah~al~oe Ar~sr~el~ey~al~p~pl~uh~gl~se~rh TyrLeuValThrLeuGluGlnAlaGlnGluGlnGlnTyrValG luGlyGlyGlyGlySer ProGlyGluProSerGlyproI leSerThrlleAsnProSerproProS erLysGiuSer HisLysSerProAsnMetLeuProThrProValLeuLeuProAlaValAspPheSerLeu GlyGluTrpLysThrGlnMetGluGluThrLysAlaGlnAspIleLeuGlyAlaValThr LeuLeuLeuGluGlyValMetAlaAlaArgGlyGlnLeuG lyProThrCysLeuS erSer LeuLeuGlyGlnLeuSerGlyGlnValArgLeuLeuL euGlyAlaLeuG lnSerLeuLeu Gl~rl~ur~ol~yr~r~rl~sy~pr~nl~eh Le~rh~ni~ue~gl~s~lr~ee~te~ll~ye erProAlaProProAlaCysAsp Le~ga~ue~se~ur~p~ri~le~se~ge~rl CysProGluVal~ispro (SEQ ID NO:204) pm0N28507 AlaAsnCysSerlleMetlleAspGlullelleHisHisLeuLysArgProProAlaPro WO 97/12985 PCTIUQGA/IC-7'7A 142 PTI'oi 7T LeuLeuAspProAsnAsnLeuAsnAspGluAspValS er leLeuMetAsP-ArgAsfLeu~ IlT uleuArgAsnelnrse uroArlanp~l~l~r~ TyrLeuValThrLeuGluGlnAlaGlnGluGlnGlnTyrValGluGlyGlGlyGlye ProGlyGluProSerGlyProl leSerThrlleAsnProSerProProS erLyse luSer Hi sLysSerProAsnMetValLeuLeuProAlaValAspPheS erLeuGlyGluTrpLys ThrGlnMetGluGluThrLysAaG1spIeLeuGyAaVaThrLeLLeu Pr~ol~yrgh~rl syss~os~alePheLeuSerPheGIn Hi~ue~gl~sa~gh~u~te~ll~ye~re~sa Ar~uh~yl~r~tl~rr~ar~ol~ss~ur~le SerLysLeuLeuArgAspSerHisVaLeuHisSerArgLeu~e~~f~yPrQ 1 u~a HisProbeuProThrPro (SEQ ID NO:205) pMON2 8508 AlaAsnCysSerlleMet l~pl~elei~seLy~r~or~ar LeuLeuAspProAsnAsnLeuAsnAspGluAspValSerIleLeuetAspArgAsnLeu Ar~ur~ne~u~rh~lr aa~y~ne~us~aerGly Il~ul~ee~gs~ul~o se~oe~ah~al~oer Ar~sr~el~ey~al~p~pl~uh~gl~se~rh Ty~ua~re~ul~al~u~nl~ra~ul~yl~ye ProGly~lupi oSerGlyProlleSerThrlleAsnProSerProProSerLysGluSer Hi~se~os~tl~ls~e~re~yl~py~rl~tl GluThrLysAlaGlnAsp IieLeuGlyAlaValThrLeuLeuLeuGluGlyValMe tAla Al~gl~ne~yr~ry~u~re~ue~yl~ue~yl ValArgLeuLeuLeuGlyAlaLeuGlnSerLeuLeuGlyThr~ lnLeuProProGlnGly Ar~rh~ai~ss~os~a~eh~ue~el~se~ur Gl~sa~gh~ue~ua~y~ye~re~sa~gl~el GlyAsnMetAlaserProAlaProProAlacysAspLeuArgValLeuS erLysLeuLeu Ar~pe~sa~ui~rr~u~rl~sr~ua~sr~ur ThrProValLeuLeuPro (SEQ ID NO:206) pMON2 8509 AlaAsnCysSerlleMet IleAspGlullelleHisHisLeuLysArgProProAlaPro LeuLeuAspProAsnJ~snLeuAsnAspGluAspValS en leLeuMetAspArgAsnLeu Ar~ur~ne~ue~ea~g~aa~ss~ul~nl~rl Il~ul~ee~gs~ul~o~se~oe~ah~al~oe Ar~sr~el~ey~al~p~pl~uh~gl~se~rh TyrLeuValThrLeuGluGlnJ\1aGlnGluGlnGlnTyrValGTuGlyG lyGlyG lyS er ProGlyc~luProSerGlyProlleSerThrlleAsnProSerProProSerLy sGluSer HisLysSerProAsrietAspPheSerLeuGiyGluTrpLysThrGmetGluGluThr LysAlaGlnAspIleLeuGlyAlaValThrLeuLeuLeuGluGlyValMetAlaAlaArg GlyGlnLeuGiyPromhrCysLeuSerSerLeuLeuelyGlnLeuSerGlyGlnValArg LeuLeuLeuGlyAlaLeuGlnSerLeuLeuGlyThrGlnLeuProProGlnGlyArgThr ThrAlaHisLysAspProAsn.AlaIlePheLeuSerPheGlnHisLeuLeuArgGlyLys Va~gh~ue~ua~yl~r~re~sa~glpel~ys Me~ae~ol~or~ay~p~ur~le~ry~ue~gs Se~sa~ui~rr~ue~n~sr~ua~sr~ur~rr WO 97/12985 PcTfLJSQAII 477A 143- ValLeuLeuProAlaVal (SEQ ID NO:207) pMON2 8510 AlaAsnCysS erIleMet IleAspoluT lelleHi sHis uy~gror~ar LeuLeuAspProAsnAsnLeuAsnAspG1uAspvals erIleLeu~et.AspArgAsnLeu~ ArLeuPr ~snLueciearpheValLyAne~l~n~aer TyrLeuValThrLeuGluGnJ~aGnGuG~nGnTyrValGl?lGlly ProGlyGluProSerGlyProIeSerThrIeAsProSerPror~ry~u IleLeuGlyAlaValThrLeuLeuLeuGluGlyValMetAlaAlaArgl011 eul ProThrCysLeuSerS erbeuLeuGlyGlnLeuSerGlyl l~ge e~uly MeILeuValGlyGlyS erThrLeuCysValArgo1uPhe~ lyG lyAsriMetAlaS erPro AlaProProAaCysAspLeuArg va1e~eLseue, r~p~r~sale AlaValAspPheSerLeu (SEQ ID NO:208) pMON2 8511 LeuLeuAspProAsrAnLeuAsnAspG1uAspVlSer~lLue~pr~ne TyrLeuValThrLeuGluGlnAlaGlnGluGlnGlnTyrva iCluGlyG lyGlyG lyS er ProGlyGluProSerlyProleSerThrleAsnProe~roSerl~e HisLysSerProAsnl~etGlyProThrCysLeuSerSerLeuLeu 01011~e~l Ar~yy~l~gh ue~e~ll~yerThrLeucysValArgoluPhe ProThrProValLueuroleuproAavaeSperLl~rpuG±Thlne GluGluThrLysAlaGlnAspI leLeuGlyAlaValThrLeuLeuLeuoluGlyValMet AlaAlaArgGlyGlnLeu (SEQ ID NO:209) pMON2 8512 AlaAsnCysSerlleMet IleAspGluIleIleHisI-isLeuLysArgProProAlaPro LeuLeuAspProAsnJ~snLeuAsnAspGluAspValS en 1eLeuMetAspArgAsnLeu Ar~ur~ne~ue~ea~g~aa~ss~ul~nl~rl Il~ul~ee~gs~ul~o~se~oe~ah~al~oe Ar~sr~elley~al~p~pl~uh~gl~se~rh TyrLeuValThrLeucluGln~laGlnGluGlnGlnTyrValGlu01 01 01 01 Se ProGlyGluProSer~lyProleSerThnl leAsnProSerProPro~ erLysoiuSer HisLysSerProAsnMetGlyThrGlnLeuPorol~ln~gThThAlHisL As~os~al~ee~rh~n~se~ur~yy~lr~ee Me~ua~yl~rh~uy~lr~uh~yl~~tlsrr WO 97/12985 Pd-lrflToa 144 Cf1n i ProThrCysLeuSerSerLeuLeuGlyGlnLeuSerGlGl~l~r~ue~u AlaLeuGlnSerLeuLeu (SEQ ID NO:210) pMON2 8513 AlaAsnCysSerIleMet IleAspGluIeIeHHisie~seu-ysAoPoPro Le~uspr 1sne n~pl~p~le~ eLeulYetAspArgAsnLeu~ ArgLeuPronLeu lueG~heal r phaly~n~ulus~a~rl TyrLeuValThrLeuGuGln~zlaGlnCluGlnGlnTyrVaGlllyylye ProGlyGluProSerGlyProI leSerThrlleAsnProSerProProSerLyGlSe Se~el~se~u~gl~sa gh~e~te~ll~yerThr LeuCysVal1Alqoelylyphetiy~la~eProll.Qr~ay~pe Arga~ue~se~ur~pe~sa~ui~rr~uecny Prolu~l~iProLeuProThrProValLeuLeuProAlaValAspPheSeeul GluTrpLysThrGMetGuGluThr rslaYSAsaG1IlLuly~aa~ ThrGlnLeuProProcln (SEQ ID NO:211) pMON2 8514 LeuLeuAspProAsn~AsnLeuAsnAspG1uAspVaSerIeLeetAspArALe TyrLeuValThrLeuGuGnAaGnGuGnGnrValGlyGlGlylySer ProGlyGluProSerGlyProIleSerThrIeAsnPSPror~ry~ue HisLysSerProAsnMetA aHisLysAspPn ll~hLeerhln GluPheGlyGlyAs~etAlaS erProAlaProProAl aCysAspLeuArgValLeuser LysLeuLeuArgAsps erHisValLeuHi sSerArgL euSerGlny~ol~li ProLeuroThrProValLeuLeuProAlaValAspPh S~eLuly~ur~s GlnMetGluGluThrLysAlaGlnAspIleLeuGyAlVlThreeuuluy Va~tlAargl~ne yroh~se~rerLeuLeuGlyGlnLeu Se~yl~l~ge ue~l~ae~nerLeuLeuGlyThrGlnLeuPro ProGlnGlyArgThrThr (SEQ ID NO:212) pMON2 8515 AlaAsnCysSer~leMetIleAspGluIleIleHisHsLLysr~or~a LeuLeuAspPrQAsnAsnLeuAsnAspG1uAspValS erIleLeu1~etAspArgAsnLeu Ar~ur~ne~ue~ea~g~aa~ss~ul~nl~rl Il~ul~ee~gs~ul~o~Se~oe~ah~al~oe Ar~sr~el~ey~al~p~pl~uh~gl~se~rh WO 97/12985 WO 9712985145 TyrLeuValThrLeuGuGlnAaGnGluGlnGnTyrValGluGlGlGllye ProGlyluProSerGlyProIleSerThrIleAsnProSerProPe Lslue HisLys SerProAsniMetAspProAsnAlal ePheLeuSerPheG InHi sLeuLeUArg GlyLysValArgPheLeu~~ tL euVaiGlyGlyS erThrLeuCysvalArgGluPheQjy Gl~ne~ae~ol~or~a~ss~ur~le~ry~ue ArgAspS erHis~ValLeuHisserArgLeuSerGlnCys ProGluValHi sProLeuPro ThrProValLeuLeuProAlaValAspPheSerLeuGlyGluTrpLThrGlretl GluThrLysAlaGlnAspIleLeuGlyAlaValThrLeuLeuLe Ci l ~leti Al~gl~ne~yr~ry~u~re~ue~yl~ue~yl Va~ge~ue~yl~ul~r~ue~yh~ne~or~nl ArgThrmhrAlaHisLys (SEQ ID NO,:213) pMON2 8516 AlaAsnCysSerlleMet l~pl~el~si~e~sr~or~ar LeuLeuAspProAsnJ~snLeuAsnAspGluAspVa1S en 1eL euMetAspArgAsnLeu Ar~ur~ne~ue~ea~g~aa~ss~ul~ni~rl I leGluAlale n~ul~o~se~oerl~rlal~o Ar~sr~el~ey~al~p~pl~uh~gl~se~rh TyrLeuValThrLeucluGlnAaGnGluGnGnTyrVal GluGlyGlGly e ProGlyGluProSerGlyprolleSerThleAsnProSerProPS erLysGluSer His se~osie~a~eh~ue~el~i~ue~gl~sa Ar~ee~te~ll~ye~re~sa~gl~ei~ysie Al~rr~ar~r~ay pe~g~le~ry~ueuArgAspS er Hi~le~se~ge~rl~s~ol~li~oe~oh~oa LeuLeuProAlaValAspPheS erLeuGlyGluTrpLysThrGl1ietGluGluThrLys AlaGlnAspIleLeuGlyAlaVaThrLeuLeuLeuGuGyVaMeAAlaAGly GinLeuGly.oThrCysLeuSerSerLeuLeuGlyGlnLeuserGlyGlnValArgLeu LeuLeuGlyAl aLeuGlnSerLeuLeuGlyThrGlnL euProProGinG lyArgThrThr AlaHisLys~spProAsn (SEQ ID NO:214) pMON2 8519 AlaAsnCysSenl leMet IleAspGluIle IleHisHisLeuLysArgProPro~laPro Le~us~os~ne~ns~u~pa~rl~ue~pr~ne Ar~ur~ne~u~rh~lr aa~y~ne~us~aerGly Il~ul~ee~gs~ul~o~se~oe~ah~al~oe Ar~sr~el~ey~al~p~pl~uh~gl~se~rh TyrLeuValThrLeuGluGlnAlaGlnGluGlnGlnTyrValGluGlyGlyGlyGlySe ProGlyGluProSerGlyProIleSerThIleAsnProSerProProSerLsGluSe Hi sbys SerProAslyetGluValfljs ProLeuProThrProValLeuLeuProAlaVal AspPhleSer7LeuGlyGluTrpLysThrGl1ietGluGluThrLysAlaG inAspI leLeu C lyAlaValThrLeuLeuLeuGluGlyValMetAlaAlaArgG lyGlnLeuGlyProThr CysbeuSerS erLeuLeuGly~lnLeuSer~lyGlnValArgLeuLeuL euGlyAlaLeu Gl~re~ul~rl~ur~o~nl~gh~rl~sy~pr AsnAla IiePheLeuSerpheGlnHi sLeuLeuArgGlyLysValArgPheLeuetLeu VaiG lyG lySerh uy~lrgl~el~~tlae~ol~or erHisValLeuHisS erArg LeuSerGinCyspro (SEQ ID NO:215) PMON2 8520 WO 97/12985 prTItmogtor 146 AlaAsnCysSerIleMet~leAspGluIleIleHisHisLeLArgr-r~a LeuLeuAspProAsnAsnLeuAsnAspGluAspVa1SerTleLeuMetAspArgAsn ArgHisPro le Ilele sl~ys~r~nl~er~l~Se~r TyrLeuVaiThrLeucluGlnAlaGlnGluGln~lnTyrVaGuGlyGlylly ProGlyGiuProSerclyProIleSerThrIleAsnProSerPPrerylur HisLysSerr rosnneteuuproToaleuePro~laValspher Th~uy~'Lr~uh l~ne~aerProAl aProProAlaCysAspLeu ProGluValHisPro (SEQ ID NO:216) pMON2 8521 AlaAsnCysSerleMetxeAspGluI~e~iseHis iLeULYSr~rAaPr LeuLeuAspProAsnAsnLeuAsnAspGluAspValSerI leLeuMet.AspArgAsnLeu Ar~ur~ne~u~rh~lr aa~y~ne~us~aerGly IleGluAlale ur~ne~n~oy~ur~rlah~al~o Ar~sr~el~ey~al~p~pl~uh~gl~se~rh TyrLeuValThrLeuGluGnAaGnGuGnGnTyrValGlGlGlGly ProGlyGluProSerGlyPro~l serThrIleAsnP~oroSerPPslue Hi sLys SerProAsni~etValLeuLeuProAlaValAspPheS erLeuG lyGluTrpLys ThrGlnMetGluGluThrLysAlaGlnAspI leLeuGlyAlaValThrLeuLeuL euGlu Gl~le~al~gl~ne~y~oh~se~re~ue~yl Le~rl~na~ge~ue~y~ae~ne~ue~yh~ne Pr~ol~yrgh~rl syss~os~alePheLeuSerPheGin His ue~gl~sa~gh~uete~ll~ye~re~sa er Ly~ue~gs~ri~le~s~rr~ue~ny~ol~li ProLeuProThrPro (SEQ ID NO:217) pMON2 8522 AlaAsnCys SerlleMet l~pl~el~si~e~sr~or~ar LeuLeuAspProAsnAsnLeuAsnAspGluAspValSerI ieLeuI'etAspArgAsn~eu Ar~ur~ne~u~rh~lr aa~y~ne~us~aerGly Il~ullee~gs~ul~o~se~oe~ah~al~oe Ar~sr~el~ey~al~p~pl~uh~gl~se~rh TyrLeuValThrLeuGluGlnJlaGlnG1uGlnGlnTyrValGluGlyG lyGlyG lySer ProGlyGluProSerGyProIleSerThrIleAsnPr Q~eroProPrLGluSe HisLysSerProAsMetAaVaAspPheSerLeuGl~ysTrGl~tGlu GluThrLysAlaGlnAspIleLeuGyAlaValThrLeuLeuLeuGGlVlMetAla Al~gl~ne~yr~ry~u~re~ue~yl~ue~yl erLeuLeuG lyThrGlnLeuProProG inGly Ar~rh~ai~ss~os~a~eh~ue~el~se~ur erThrLeuCysValArgGluPheGly Asie~ae~ol~or~ay~pe~ga~ue~se~ur WO 97/12985 Pd-,P/IrTen I 147 AspSerHisValese~r~ue~nysr ua~s~oe~oh ProValLeuLeuPro (SEQ ID NO:218) pMON2 8523 ~ealr~a~ly~s~ulus aerGly Ii eGluAlaIle ur~ne~n~oy~ur~r ah~al~oer ArgHis Prol le Iiel sl~ys~r~nl~er~l~se~rh TyrLeuValThrLeuluGlnAlaGlnlulnGlnTyrValGlGlGlly~ye ProGlyGluProSerGyProIleSerThrIeAsfProSer ProSLy lue LysAlaGlnAspIieLeuGlyAlaVa1ThrLeuLeuLeuGluGlyValMetAlaAlaArg GlyGlnLeuGlyProThrCysLeuSerSerLLeueuly~lnLeuSerGln~lr LeuLeuLeuGlyAla~euGlnSerLeuLeuGlyThrGlnLeuProProGlnGlyArgThr ThrAlaHisLysAspProAsAaIePheLeuSerPheGnHsLLeur~y ValArgPheLeul~etLeuValGlyGlyS erThrLeuCysValArgG luPheGlyAsnmet AlaSerProAlaProProAl aCysAspLeuArgValLeus erLysLeuLeuArgAspS er Hi~le~se~ge~rl~s~ol~li~oe~oh~oa LeuLeuProAlaVal (SEQ ID NO:219) pMON2 8524 AlaAsnCysSerIleMet l~pl~el~si~e~sr~or~ar LeuLeuAspProAsnAsnLeuAsnAspGluAspVaiSerI leLeuMetAspArgAsnLeu Ar~ur~ne~u~rh~lr aa~y~ne~us~aerGly I leGluAlale ur~ne~n~oy~ur~rlah~al~o Ar~sr~el~ey~al~p~pl~uh~gl~se~rh TyrLeuValThrLeucluGlnAlaGlnGluGlnGlnTyrValGluGlyGlGlGlyS ProGlyGluProSerlyProIleSerThrIleAsnProSerProProSLGlue Hi sLys SerProAsn1etGlyGuTrpLysThrG1ietGluGluThrLysAlaG ln.Asp Il~ul~aa~re~ue~u~ya~tl~ar~yl~ul ProThrCysLeuSerSere ul~ne~rlyl~lr~ue~ul Al~ul~re~ul~rl~u~or~nl~gh~rl~sy AspProAsnAlaI lePheLeuS erPheGlnHi sLeuLeuArgGlyLysValArgPheLeu Me~ua~yl~r~re~sa gluh~yse~aerProAla ProProAlaCysAspLeuArgValLeuSerLy 3 s~eu euArgAspSerHi sValLeuHi s S erArgLeuSerGlnCyz ProGluValHis ProLeuProThrProValLeuLeuProAla ValAspPheSerLeu (SEQ ID NO:220) pMON,28525 AlaAsnCysSerlleMet IleAspGluIle IleHisHisLeuLysArgProPro~laPro LeuLeuAspProAsnAsnLeuAsnAspGluAspValSerIleLeuetAspArgAsnLeu Ar~ur~ne~u~rh~lr aa~y~ne~us~aerGly I leGluAlale ur~ne~n~oy~ur~rlah~al~o Ar~sr~el~ey~al~p~pl~uh~gl~se~rh TyrLeuValThrLeuGluGln~laGnGuGnGlTyrVaGu GlyGlGlylS ProGlyGluProSerGlyProleSerThrleAsnProSerPoroerLsGluSe HisLysSerProAsnietGlyProThrCysLeuSerSerLeuLeuGlyGlnLeSeCly Gl~lr~ue~ul~ae~n~re~ul~rl~ur~ol WO 97/12985 Pi-,r/FTQ04/ 148 JC/ Lcni a Gl~gh~rlai~ss osnl~eh~uer~heGlnkiisLeuLeu Ar~yy~lr h~ue~uaGly~lyS erThrLeuCysValArgG lPhe GlyAsnMetAaSerPo oa~roPlayssLeur~le~ry~ue ThrProValLeuLeuProAlaValAspPheSLGiy~ur~sh~r~tl GluThrLysAlaGlnAspIleLeu~lyAlaValThLLeeullyaeta AlaArgGlyclnLeu (SEQ ID NO:221) pMON2 8526 LeULeuAPro ~AulSereAgAlP1aV±yssnLeul~nl~r TyrLeuValThrLeuGluGlnAlaGnGuGlGlnTyrVaiilyl~ye ProGlyGluProSerGlyProIleSerThrIlAPSerr oe~sluSer His~ysSerProAsnletGlyTrGlnLeuPProronGlAghr rl~ sLys AspProAsnAIeIheurPhe~lnuseu~~LAgi~salr~e SerArgLeuserGlnCy 5 ProGluValHis ProLeuProThrProValLeuLeuProAla ValAspPheSerLeuGuTr PLs~r~litGluGlu~ry~al~p ThrCysLeuSerSerLeuLeuGlyGlnLeuSerGlyGlnVlArge~ue~yl LeuGlnSerLeuLeu (SEQ ID NO:222) pMON2 8527 AlaAsnCysSerIleMetIleAspGluIeIleHisHsLLysr~or~a LeuLeuAspProAsnAsnLeuAsnAspG1uAspValS er leLeuMetAspArgAsneu ArgLeuProAeulSnerciuelrpheVly~s~ulus~a~r TyrLeuValThrLeuGluGlnAlaGlnGluGlnGlnTyrViil~ylyl~y GluVaiHisProLeuProThrProValLeuLeuPrAaVasi eere~yl TrpLysThrGlriIetGuGuThrLysAaGi~spI eLeuGiyAiaVaiThrLeuLeu GinLeuProProGin (SEQ ID NO:223) pMON2 8528 AiaAsnCysSerleMet.leAspGlulleleHisHisLeuLysArgProProAlaPro LeuLeuAspProAsn~snLeuAsnAspG1uAspVaSIie~ue~pr~ne IleGluAlale ur~ne~n~oy~ur~rlah~al~o WO 97/12985 PCT/US9 I r.77A 149 ArgHisPro~l~el~y1al~p~pl~u er~uyse~rh TyrLeuValThrLeuGluGlnAlaGlnGluGlnGlnTyrValGluGlGlylyly ProGlyGluProSerGlyProIleSerThrIleAsnProSerProPrSery~ue H-i sLys SerProAsnMetAlaHisLysAspProAsnAlaI lePheLeuS erPheG inHis erGlnCysProGluValHi sPro LeuProThrProValLeuLeuProAlaValAspPheS erLeuGlyGlUTrpLysThrGln MetGluGluThrLysAlaGlnp\PTeLeuGyAaVaThrLeLLeul~y GinGlyArgThrThr (SEQ ID NO:224) -pM0N28529 AlaAsnCysSerlleMet l~pl~el~si~e~sr~or~ar LeuLeuAspProAsInL7snLeuAsnAspGuAspVaSerIeLeMtAspr~n Ii eGluAlallee gs~ul~oy~u~oe~ah~al~oe TyrLeuValThrLeuG luGlnAlaGlnGluolnGinTyrValG luGlyG lyGlyG lyS er ProGlyGluProSerGlyProleSerThrleAsnProSerPrPSerLysGiuSer HisLysSerProAsnxetAspProAsn~laIlePheLeuSerPheGlnHisLeuLeuArg erThrLeuCysValArgGluPheGly ProVal LeuLeuProAiaValAspPheS erLeuGlyG 1uTrpLysThrG inMe tG 1uGlu ThrLysAlaclnAspI leLeuGlyAlaValThrLeuLeuLeueluGlyValMetAlaAla erSerLeuLeuclyelnLeuS erGlyGlnVal ThrThrAlaHisLys (SEQ ID NO:225) pMON2 8530 Al~ny~rl~tl~pl~e~ei~se~sr~or~ar LeuLeuAspProAsnAsnLeuAsnAspGluAspValS er leLeuMetAspArgAsn~eu TyrLeuValThrLeuG1uGnAaGnGuGnGnTyrVaG1uGlyGlGlGlyS ProGlyGluProSerGlyProIleSerThIleAsnProSerProPS erLysGiuSer HilsLysSerProAsniMetAlaIlePheLeuSerPheGlnHisLeuLeuArgGlyLysVal ArgPheLeuMet.LeuValGlyGlySerh uy~lr~l~el~rmtl SerProAlaProProAlaCysAspLeuArgValLeuS erLysLeuLeuArgAsps erHi s Va~ui~rr~ueGny~o~ua~sr~ur~rr~le LeuProAlaValAspPheSerLeuGyGuTrpLysr rG~etGlGluThLAl GiriAspI leLeuGlyAlaValThrLeuLeuLeuGluG lyValMet.AlaAlaArgGlyGln LeuclyProThrCysLeuSerSerLeuLeuGlyGlnLeuSerGlyGlnValArgLeuLeu LeuGlyAlaLeuGlnS erLeuLeuGlyThrGlnLeuProProG lnGlyArgThrThrAla HisLysAspProAsn (SEQ ID NO:226) PMON2 8533 WO 97/12985 Vf-rffY LeuLeuAspProAsnAsnLeuAsnAspGluAspVaSerIeLeMtAspr~ne Tyr~Lu~luThrlaen~ uGl1n~rall~l 1 y~ylye AspPheSerLeuGyu~r ~ysrl~ thrcluhrsl~e~,ilnsleu CysLeuSerSerLeuLeuGlyGlnLeuSerGlylnValArgLLeeullau GinS erLeuL euGlyh ne~r~oi~yrgh rl~ sLysAspPro AsnAlalePheLeuSerPhecinHi sLeuLeuArgGlyy l~gh~e~te ProAl aProProAlaCysAspLeuArgValLeu~erLy 5 s~eu euArgAspS erHi sVal LeuHisSerArgLeuSerGinCysPro (SEQ ID NO: 227) pMON2 8534 AlaAsneyss erleMet IieAspGiulle IleHi sisLeuLysArgProPro~laPro LeuLeuAspPrQAsnAsnLeuAsnAspG1uAspVaiS e ileLeuMetAspArgAsnLeu leGluAlal ur~ne~n~oy~ur~rlah~al~oe Ty~ua~reul~ l~n~ul~ny~ lluGlyGlyGlyGlySer ProGlyciuProSerGlyProleSerThnleAsnProSerProPrery lur HisLysSer~r~t~r~ro rn~ al~euprO~roplVal~sphe~r Le~ul~n~ue i~a~ge~ueul~ae~ nS erLeuLeu LeuS erPheGlnHis ue~gl~sa~ghee~te~ll~ye Th~uy~lr~uhel ys~yl~~tAlaS erProAlaPropro LeuSerGinCysProGiuValHisPro (SEQ ID NO: 228) pMON2 8535 AiaAsnCysSerleMet IleAspGlullelleHisHisLeuLysArgProProAiaPro LeuLeuAspProAsnAsnLeuAsnAspGiuAspVaiS e ileLeuMetAspArgAsnLeu erPheVaiArgAiaVaiLysAsnLeu~~luAsnAlaS erGiy IieGiuAiaIieLeuArgAsnLeuGlnProCys~euPrQ 5 erAiaThrAiaAiaProSer TyrLeuVaThrLeuGuGi~laGnGuGnGnTrlGiyGiGlyl~e ProGlyGiuProSerGiyProlleSerThr IieAsnProSerProProSerLysGiuSer HisLysSerProAsn 14~l~uetolVaileupheeeulu rp~ys Th~ne~ul~ry~al~p ee~yl~lh~ue~ulyui le~al~r~yl~ul~r~ry~ue~e~ue~yl Lue~yl~lr~ue~ul~ae~ne~ue~yhcne Pr~ol~yr~rh~ai~s~pr~nl~eh~ue~el WO 97/1 2985 PCTfFTQq4/ic-F"A 151 Ar~le~ryse~ur peri~le~serArgLeuSerGlnCys ProGluValHisProLeuProThrPro (SEQ ID NO:229) pMON28536 LeuLeuAspProAsnAsnLeuAsnAspcluAspValSerl u~ts~r~ne TyrLeuValThrLeuGuGn~laGnGuGnGnTyrVlGlllyyly ProGlyGluProSerGly proIleh lesrone 5 Pror~ry~u GluThrLysAlacnAspIleLeulyaalahaLehLeLulu~ya~t ValArLueuLeu~lyeu~eln~eLueu ly~he, e~r~r 1 l~l GlyAsnGlyGlyAsnietAaSerProAarPro~rAlCAspe~ga~u LysLeuLeuArgAspSer~j sValLeu-is rr~u~rl~srol~li ProbeuProThrProValLeuLeuPro (SEQ ID NO:230) pMON2 8537 LeuLeuAspProAsn~snLeuAsnAspGluAspVa1SerI leLeuiMetAspArgAsflLeu TyrLeuValThrLeuGluclnAlaGlnGluGlnGlnTyrValGluGllllye ProGlycluProSerGlyProIleSerThrIleAsnProSPorerLysGiuSer HisLys SerProAsnMetAspPheSerLeuGyGuTrpLysThrneGltGlulhr LysAlaGinAspI leLeuGlyAiaValThrLeuLeuLeuGluGlyValMetAlaAlaArg GlyGlnLeuGlyProThrCysLeuSerSerLeuLeuGlyGSGlln~lr LeuLeuLeuGlyAlaLeuGlnS erLeuLeuGlyThrG lnLeuProProc~lnGlyArgThr ThrAla-i sLysAspProAsnAlal lePheLeuSerPheGlnHisLeuLeuArgGlyLys Va~gh~ue~ua~yl~r~re~sa~gl~el~ys Gly~lyAs1~etAlaS erProAlaProProAlaCysAspLeuArg~~ iLeuS erLysLeu Le~gs~ri~le~se~g~ue~ny~ol~li~oe ProThrProValLeuLeuProAlaVal (SEQ ID NO:231) pMON2 8538 AlaAsnCysSerlleMetlleAspGlulleleHisHisLeuLysArgProPrQAlaPr LeuLeuAspProAsnAsnLeuAsnAspGluAspValS erleLeuMetAspArgAsnLeu erPheValArgAlaValLysAsflLeuQluAsnAlaS erGly I leGluAlale ur~ne~n~oy~ur~rlah~al~o Ar~sr~el~ey~al~p~pl~uh~gl~se~rh TyrLeuValmhrLeuGluGlnAlaGlnGlulGlnTVal101 01111~y~e ProGlyGluProSerGlyProlleSerThrlleAsnProSerPror~ry~u HisLysSerProAsnMetGlyGluTrpLysThrGl~etGlh~slahln s WO 97/12985 PfIlrIFTO IleLeuGlyAlaValThrLeuLeuLeuGlu~lyValMetAlaAlariyleuy ProThrCysLeuSererseLlynLu~eG~lGlVariue~ul AspProAsnAlaIl ePheLeuS erPheGinHis ue~gl~y~lr~ee LeuLeuProAiaValAspPheSerLeu (SEQ ID NO :232) pMON28539 AlaAsnCysSerIleMetIleAspGluIleIleHisHisLLysr~or~ar Le~us~o~ns us~s~us~lerIl eLeuMetAspArgAsnLeu~ TyrLeuValThrLeuGuGn~laGnGuGnGnTyVlGlly~yl~ye ProGlyGluProS erGlyProlleSerThrlleAsnProSerProProS erLysGluSer HisLysSerProAsnmetGlyProThrCysLeuSerSLeeullnuery GlargeeuelyleulereeulTGneurron Ar~yy~l~gh ue~e~ll~yerThrLeuCysValArgc luPhe GlyGlyAsnGlyG lyAsnMetAlaS erProAlaProProAlaCysAspLeuArgValLeu HisProLeuProThrProValLeuLeuProAlaValAspPheSere~yl~py ThrGlniMeteluGluThrLysAaG1spIleLeuGyAlVlThr~ue~ul GlyValMetAlaAlaArgGlyiln~eu (SEQ ID NO:233) pMON2 8540 AlaAsnCysSerIleMeL IleAspGluIleIleEisHisLeuLysArgProProQlaPr LeuLeuAspProAsn~snLeuAsnAspG1uAspVa1S erlleLeuMetAspArgAsnLeu ArLeuPr ~snLueciearpheValAne~l~n~aer TyrLeuValThrLeuGuGllaGnGuGnGnTyrVlGlGllylly ProGlyGluPe~yro~lerG~hrIsnro~erPror~ry~u AspProAsnAlallePheLeuserPheGlnHisLeuLeuArgG lyLysValArgpheLeu AlaSe~ol~oProaro pOAaCaeSLLeeur spr LeuLeuProAlaValAspPheS erLeuGlyGluTrpLysThrG lrMetG luGluThrLys AlaGlnAspIleLeuGlyAlaValThrLeuLeuLeuG luGlyValMetAlaAlaArgGly GlnLeuGlyProThrCysLeuSerSerLeuLeuGlyGlnLeuSeGl large LeuLeuGlyAlaLeuGlnSerLeuLeu (SEQ ID NO:234) pMON2 8541 AlaAsnCysSerlleMet IleAspGluIle IleHisHisLeuLysArgProproAlaPro LeuLeuAspProAsnAsnLeuAsnAspGluAspValS er leLeuMetAspArgAsnLeu Ar~ur~ne~ue~ea~g~aa~ss~ul~nl~rl WO 97/12985 Pd-lr[Flon 153 WAD/~~n i I I leGluAla~l~ur~ne~n oy~ur~rlah~al~oe Ser~hGln sro~uArgislrLeu~alrghe~Lue~ua~yl~ LeUGnyshroGnleu~arOProG~n (SEQ ID o:235)u~o~aalsph pMON28542 AlaAsnCysSerIleMetIleAspGluIleIleHis se~y~gr~r~ar LeuLeuAspProAsPJ~snLeuAsnAspGuAspVlS er leL euMe tAspArgAsnLeu IleGiul~ee~gs~ul~oyse~oe~ah~al~o TyrLeuValThrLeuGluGinAlaGlnGluGlnGlnTyrVaiilyl~ye ProGiyGluProSerGlyProlleSerThrl leAsriProSerProproS erLysGluSer H-is serr~sietl sLysAspProAsnzdallePheLeuSerPheGlnHi GluPheGyGyAsnGyGys ~eta~errlPrPrAlaCysAspLeuArg Va~ue~se~urgs ri~le~ sSerArgLeuSerGlnCysPro GluValHisoePro~euro~ahr~eProlaValsph eruiyl Gl~ne~rlyl~lr ueue~yl~ulnSerbeuLeuGlyThr GlnLeuProProGlnGlyArgThrThr (SEQ ID NO:236) pMON2 8543 AlaAsnCysSerlleMet IleAspGlulle i~se~y~gr~r~ar LeuLeuAspProAsn~JsnLeuAsnAspGuAspValSI leL euMetAspArgAsnLeu TyrLeuValThrLeuGluGln~laGlnGluGlnGlnTyVilGli~yl~l~ye Pr.oGlyGluProSerGyProleSerThnleAsnPrSerooery lur HisLysSerProAs~MetAspProAsn~laIiePheLeuSerPheGin~isLeuLeuArg GlYAsnGiYGiyAsnMetAlaSerProAiaProProAlaCysAspLeuArgvaiLeuSer ProLrohoaeuLero~rproalaeuleup~h~r~ul~l~p s ProGinGiyArgThrThrAiaHis~ys (SEQ ID NO:237) WO 97/1 2985 prlr/TTC!n 154 PMON2 8544 AlaAsnCysSerIleMet~leAspluIleIle~isHisLeuLysArgPPolar TyrLelThrhr~euGlu~lGnlaCnOGlnTalluylyylye ProGlyGluProSerGlyProIleSerThr~lAProe~or~ry~u HisLYsSerProAsnMetAlaIlePheLeuSerPheGlnHise-~gl~sa ThlProVaLLeueProAlaVAspspeeLGlluryshlietu Va~ge~u~ul ae~l~re~ulyThrG lnL euProProG inGly ArgThrThrAlaHisLysAspPrQo~fl (SEQ ID NO:238) pM0N28545 LeuLeuAspProAsn~~snLeuAsnAspGlAVal eleLeuMetAspArgAsnLeu~ IleGluAlaleursnelnryseroelahlaaror TyreualhiLeuGluclnAlaGlnGluGlnGlnTyrValGlGlyGlyllye Pr0yGluGrorelyPIeSrhr~es~oe~or~ry~u GlyLysValArgPheLeu~eLeuVaGyG1ySThrLeysarglhey Gl~~tl~rr~ar~r ay~pe~ga~uerLysLeuLeu ArgAspSerHisaj ui e~ge~rlny~ol~l~sr~ur ThrProVaLLeueuprQaiaalAsphS~eLeul~ur~sh~r~t Va~ge~ueul~ae nere~ul rlflyArgThrThr~la H-isLys (SEQ ID NO:239) pMON32132 Serr~aPo ProprO~yApeArgacy r~seue~r~p 5 ri LeuProAlaVAsp~hSere erGlTLThr~r~tl~uh~sl LeuGlyProThrCysLeuSerSerLeuLeuGlyGl1euSerGlyGlnValArgLeuLeu LeuGlyAlaLeuGSerLeuLeuG~r~lLPror~nl~gh~r PheLeuMetLeuValGlyGlySerThrLeuCysViAr (SEQ ID NO: 252) PMON3 2133 WO 97/12985 PCT/FIQGA/iCPYITA ValLeuHis rr~u~rl~srol liProLeuProThrProValLeu LeuProAlaValAspPheSerLeuGyGuTrpLysThrG1et~lGlhr~s GlnAspIleLeuGlyAlaValThreLeuLeu~luGlyuGlyvAlaeAlaAglyln LeuGlyProThrCysLeuSerSerLeuLeuGlyGlnLeuSerG lyclnValArgLeuLeu Le~yl~ul~re~ul~r~nl~gh~rl~sy~pr As~al~ee~rh~ni~u~ur~yy~lr~ee~te ValGlyGlySerThrLeucysValArg (SEQ ID NO:253) PM0N32134 S erProAlaProProAlaCysAspLeuArgValLeuS erLysLeuLeuArgAspS erHi s Va~ui~rr~ue~ny~o~ua~sr~ur~rr~le LeuProAlaValAspPheSerLeuGlycluTrpLysThrGlri Ltl C luThrLysAla GlriAspz leLeuGlyAlaValThrLeuLeuLeuGluGlyValMetAlaAlaArgGll LeuGlyProThrCysLeuSerSerLeuLeuclyGl1euSerGlyGlnValArgLeuLeu LeuGlyAlaLeuGlnSere ul~rlne~orGr~l~gh~rl HisLysAspProAsnAlaIlePheLeuSerPheGlnHisLeuLeAGly salr PheLeuMetLeuValolyolySerThrLeuCysValArg (SEQ ID NO: 254) WO 97/12985 PCT/US96/1577 4 156 The following examples will illustrate the invention in greater detail although it will be understood that the invention is not limited to these specific examples.

EXAMPLE 1 Construction of parental BHK exDression vctor A. Removal of AflIII site from mammalian expression plasmid.

A new mammalian expression vector was constructed to accept NcoI-HindIII or AflIII-HindIII gene fragments inframe and 3' to the hIL-3 receptor agonist pMON13146

(WO

94/12638) gene and a mouse IgG2b linker fragment. First, the single AflIII site was removed from pMON3934, which is a derivative of pMON3359. pMON3359 is a pUCl8-based vector containing a mammalian expression cassette. The cassette includes a herpes simplex viral promoter IE110 (-800 to +120) followed by a modified human IL-3 signal peptide sequence and an SV40 late poly-adenylation (poly-A) signal which has been subcloned into the pUC18 polylinker (See Hippenmeyer et al., Bio/Technology, 1993, pp.1037-1041).

The modified human IL-3 signal sequence, which facilitates secretion of gene products outside of the cell, is flanked by a BamHI site on the 5' end and a unique NcoI site on the 3' end. A unique HindIII site is 3' to the NcoI site and to the poly-A sequence. The DNA sequence encoding the signal peptide is shown below (restriction enzyme sites are indicated above). The ATG (methionine) codon within the NcoI site is in-frame with the initiator ATG of the signal peptide (underlined); WO 97/12985 PCT/US96/15774 157 BamHI NcoI (SEQ ID NO:255) The single AflIII site was removed from pMON3934 by digestion with AflIII followed by filling in the overhangs by addition of a DNA polymerase and nucleotides. The digested DNA fragment was purified via Magic PCR-Clean up kit (Promega) and ligated with T4 DNA ligase. The ligation reaction was transformed into DH5aM and the cells were plated onto LB-agar plus ampicillin. Individual colonies were screened for the loss of the AflIII site by restriction analysis with AflIII and HindIII which results in a single fragment if the AflIII site was removed. The resulting plasmid was designated pMON30275.

B. Transfer of hIL-3 receptor agonist pMON13416/IgG2b cassette into pMON30275.

The NcoI-HindIII fragment (ca. 425 bp) from pMON30245 was ligated to the NcoI-HindIII fragment (ca. 3800 bp) of the pMON30275. pMON30245 (WO 94/12638) contains the gene coding for hIL-3 receptor agonist pMON13416 joined to a mouse IgG2b hinge fragment. Immediately 3' to the IgG2b hinge and 5' to the HindIII site is an AflIII site. Genes can be cloned into the AflIII-HindIII sites as NcoI-HindIII or AflIII-HindIII fragments in frame with the hIL-3 variant pMON13416/IgG2b hinge to create novel chimeras. The NcoI site and the AflIII site have compatible overhangs and will ligate but both recognition sites are lost. The plasmid, pMON30304 containing the DNA sequence of (SEQ ID NO:78), coding for hIL-3 variant pMON13416 joined with a mouse IgG2b hinge region, was a result of this cloning.

EXAMPLE 2 WO 97/12985 PCTIS96/1 5774 158 onstructionof an intermediate plasmid contanini ne opy f he c-mp ligand (1-153) ene of the dimer template In order to generate a plasmid DNA with the coding sequence of c-mpl (1-153) ligand followed by a unique EcoRI restriction site, the gene is isolated via reverse transcriptase/polymerase chain reaction (RT/PCR). Human fetal (lot #38130) and adult liver (lot #46018) A+ RNA are obtained from Clontech (Palo Alto, CA) for source of c-mpl ligand messenger RNA (mRNA). The first strand

CDNA

reactions are carried out using a cDNA CycleTM Kit obtained from Invitrogen (San Diego, CA). In the RT reaction, random primers and oligo dT primer are used to generate cDNA from a combination of human and fetal liver mRNA. For amplification of c-mpl ligand gene fragment encoding amino acids 1-153, the RT product serves as the template for PCR with a combination of the primers, Forward primer: c-mplNcoI (SEQ ID NO:13) and Reverse primer: Ecompl. The c-mplNcol primer anneals to the c-mpl ligand gene (bases #279-311 based on c-mpl ligand sequence from Gene bank accession #L33410 or de Sauvage et al., Nature 369: 533-538 (1994)) and encodes a NcoI restriction enzyme site immediately 5' to the first codon (Ser+l) of c-mpl ligand. The NcoI restriction enzyme site codes for methionine and alanine codons prior to Ser+1 and includes codon degeneracy for the Ala codon and the first four codons (Ser, Pro, Ala, Pro) of c-mpl ligand. The Ecompl primer anneals to bases #720- 737 of c-mpl ligand and encodes an EcoRI site (GAATTC) inframe with the c-mpl ligand gene immediately following Arg- 153. The ECORI site creates Glu and Phe codons following Arg-153. The ca. 480 bp PCR product was purified, digested with NcoI and EcoRI and ligated to the NcoI-EcoRI vector fragment of pMON3993 (ca. 4550 pMON3993 was a derivative of pMON3359 (described in Example The human WO 97/12985 PCT/US96/15774 159 IL-3 signal peptide sequence, which had been subcloried as a BamHI fragment into the unique BamHI site between the IE110 promoter and poly-A signal, contains an NcoI site at its 3' end and is followed by a unique EcoRI site. The plasmid, pMON26458 containing the DNA sequence of (SEQ ID NO:79), coding for c-mpl ligand amino acids 1-153 (SEQ ID NO:161), was the result of this cloning.

EXAMPLE 3 Construction of the parental plasmids containing the second genes of the dimer templates For amplification of c-mpl ligand gene fragments starting at amino acid 1 (Ser) with a termination codon following amino acid 153 (Arg), the RT reaction from Example 2 serves as the template for PCR with a combination of the following primers; c-mplNcol (SEQ ID NO:13) (forward primer) and cmplHindIII (SEQ ID NO:15) (reverse primer). The c-mplNcol (SEQ ID NO:13) primer is described in Example 2. The cmplHindIII (SEQ ID NO:15) primer, which anneals to bases #716-737 of c-mpl ligand, adds both a termination codon and a HindIII restriction enzyme site immediately following the final codon, Arg 153 Two types of PCR products are generated from the RT cDNA samples, one with a deletion of the codons for amino acids 112-115 and one without the deletion of these codons.

The c-mpl ligand PCR products (ca. 480 bp) are digested with NcoI and HindIII restriction enzymes for transfer to a mammalian expression vector, pMON3934. pMON3934 is digested with NcoI and HindIII (ca. 3800 bp) and will accept the PCR products.

Plasmid, pMON32132 (SEQ ID NO:249), coding for c-mpl ligand amino acids 1-153 (SEQ ID NO:252) was a result of WO 97/12985 PCT/US96/15774 160 this cloning. Plasmid, pMON32134 (SEQ ID NO:250), cbding for c-mpl ligand amino acids 1-153 (SEQ ID NO:253) was a result of this cloning. Plasmid, pMON32133 (SEQ ID NO:251), coding for c-mpl ligand amino acids 1-153 with a deletion of codons 112-115 (A112-115) (SEQ ID NO:254) was also a result of this cloning.

EXAMPLE 4 Generation of PCR dimer template 5L with a -12-115 dele n in the second c-mol licand Gene A PCR template for generating novel forms of c-mpl ligand is constructed by ligating the 3.7 Kbp BstXI/EcoRI fragment of pMON26458 to the 1 Kbp NcoI/BstXI fragment from pMON32133 (containing a deletion of amino acids 112-115) along with the EcoRI/AflIII 5L synthetic oligonucleotide linker 5L-5' (SEQ ID NO:18) and 5L-3' (SEQ ID NO:19).

The EcoRI end of the linker will ligate to the EcoRI end of pMON26458. The AflIII end of the linker will ligate to the NcoI site of pMON32133, and neither restriction site will be retained upon ligation. The BstXI sites of pMON26458 and pMON32133 will ligate as well. Plasmid, pMON28548, is a result of the cloning and contains the DNA sequence of (SEQ ID NO:80) which encodes amino acids 1-153 c-mpl ligand fused via a GluPheGlyGlyAsnMetAla (SEQ ID N0:222) linker to amino acids 1-153 c-mpl ligand that contains a deletion of amino acids 112-115 (SEQ ID NO:162).

EXAMPLE Generation of PCR dimer template 4L A PCR template for generating novel forms of c-mpl ligand is constructed by ligating the 3.7 Kbp BstXI/EcoRI WO 97/12985 PCT/US96/15774 161 fragment of pMON26458 to the 1 Kbp NcoI/BstXI fragment from pMON32132 along with the EcoRI/AflIII 4L synthetic oligonucleotide linker 4L-5' (SEQ ID NO:16) and 4L-3'

(SEQ

ID NO:17).

The EcoRI end of the linker will ligate to the EcoRI end of pMON26458. The AflIII end of the linker will ligate to the NcoI site of pMON32132, and neither restriction site will be retained upon ligation. The BstXI sites of pMON26458 and pMON32132 will ligate as well. The plasmid, pMON28500, is a result of the cloning and contains the DNA sequence of (SEQ ID NO:82) which encodes amino acids 1-153 c-mpl ligand fused via a GluPheGlyAsnMetAla (SEQ ID NO:223) linker (4L) to amino acids 1-153 c-mpl ligand (SEQ ID NO:163).

EXAMPLE 6 Generation of PCR dimer template A PCR template for generating novel forms of c-mpl ligand is constructed by ligating the 3.7 Kbp BstXI/EcoRI fragment of pMON26458 to the 1 Kbp NcoI/BstXI fragment from pMON32132 along with the EcoRI/AflIII 5L synthetic oligonucleotide linker 5L-5' (SEQ ID NO:18) and 5L-3'

(SEQ

ID NO:19).

The EcoRI end of the linker will ligate to the EcoRI end of pMON26458. The AflIII end of the linker will ligate to the NcoI site of pMON32132, and neither restriction site will be retained upon ligation. The BstXI sites of pMON26458 and pMON32132 will ligate as well. Plasmid, pMON28501 is a result of the cloning and contains the DNA sequence of (SEQ ID NO: 82) which encodes amino acids 1-153 c-mpl ligand fused via a GluPheGlyGlyAsnMetAla (SEQ ID N0:222) linker (5L) to amino acids 1-153 c-mpl ligand (SEQ ID NO:164).

WO 97/12985 PCTIUS96/15774 162 EXAMPLE 7 Generation of PCR dimer temolates 8L A PCR template for generating novel forms of c-mpl ligand is constructed by ligating the 3.7 Kbp BstXI/EcoRI fragment of pMON26458 to the 1 Kbp NcoI/BstXI fragment from pMON32134 along with the EcoRI/AflIII 8L synthetic oligonucleotide linker 8L-5' (SEQ ID NO:20) and 8L-3'

(SEQ

ID NO:21).

The EcoRI end of the linker will ligate to the EcoRI end of pMON26458. The AflIII end of the linker will ligate to the NcoI site of pMON32134, and neither restriction site will be retained upon ligation. The BstXI sites of pMON26458 and pMON32134 will ligate as well. Plasmid, pMON28502 is a result of the cloning which contains the DNA sequence of (SEQ ID NO:83) and encodes amino acids 1-153 cmpl ligand fused via a GluPheGlyGlyAsnGlyGlyAsnMetAla

(SEQ

ID NO:224) linker (8L) to amino acids 1-153 c-mpl ligand (SEQ ID NO:165).

EXAMPLES 8-44 Generation of novel c-mDl ligand aenes with new N-terminus and C-terminus A. PCR generation of genes encoding novel c-mpl ligand receptor agonists.

Genes encoding novel c-mpl ligand receptor agonists were generated using Method III (Horlick et al., Prot. Eng.

5:427-433, 1992 The PCR reactions were carried out using dimer templates, pMONs 28500, 28501, 28502 or 28548 and one of the sets of synthetic primer sets below (The first number WO 97/12985 PCT/US96/15774 163 refers to the position of the first amino acid in the original sequence. For example, the 31-5' and 31-3' refers to the 5' and 3' oligo primers, receptively, for the sequence beginning at the codon corresponding to residue 31 of the original sequence.).

31-5' (SEQ ID NO:22) and 31-3' (SEQ ID NO:23), 35-5' (SEQ ID NO:24) and 35-3' (SEQ ID NO:25), 39-5' (SEQ ID NO:26) and 39-3' (SEQ ID NO:27), 43-5' (SEQ ID NO:28) and 43-3' (SEQ ID NO:29), 45-5' (SEQ ID NO:30) and 45-3' (SEQ ID NO:31), 49-5' (SEQ ID NO:32) and 49-3' (SEQ ID NO:33), 82-5' (SEQ ID NO:34) and 82-3' (SEQ ID NO:35), 109-5' (SEQ ID NO:36) and 109-3' (SEQ ID NO:37), 115-5' (SEQ ID NO:38) .and 115-3'

(SEQ

ID NO:39), 120-5' (SEQ ID NO:40) and 120-3' (SEQ ID NO:41), 123-5' (SEQ ID NO:42) and 123-3' (SEQ ID NO:43), 126-5' (SEQ ID NO:44) and 126-3' (SEQ ID The templates and oligonucleotide sets used in the PCR reactions are shown in Table 4. The products that were generated were about 480 bp and were purified via Magic PCR Clean up kits (Promega).

B. Subcloning of novel c-mpl receptor agonist gene products into mammalian expression vector for generation of chimeras.

The c-mpl receptor agonist gene PCR products were digested with NcoI and HindIII or AflIII and HindIII restriction enzymes (ca. 470 bp) for transfer to a mammalian expression vector. The expression vector, pMON30304, was digested with NcoI and HindIII (ca. 4200 bp) and accepts the PCR products as NcoI-HindIII or AflIII-HindIII fragments.

The restriction digest of the PCR product and the resulting plasmids are shown in Table 4.

WO 97/12985 PCT/US96/157 74 164 TABLE 4 Example PCR template Example 8 pMON28501 Example 9 pMON28501 Example 10 pMON28501 Example 11 pMON28501 Example 12 pMON28501 Example 13 pMON28501 Example 14 pMON28501 Example 15 pMON28501 Example 16 PF/.mi28501 Example 17 pMON28501 Example 18 pMON28501 Example 19 pM0N28501 Example 20 pM0N28500 Example 21 pMON28500 Example 22 pMON28S00 Example 23 pMON28SOO Example 24 pMON28500 Example 25 pMON28500 Example 26 pMON28500 Example 27 pMON28500 Example 28 pMON28500 Example 29 pM0N28500 Example 30 pMON28500 Example 31 pkASN28500 Example 32 pMON28502 Example 33 pMON28502 Example 34 pMON28502 Example 35 pMON28502 PCR Product Primer set 31 35 39 43 45 49 82 109 116 120 123 126 31 35 39 43 45 49 82 109 116 120 123 126 31 35 39 43 PCR Product Restriction Digest NcoI/HindIII AflI/HindIII NcoI/HindIII NcoI/HindIII NcoI/HindIII NcoI/HindlII NcoI/HindIII NcoI/HindIII NcoI/HindIII NcoI/HindIII NcoI/HindIII NcoI/indIII NcoI/HindIII AflIII/HindIII NcoI/HindIII NcoI/HindIII NcoI/HindII NcoI/HindIII NcoI/HindIII NcoI/HindIII NcoI/HindIII NcoI/HindIII NcoI/HindIII NcoI/HindIII NcoI/HindIII AflIII/HindIII NcoI/HindIII NcoI/HindIII Resulting Breakpoint Linker Plasmid pMON SL 8505 SL 28506 5L 28507 5L 28508 5L 28509 SL 28510 5L 28511 St 28512 SL 28513 St 28514 SL 28515 5L 2816 4L 28519 4L 28520 4L 28521 4L 28522 4L 28523 4L 28524 4L 28525 4L 28526 4L 28527 4L 28528 4L 28529 4L 28530 8L 28533 8L 28534 8L 28535 8L 28536 in c-mpl ligand 30-31 34-35 38-39 42-43 44-45 48-49 81-82 108-109 115-116 119-120 122-123 125-126 30-31 34-35 38-39 42-43 44-45 48-49 81-82 108-109 115-116 119-120 122-123 125-126 30-31 34-35 38-39 42-43 WO 97/1 2985 PCTIUS96/15774 165 TABLE 4 cont.

Example 4 PCR template Example 36 Example 37 Example 38 Example 39 Example 40 EXAM~PLE 41 Example 42 Example 43 Example 44 PV.)N428502 PMON2 8502 pMON28502 PM0N28502 pMON2 8502 pM0N28 502 PMON2 8502 PMON2 8502 PMON2 8548 PCR Product Primer set 45 49 82 109 116 120 123 126 123 PCR Product Restriction Digest NcoI/HindIII NcoI/HindIII NcoI/HindIII Nol/HindIII NcoI/HindIII NcoI/Hindiii NcoI/HindIII NcoI/HindIII NcoI/HindIII Resulting Linker Piasmid pMON 8L 28537 8L 28538 8L 28539 8L 28540 8L 28541 8L 28542 8L 28543 8L 28544 5L 28545 Breakpoint in c-mpl ligand 44-45 48-49 81-82 108-109 115-116 119-120 122-123 125-126 122- 12 3 EXAMPLE 4 Contuto 1fD015960 Construction of pMON15960, an intermediate plasmid used for constructing plasmids containing DNA sequences encoding

G-

CSF Ser 17 with a new N-terminus and C-terminus. Plasmid pACYC177 (Chang, A.C.Y. and Cohen, S.N. J. Bacteriol.

134:1141-1156, 1978) DNA was digested with restriction enzymes FHindIII and BarnHl, resulting in a 3092 base pair HindIlI, BamHI fragment. Plasmid, pMON13037 (WO 95/21254), DNA was digested with BglII and FspI, resulting in a 616 base pair BglII, EspI fragment. A second sample of plasmid, pMON13037, DNA was digested with NcoI and HindlII, resulting in a 556 base pair NcoI, HindIII fragment. The synthetic DNA oligonucleotides lGGGSfor (SEQ ID NO:76) and 1GGGSrev (SEQ ID NO:77) were annealed to each other, and then digested with Af 1111 and FspI, resulting in a 21 base pair Af lIII, FspI fragment. The restriction fragments were ligated, and the ligation reaction mixture was used to WO 97/12985 PCT/US96/15774 166 transform E. coli K-12 strain JM101. Transformant bacteria were selected on ampicillin-containing plates. Plasmid

DNA

was isolated and analyzed by restriction analysis to confirm the correct insert.

EXAMPLE 46 Construction of DMnN15981 Construction of pMON15981, a plasmid containing

DNA

sequences encoding a multi-functional hematopoietic receptor agonist. Plasmid, pMON15960, DNA was digested with restriction enzyme SmaI and used as template in a PCR reaction using synthetic DNA oligonucleotides 38 stop

(SEQ

ID NO:65) and 39 start (SEQ ID NO:64) as primers, resulting in the amplification of a DNA fragment of 576 base pairs.

The amplified fragment was digested with restriction enzymes HindIII and Ncol, resulting in a HindIII, NcoI fragment of 558 base pairs. Plasmid, pMON13181, DNA was digested with HindIII and AflIII, resulting in a HindIII, AflIII fragment of 4068 base pairs. The restriction fragments were ligated, and the ligation reaction mixture was used to transform

E.

coli K-12 strain JM101. Transformant bacteria were selected on ampicillin-containing plates. Plasmid DNA was isolated, analyzed by restriction analysis, and sequenced to confirm the correct insert. The plasmid, pMON15981, contains the DNA sequence of (SEQ ID NO:155) which encodes the following amino acid sequence: MetAlaAsnCysSerlleMetlleAspclullelleHisHisLeuLysA ProPro ProLeuLeuAspProAsn~seuAsnAspGlValSerIleLeuMetAspArgAsn LeuArgLeuProAsnLeuGluSerPheValArgAlaValLysAsnLeuGluA slae GlyIleGluAlaIleLeuArgAsnLeuGlnProCysLeuProSerAlaThrAlaAlaPro SerArgHisProIleIleIeLysAlaGlyAspTrpGlnGluPheArgGuLysLeuThr PheTyrLeuValThrLeuGuGlnAlaGlnGluGlnGlnTyrValGluGlyGlyGlyGly SerProGlyGluProSerGlyProIleSerThrIleAsnProSerproProSerLysGlu SerHisLysSerProAsnMetAlaTyrLysLeuCysHisProGluGluLeuValLeuLeu GlyHisSerLeuGlyIleProTrpAlaProLeuSerSerCysProSerGlnAlaLeuGln LeuAlaGlyCysLeuSerGlnLeuHiserGlyLeuheLeuTyrGlnGly LeuLeuGn AlaLeuGluGlyIleSerProGluLeuGlyProThrLeuAspThrLeuGlnLeuAs pa WO 97/12985 PCTIUS96,1 5774 167 AlaASpPheAlaThrThrleTrpGGlMtGliLelytlarlau GlnProThrGln~lyAlaMetProAlaPheAlaSerAlaPheGlnr~r~a~yl LeuAlaclnProlylyGlySerAsMtAlaThr~oe~yr~ae~re AlaLeuGln~luLysLeuCysAlaThr (SEQ ID NO:195) EXAMPLE 47 Constuio of0MN1982 Construction of pMON15982, a plasmid containing

DNA

sequences encoding a multi-functional hematopojetic receptor agonist. Plasmid, pMON15960, DNA was digested with restriction enzyme SinaI and used as template in a PCR reaction using synthetic DNA oligonucleotide--96 stop

(SEQ

ID NO:67) and 97 start (SEQ ID NO:66) as primers, resulting in the amplification of a DNA fragment of 576 base pairs.

The amplified fragment was digested with restriction enzymes HindIIl and NcoI, resulting in a HindlII, NcoI fragment of 558 base pairs, Plasmid, pMONl3l8l, DNA was digested with HindIlI and Af lIII, resulting in a HindlII, Af 1111 fragment of 4063 base pairs. The restriction fragments were ligated, and the ligation reaction mixture was used to transform

E.

coli K-12 strain JMl01. Transformant bacteria were selected on ampicillin-containing plates. Plasmid DNA was isolated, analyzed by restriction analysis, and sequenced to confirm the correct insert. The plasmid, pMON15982, contains the DNA sequence of (SEQ ID NO:157) which encodes the following amino acid sequence: MetAlaAsnCys Sen leMetI leAspGluIl ele si~e~sr~r~o ProLeuLeuAspProAsnAsnLeuAsspGluAsValS en 1eLeuMetAspArgAsn LeuArgLeuProAsnLeuch~ lpr~a~lyss~e~u~nlae SerArgHisProIleIleIleLysAla~lyp~lQ 1 0 1 ~g~uyseuh PheTyrLeu~~a ThrLeuGluGlnAl aGlnGluGlnG lnTyrValoluGlyGly~ lyGly AlaLeuGlnProThrGlnGlyAla~e~uoeAlaPhel~rl~el~grO WO 97/12985 PCTIUS96'1 5774 168 GiyGlYValLeuVa1AlaS erHi sLeuGinSerPheLeuGluVal SerTyr .rgval~eu ArgHi seuAiaGlnProGlyGlyGlySerAspMetAlThrProe~yr~a SerLeuProGlnSerPhe LeuLyser~ey 5 5 l~aljg~yleGlnGlyAsp AlaLeuGlnLeuAlaGlyCysLeuSerGlnLeH. Serly~uh~uy~nl LeuLeuGlnAlaLeuGluGlylleSer (SEQ ID NO:196) EXAMPLE 48 Construto of)ON Construction of pMON15965, a plasmid containing

DNA

sequences encoding a multi-functional hematopoietic receptor agonist. Pliasmid, pMON15960, DNA was digested with restriction enzyme SinaI and used as template in a PCR reaction using synthetic DNA oligonucleotides 142 stop

(SEQ

ID NO:73) and 141 start (SEQ ID NO:72) as primers, resulting in the amplification of a DNA fragment of 576 base pairs.

The amplified fragment was digested with restriction enzymes HindIII and NcoI, resulting in a H-indlII, NcoI fragment of 558 base pairs. Plasmid, pMON13l8l, DNA was digested with HindIlI and AflIII, resulting in a HindIlI, Af 1111 fragment of 4068 base pairs. The restriction fragments were ligated, and the ligation reaction mixture was used to transform

E.

coli K-12 strain JMl0l. Transformant bacteria were selected on ampicillin-containing plates. Plasmid DNA was isolated, analyzed by restriction analysis, and sequenced to confirm the correct insert. The plasmid, pMON15965, contains the DNA sequence of (SEQ ID NO:157) which encodes the following amino acid sequence: MetAlaAsnCysSerlleMetlleAspGlulleleH iHis~uy~gr~o ProLeuLeuAsp proAu snplAspVlSrl uets~gs SerArgHisPro lle'l~s~al sCp nl~h~gluLysLeuThr Ph~re~lh~u~ul~al ul~l~ra~ul~ylyGly SerProGlycluProSer~lyPr 0 IleSerThrlleAsnProSerProProSerLysGlu Se~sy~rr~ne~ae~a~el~gr~al~ya~ua WO 97/12985 PCT/US9615774 169 AlaSerHi sLeuGinSerPheLeuGluVal SerTyrArgValLeuArgHj sLeuAlaGln ProGlyGlyGlySerAspMetAlaThrProLeuGlyProAlaSSLeur~ne PheLeuLeuLysS erLeuGluGlnValArgLys IleGlnGlyAspGlyAlaAlaLeuGln Gl~se~sl~ry~se~s~sr~ul~ua~ue~yi S erLeuclyl leProTrpAlaProLeuSerSerCysProSerGl laLeuGlLla GlyCysLeuSer GlnLeuHisSerGlyLeuPheLeuTyrclnGlyLeuLeuCliae GluGlylleSerProGluLeuGlyProThrLeuAspThrLeuGnLAspa~a PheAlaThrThrIleTrpGlnGletGluGluLeuGlyMetAlPAlaelnr ThrGlnGlyAlaMetProAlaPheAla (SEQ ID NO:196) EXAMPLE 49 C:onstruction of pMON15966 Construction of pMON15966, a plasmid containing

DNA

sequences encoding a multi-functional hematbpoietic receptor agonist. Plasmid, pMON15960, DNA was digested with restriction enzyme SinaI and used as template in a PCR reaction using synthetic DNA oligonucleotides 126 stop (SEQ ID NO:68) and 125 start (SEQ ID NO:69) as primers, resulting in the amplification of a DNA fragment of 576 base pairs. The amplified fragment was digested with restriction enzymes HindIlI and NcoI, resulting in a liindIII, NcoI fragment of 558 base pairs. Plasmid, pMONl3l8l, DNA was digested with HindIII and AflIlI, resulting in a HindlII, AflIII fragment of 4068 base pairs. The restriction fragments were ligated, and the ligation reaction mixture was used to transform coli K-12 strain JMlO1.

Transformant bacteria were selected on ampicillin-containing plates. Plasmid DNA was isolated, analyzed by restriction analysis, and sequenced to confirm the correct insert. The plasmid, pMON15966, contains the DNA sequence of (SEQ ID NO:158) which encodes the following amino acid sequence: Me~as~se~ee~es~u~el~si~uy~gr~ol ProLeubeuAspProAsnAsnLeuAsnAspGluAspValSerl leLeuMetAspArgAsn Le~ge~o ne~uerPheValArgAlaValLysAsn~~eu luAsnAl aS er GlyIleGluAlaIleLeuArgAsnLeuGlnProCys~euPr 05 erAlaThrAlaAlaPro Se~gi~ol~el~sl~y~pr~nl~er~uy~uh Ph~re~lh~ul~nl~n~ul~ny~ll~yl~yl WO 97/12985 PCT/US96/15774 170 SerProGlyGluProSerGlyProIleSerTb1 esnrerProPro-SerLysGlu SerHisLysS erProAsnletAlaMetAlaProAlaLeuGlPrhr~nl~ae GlnSerPheLeuGlVale~rr~le~gi~e~ai~ol~yl Ser~u~l~lnal~g~yIleGlnGlyAspGlyAlaAlaLeuGlnGluLy eus AlaThrTyrLysLeuCysHi sProGluGluLeuValLeuLeuGlyHi sS erLeuGlylle ProGluLeuGlyProThrLeuAspThrLeuGlnLespalasheahr IleTrpGlnGl~etGluGluLeuGly (SEQ ID NO:198; EXMPLE Contuin ofU DM 56Z Construction of pMON15967, a plasmid containing

DNA

sequences encoding a multi-functional hematopoietic receptor agonist. Plasmid, pMON15960, DNA was digested with restriction enzyme SinaI and used as template in a PCR reaction using synthetic DNA oligonucleotides 132 stop

(SEQ

ID NO:71) and 133 start (SEQ ID NO:70) as primers, resulting in the amplification of a DNA fragment of 576 base pairs.

The amplified fragment was digested with restriction enzymes HindIIl and NcoI, resulting in a HindIlI, NcoI fragment of 558 base pairs. Plasmid, pMONl3l81, DNA was digested with HindIlI and Af 1111, resulting in a HindpII, AfiIII fragment of 4068 base pairs. The restriction fragments were ligated, and the ligation reaction mixture was used to transform

E.

coli K-12 strain JMl0l. Transfornant bacteria were selected on ampicillin-containing plates. Plasmid DNA was isolated, analyzed by restriction analysis, and sequenced to confirm the correct insert. The plasmid, pM0N15967, contains the DNA sequence of (SEQ ID NO: 159) which encodes the following amino acid sequence: MetAlaAsnCys SerleMetllesp spu lulleHisHisLe L~sr~orAla ProLeuLeuAspProAseuAsnAspGlAValerlleLeuMetAspArgAsn Le~ge~o ne~uerPheValArgAlaValLysAsfLeu~~luAsnAlaSer Gl~el~al~ur~ne~n~oy~ur~rl~rl~ar WO 97/12985 PCT/US96/1 5774 171 PheTyrLeuValThrLeuGlulnAlaGlnGluGl~Tal~l~yl~yl SerProGlyGluProSerGlyProl leS erThrIl1eAsnProS erProProserLysGlu SerHisLysSerProAsnMetAlaThrGllaePlahlaelae Gly~o~l~ererLeuProalnserPheLeuLeuLysSerLeuGluGlnValArgLys IleGlnGlyAspGlyAlaAlaLeuGlnGuLysLeuCyAlaThryyseysi ProGluGluLeuValLeuLeuGly~isSerLeuGl leProTrpAlaProLeuSerSer CysProSerGlnAlaLeuGlnLeuAlaGlyCysLeuSerGlnLeiferleuh LeuTyrGlnGlyLeuLeuGlnAlaLeuGluGlyIleSerPrGluelyrhru AspThrLeuclnLeuAspValAlaAspPheAlaThrThr leTrpl~ne~u LeuGlyMetAlaProAl aLeuGi nPro EXAMPLE_51 Construction of MONI 180. aninemdaePa iu dfr constructing pismids that contain DNA se1uence encoding multi-ucinlhmtpjtcrcpo agonistss PlasmiLd, pMONl3 046 (WO 95/21254), DNA was digested with restriction endonucleases XmaI and SnaBI, resulting in a 4018 base pair vector fragment. The 4018 base pair XmaI- SnaBI fragment was purified using a Magic DNA Clean-up System kit (Promega, Madison, WI) in which the 25 base pair XmaI-SnaBI insert fragment is not retained. The complimentary pair of synthetic oligonucleotides, glyxal (SEQ ID NO:74) and glyxa2 (SEQ ID NO:75), were designed to remove sequence encoding a factor Xa cleavage site. When properly assembled these oligonucleotides also result in XmaI and SnaBI ends. The primers, Glyxal and glyxa2, were annealed in annealing buffer (20mM Tris-HC1 pH7.5, 10 mM MgCl 2 50 mM NaCi) by heating at 70'C for ten minutes and allowed to slow cool. The 4018 base pair XmaI-SnaBI fragment from pM0N13046 was ligated with the assembled oligonucleotides using T4 DNA ligase (Boehringer Mannheim, Indianapolis, IN). A portion of the ligation reaction was used to transform E. coli strain DH-5cL cells (Life Technologies, Gaithersburg, MD). Transformant bacteria were WO 97/12985 PCT/US96/157 7 4 172 selected on ampicillin-containing plates. Plasmid DNA was isolated from the transformants and analyzed using a PCR based assay. Plasmid DNA from selected transformants was sequenced to confirm the correct insertion of the oligonucleotides. The resulting plasmid was designated pMON13180 and contains the DNA sequence of (SEQ ID EXAMPLE 52 Construction of DMON3181, an intermediate lasmid ed for constructina Dlasmids that contain DNA sequences encoding multi-functional hematooeic recptor agoniss Plasmid, pMON13047 (WO 95/21254), DNA was digested with restriction endonucleases Xmal and SnaBI, resulting in a 4063 base pair vector fragment. The 4063 base pair XmaI- SnaBI fragment was purified using a Magic DNA Clean-up System kit (Promega, Madison, WI) in which the 25 base pair XmaI-SnaBI insert fragment is not retained. The complimentary pair of synthetic oligonucleotides, glyxal (SEQ ID NO:74) and glyxa2 (SEQ ID NO:75), were designed to remove sequence encoding the factor Xa cleavage site. When properly assembled these oligonucleotides also result in XmaI and SnaBI ends. Glyxal and glyxa2 were annealed in annealing buffer by heating at 70 0 C for ten minutes and allowed to slow cool. The 4063 base pair XmaI-SnaBI fragment from pMON13047 was ligated with the assembled oligonucleotides using T4 DNA ligase (Boehringer Mannheim, Indianapolis, IN). A portion of the ligation reaction was used to transform E. coli strain DH5a cells (Life Technologies, Gaithersburg, MD). Transformant bacteria were selected on ampicillin-containing plates. Plasmid DNA was isolated from the transformants and analyzed using a PCR based assay. Plasmid DNA from selected transformants was sequenced to confirm the correct insertion of the WO 97/12985 PCT/US96/15774 173 oligonucleotides. The resulting plasmid was designated pMON13181 and contains the DNA sequence of (SEQ ID EXAMPLE 53 Construction of pMON13182 The new N-terminus/C-terminus gene in pMON13182 was created using Method I as described in Materials and Methods. Fragment Start was created and amplified from G- CSF Serl7 sequence in pMON13037 using the primer set, 39 start (SEQ ID NO:64) and L-ll start (SEQ Fragment Stop was created and amplified from G-CSF Serl7 sequence pMON13037 using the primer set, 38 stop (SEQ ID and L-ll stop (SEQ ID NO:61). The full-length new N terminus/C-terminus G-CSF Serl 7 gene was created and amplified from the annealed Fragments Start and Stop using primers 39 start and 38 stop.

The resulting DNA fragment which contains the new gene was digested with restriction endonucleases NcoI and HindIII and purified using a Magic DNA Clean-up System kit (Promega, Madison, WI). The intermediate plasmid, pMON13180, was digested with restriction endonucleases HindIII and AflIII, resulting in a 4023 base pair vector fragment, and purified using a Magic DNA Clean-up System kit (Promega, Madison, WI). The purified restriction fragments were combined and ligated using T4 DNA ligase (Boehringer Mannheim, Indianapolis, IN). A portion of the ligation reaction was used to transform E. coli strain DH5a cells (Life Technologies, Gaithersburg, MD). Transformant bacteria were selected on ampicillin-containing plates. Plasmid DNA was isolated and sequenced to confirm the correct insert. The resulting plasmid was designated pMON13182.

WO 97/12985 PCTIUS96/1 5774 174 E. coli strain JM101 was transformed with pMON13182 for protein expression and protein isolation from inclusion bodies.

The plasmid, pMON13182, contains the DNA sequence of (SEQ ID NO:94) which encodes the following amino acid sequence: Asn Cys Ser Ile Met Ile Pro Pro Ala Pro Leu Leu Val Ser Ile Leu Met Asp Ser Phe Val Arg Ala Val Glu Ala Ile Leu Arg Asn Ala Ala Pro Ser Arg His Gin Glu Phe Arg Glu Lys Gin Ala Gin Glu Gin Gin Gly Gly Gly Ser Gly Gly His Pro Glu Glu Leu Val Trp Ala Pro Leu Ser Ser Gly Cys Leu Ser Gin Leu Leu Leu Gin Ala Leu Glu Leu Asp Thr Leu Gin Leu Trp Gin Gin Met Glu Glu Thr Gin Gly Ala Met Pro Ala Gly Gly Val Leu Val Val Ser Tyr Arg Val Leu Ser Gly Gly Ser Gin Ser Arg Lys Ile Gin Gly Asp Ala Thr (SEQ ID NO:166) Asp Asp Arg Lys Leu Pro Leu Tyr Gly Leu Cys His Gly Asp Leu Ala Ala Arg Phe Gly Glu Pro Asn Asn Gin Ile Thr Val Ser Leu Pro Ser Ile Val Gly Phe Ser His Leu Ala Ile Asn Leu Leu Pro Ile Phe Glu Asn Gly Ser Gly Ser Ala Met Ala His Leu Leu Ala lie Asn Arg Glu Cys Ile Tyr Gly Met His Gin Leu Pro Asp Ala Ser Leu Ala Lys Leu His His Leu Asn Leu Pro Asn Ala Leu Pro Lys Ala Leu Val Gly- Gly Ala Tyr Ser Leu Ala Leu Phe Leu Glu Leu Phe Ala Pro Ala Ala Phe Gin Ser Gin Pro Ser Leu Gin Glu Leu Asp Asn Ser Ser Gly Thr Gly Lys Gly Gln Tyr Gly Thr Leu Gin Phe Ser Glu Lys Lys Arg Glu Asp Leu Glu Gly Ile Ala Thr Asp Trp Leu Glu Ser Pro Leu Cys Ile Pro Leu Ala Gin Gly Pro Thr Thr lle Gin Pro Arg Arg Leu Glu Gly Gly Gln Val Leu Cys EXAMPLE 54 Construction of MN3183 The new N-terminus/C-terminus gene in pMON13183 was created using Method I as described in Materials and Methods.

"Fragment Start" was created and amnlified fr- r_- CSF Ser 17 sequence in pMON13037 using the primer set, 39 start (SEQ ID NO:64) and L-l1 start (SEQ ID ,LL <J

A

4U Fragment Stop was created and amplified from G-CSF Serl7 sequence in pMON13037 using the primer set, 38 stop (SEQ ID and L-ll stop (SEQ ID NO:61). The full-length new N

I

WO 97/12985 PCT/US96/15774 175 terminus/C-terminus G-CSF Serl 7 gene was created and amplified from the annealed Fragments Start and Stop using 39 start and 38 stop.

The resulting DNA fragment which contains the new gene was digested with restriction endonucleases NcoI and HindIII and purified using a Magic DNA Clean-up System kit (Promega, Madison, WI). The intermediate plasmid, pMON13181, was digested with restriction endonucleases HindIII and AflIII, resulting in a 4068 base pair vector fragment, and purified using a Magic DNA Clean-up System kit (Promega, Madison, WI). The purified restriction fragments were combined and ligated using T4 DNA ligase (Boehringer Mannheim, Indianapolis, IN). A portion of the ligation reaction was used to transform E. coli strain DH5a cells (Life Technologies, Gaithersburg, MD). Transformant bacteria were selected on ampicillin-containing plates. Plasmid DNA was isolated and sequenced to confirm the correct insert. The resulting plasmid was designated pMON13183.

E. coli strain JM101 was transformed with pMON13183 for protein expression and protein isolation from inclusion bodies.

The plasmid, pMON13183, contains the DNA sequence of (SEQ ID NO:95) which encodes the following amino acid sequence: Asn Pro Val Ser Glu Ala Gin Gin Gly Ser His Trp Gly Leu Leu Cys Ser Ile Met Ile Pro Ala Pro Leu Leu Ser Ile Leu Met Asp Phe Val Arg Ala Val Ala Ile Leu Arg Asn Ala Pro Ser Arg His Glu Phe Arg Glu Lys Ala Gin Glu Gln Gin Glu Pro Ser Gly Pro Lys Glu Ser His Lys Pro Glu Glu Leu Val Ala Pro Leu Ser Ser Cys Leu Ser Gin Leu Leu Gin Ala Leu Glu Asp Thr Leu Gin Leu Asp Glu Ile Asp Pro Asn Arg Asn Leu Lys Asn Leu Leu Gin Pro Pro Ile Ile Leu Thr Phe Tyr Val Glu Ile Ser Thr Ser Pro Asn Leu Leu Gly Cys Pro Ser His Ser Gly Gly Ile Ser Asp Val Ala Ile His His Leu Lys Asn Leu Asn Asp Glu Arg Leu Pro Asn Leu Glu Asn Ala Ser Gly Cys Leu Pro Ser Ala Ile Lys Ala Gly Asp Tyr Leu Val Thr Leu Gly Gly Gly Gly Ser Ile Asn Pro Ser Pro Met Ala Tyr Lys Leu His Ser Leu Gly Ile Gin Ala Leu Gin Leu Leu Phe Leu Tyr Gin Pro Glu Leu Gly Pro Asp Phe Ala Thr Thr Arg Asp Glu Ile Thr Trp Glu Pro Pro Cys Pro Ala Gly Thr Ile WO 97/12985 PCT/US96/1 5 7 7 4 176 Trp Gln Gln Met Glu Glu Leu Gly Met Ala Pro Ala LeuGln Pro Thr Gln Gly Ala Met Pro Ala Phe Ala Ser Ala Phe Gln Arg Arg Ala Gly Gly Val Leu Val Ala Ser His Leu Gln Ser Phe Leu Glu Val Ser Tyr Arg Val Leu Arg His Leu Ala Gln Pro Ser Gly Gly Ser Gly Gly Ser Gln Ser Phe Leu Leu Lys Ser Leu Glu Gln Val Arg Lys Ile Gln Gly Asp Gly Ala Ala Leu Gln Glu Lys Leu Cys Ala Thr (SEQ ID NO:167) EXAMPLE Construction of DMON13184 The new N-terminus/C-terminus gene in pMON13184 was created using Method I as described in Materials and Methods. Fragment Start was created and amplified from

G-

CSF Serl7 sequence in pMON13037 using the primer set, 97 start (SEQ ID NO:66) and L-ll start (SEQ ID Fragment Stop was created and amplified from G-CSF Serl7 sequence in pMON13037 using the primer set, 96 stop (SEQ ID NO:67) and L-11 stop (SEQ ID NO:61). The full-length new N terminus/C-terminus G-CSF Serl 7 gene was created and amplified from the annealed Fragments Start and Stop using 97 start and 96 stop.

The resulting DNA fragment which contains the new gene was digested with restriction endonucleases NcoI and HindIII and purified using a Magic DNA Clean-up System kit (Promega, Madison, WI). The intermediate plasmid, pMON13180, was digested with restriction endonucleases HindIII and AflIII, resulting in a 4023 base pair vector fragment, and purified using a Magic DNA Clean-up System kit (Promega, Madison, WI). The purified restriction fragments were combined and ligated using T4 DNA ligase (Boehringer Mannheim, Indianapolis, IN). A portion of the ligation reaction was used to transform E. coli strain DH5x cells (Life Technologies, Gaithersburg, MD). Transformant bacteria were selected on ampicillin-containing plates. Plasmid DNA was WO 97/12985 PCTIUS96/15774 isolated and sequenced to confirm the correct insert. The resulting plasmid was designated pMON13184.

E. coli strain JM101 was transformed with pMON13184 for protein expression and protein isolation from inclusion bodies.

The plasmid, pMON13184, contains the DNA sequence of (SEQ ID NO:96) which encodes the following amino acid sequence: Asn Pro Val Ser Glu Ala Gin Gin Gly Pro Thr Gin Arg Leu Gly Gin Leu Leu Pro Ser Ile Cys Pro Ser Phe Ala Ala Glu Ala Gly Thr Ile Pro Arg Glu Gly Val Cys Gly Ser Gly Ser Ser Ile Met Ile Ala Pro Leu Leu Ile Leu Met Asp Val Arg Ala Val Ile Leu Arg Asn Pro Ser Arg His Phe Arg Glu Lys Gin Glu Gin Gin Gly Ser Gly Gly Leu Asp Thr Leu Trp Gin Gin Met Thr Gin Gly Ala Ala Gly Gly Val Val Ser Tyr Arg Ser Gly Gly Ser Arg Lys Ile Gin Ala Thr Tyr Lys His Ser Leu Gly Gin Ala Leu Gin Leu Phe Leu Tyr (SEQ ID NO:168) Asp Glu Ile Asp Pro Asn Arg Asn Leu Lys Asn Leu Leu Gin Pro Pro Ile Ile Leu Thr Phe Tyr Val Glu Gly Ser Asn Gin Leu Asp Glu Glu Leu Met Pro Ala Leu Val Ala Val Leu Arg Gin Ser Phe Gly Asp Gly Leu Cys His Ile Pro Trp Leu Ala Gly Gin Gly Leu Ile His Asn Leu Arg Leu Glu Asn Cys Leu Ile Lys Tyr Leu Gly Gly Met Ala Val Ala Gly Met Phe Ala Ser His His Leu Leu Leu Ala Ala Pro Glu Ala Pro Cys Leu Leu Gin His Asn Pro Ala Pro Ala Val Gly Pro Asp Ala Ser Leu Ala Lys Leu Glu Leu Ser Ala Leu Asp Asn Ser Ser Gly Thr Gly Glu Phe Pro Ala Gin Gin Ser Gin Leu Ser Gin Leu Lys Glu Leu Gly Ala Asp Leu Ser Leu Ala Ala Phe Ser Pro Leu Glu Val Ser Leu Glu Arg Asp Glu Ile Thr Trp Glu Pro Gly Thr Leu Gin Phe Ser Glu Lys Leu Cys His Gly EXAMPLE 56 Construction of DMON13185 The new N-terminus/C-terminus gene in pMON13185 was created using Method I as described in Materials and Methods. Fragment Start was created and amplified from G- CSF Ser 17 sequence in pMON13037 using the primer set, 97 start (SEQ ID NO:66) and L-l1 start (SEQ ID Fragment Stop was created and amplified from G-CSF Ser 17

_~I

WO 97/12985 PCT/US96/15774 178 sequence in pMON13037 using the primer set, 96 stop (SEQ ID NO:67 and L-ll stop (SEQ ID NO:61). The full-length new N terminus/C-terminus G-CSF Serl 7 gene was created and amplified from the annealed Fragments Start and Stop using 97 start and 96 stop.

The resulting DNA fragment which contains the new gene was digested with restriction endonucleases NcoI and HindIII and purified using a Magic DNA Clean-up System kit (Promega, Madison, WI). The intermediate plasmid, pMON13181, was digested with restriction endonucleases HindIII and AflIII, resulting in a 4068 base pair vector fragment, and purified using a Magic DNA Clean-up System kit (Promega, Madison, WI). The purified restriction fragments were combined and ligated using T4 DNA ligase (Boehringer Mannheim, Indianapolis, IN). A portion of the ligation reaction was used to transform E. coli strain DH5a cells (Life Technologies, Gaithersburg, MD). Transformant bacteria were selected on ampicillin-containing plates. Plasmid DNA was isolated and sequenced to confirm the correct insert. The resulting plasmid was designated pMON13185.

E. coli strain JM101 was transformed with pMON13185 for protein expression and protein isolation from inclusion bodies.

The plasmid, pMON13185, contains the DNA sequence of (SEQ ID NO:67) which encodes the following amino acid sequence: Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg Pro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp Val Ser Ile Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu Ser Phe Val Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly Ile Glu Ala Ile Leu Arg Asn Leu Gln Pro Cys Leu Pro Ser Ala Thr Ala Ala Pro Ser Arg His Pro Ile Ile Ile Lys Ala Gly Asp Trp Gln Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu Gln Ala Gin Glu Gln Gln Tyr Val Glu Gly Gly Gly Gly Ser Pro Gly Glu Pro Ser Gly Pro Ile Ser Thr Ile Asn Pro Ser Pro Pro Ser Lys Glu Ser His Lys Ser Pro Asn Met Ala Pro Glu Leu Gly Pro Thr Leu Asp Thr Leu Gln Leu Asp Val Ala Asp Phe Ala Thr WO 97/12985 PCT/US96/15774 179 Thr Ile Trp Gin Gin Met Glu Glu Leu Gly Met Ala ProAla Leu Gin Pro Thr Gin Gly Ala Met Pro Ala Phe Ala Ser Ala Phe Gin Arg Arg Ala Gly Gly Val Leu Val Ala Ser His Leu Gin Ser Phe Leu Glu Val Ser Tyr Arg Val Leu Arg His Leu Ala Gin Pro Ser Gly Gly Ser Gly Gly Ser Gin Ser Phe Leu Leu Lys Ser Leu Glu Gin Val Arg Lys Ile Gin Gly Asp Gly Ala Ala Leu Gin Glu Lys Leu Cys Ala Thr Tyr Lys Leu Cys His Pro Glu GIu Leu Val Leu Leu Gly His Ser Leu Gly Ile Pro Trp Ala Pro Leu Ser Ser Cys Pro Ser Gin Ala Leu Gin Leu Ala Gly Cys Leu Ser Gin Leu His Ser Gly Leu Phe Leu Tyr Gin Gly Leu Leu Gin Ala-Leu Glu Gly Ile Ser (SEQ ID NO:169) EXAMPLE 57 Construction of pMON13186 The new N-terminus/C-terminus gene in pMON13186 was created using Method I as described in Materials and Methods. Fragment Start was created and amplified from G- CSF Serl 7 sequence in pMON13037 using the primer set, 126 start (SEQ ID NO:68) and L-ll start (SEQ ID Fragment Stop was created and amplified from G-CSF Serl7 sequence in pMON13037 using the primer set, 125 stop (SEQ ID NO:69) and L-l1 stop (SEQ ID NO:61). The full-length new N terminus/C-terminus G-CSF Serl 7 gene was created and amplified from the annealed Fragments Start and Stop using 126 start and 125 stop.

The resulting DNA fragment which contains the new gene was digested with restriction endonucleases NcoI and HindIII and purified using a Magic DNA Clean-up System kit (Promega, Madison, WI). The intermediate plasmid, pMON13180, was digested with restriction endonucleases HindIII and AflIII, resulting in a 4023 base pair vector fragment, and purified using a Magic DNA Clean-up System kit (Promega, Madison, WI). The purified restriction fragments were combined and ligated using T4 DNA ligase (Boehringer Mannheim, Indianapolis, IN). A portion of the ligation reaction was used to transform E. coli strain DH5a cells (Life WO 97/12985 PCT/US96/15774 180 Technologies, Gaithersburg, MD). Transformant bacteria were selected on ampicillin-containing plates. Plasmid DNA was isolated and sequenced to confirm the correct insert. The resulting plasmid was designated pMON13186.

E. coli strain JM101 was transformed with pMON13186 for protein expression and protein isolation from inclusion bodies.

The plasmid, pMON13186, contains the DNA sequence of (SEQ ID NO:98) which encodes the following amino acid sequence: Asn Cys Ser Pro Pro Ala Val Ser Ile Ser Phe Val Glu Ala Ile Ala Ala Pro Gin Glu Phe Gin Ala Gin Gly Gly Gly Leu Gin Pro Gin Arg Arg Phe Leu Glu Ser Gly Gly Glu Gin Val Lys Leu Cys Leu Leu Gly Cys Pro Ser His Ser Gly Gly Ile Ser Asp Val Ala Ile Met Ile Pro Leu Leu Leu Met Asp Arg Ala Val Leu Arg Asn Ser Arg His Arg Glu Lys Glu Gin Gin Ser Gly Gly Thr Gin Gly Ala Gly Gly Val Ser Tyr Ser Gly Gly Arg Lys Ile Ala Thr Tyr His Ser Leu Gin Ala Leu Leu Phe Leu Pro Glu Leu Asp Phe Ala Asp Glu Asp Pro Arg Asn Lys Asn Leu Gin Pro Ile Leu Thr Tyr Val Gly Ser Ala Met Val Leu Arg Val Ser Gin Gin Gly Lys Leu Gly Ile Gin Leu Tyr Gin Gly Pro Thr Thr Ile Asn Leu Leu Pro Ile Phe Glu Asn Pro Val Leu Ser Asp Cys Pro Ala Gly Thr Ile Ile Asn Arg Glu Cys Ile Tyr Gly Met Ala Ala Arg Phe Gly His Trp Gly Leu Leu Trp His His Leu Asn Leu Pro Asn Ala Leu Pro Lys Ala Leu Val Gly Gly Ala Met Phe Ala Ser His His Leu Leu Leu Ala Ala Pro Glu Ala Pro Cys Leu Leu Gin Asp Thr Gln Gin Leu Asp Asn Ser Ser Gly Thr Gly Ala Ser Leu Ala Lys Leu Glu Leu Ser Ala Leu Met Lys Glu Leu Gly Ala Asp Leu Ser Pro Ala Gin Gin Ser Gin Leu Ser Gin Leu Gin Glu Arg Asp Glu Ile Thr Trp Glu Pro Ala Phe Ser Pro Leu Glu Val Ser Leu Glu Leu Glu Leu Gly (SEQ ID N0:170) EXAMPLE 58 Construction of pMON13187 The new N-terminus/C-terminus gene in pMON13187 was created using Method I as described in Materials and Methods. Fragment Start was created and amplified from G- CSF Ser 17 sequence in pMON13037 using the primer set, 126 start (SEQ ID NO:68) and L-11 start (SEQ ID WO 97/12985 PCT/US96/15774 181 Fragment Stop was created and amplified from G-CSF Serl7 sequence in pMON13037 using the primer set, 125 stop (SEQ ID NO:69) and L-ll stop (SEQ ID NO:61). The full-length new N terminus/C-terminus G-CSF Ser 17 gene was created and amplified from the annealed Fragments Start and Stop using 126 start and 125 stop.

The resulting DNA fragment which contains the new gene was digested with restriction endonucleases NcoT and HindIII and purified using a Magic DNA Clean-up System kit (Promega, Madison, WI). The intermediate plasmid, pMON13181, was digested with restriction endonucleases HindIII and AflIII, resulting in a 4068 base pair vector fragment, and purified using a Magic DNA Clean-up System kit (Promega, Madison, WI). The purified restriction fragments were combined and ligated using T4 DNA ligase (Boehringer Mannheim, Indianapolis, IN). A portion of the ligation reaction was used to transform E. coli strain DH5a cells (Life Technologies, Gaithersburg, MD). Transformant bacteria were selected on ampicillin-containing plates. Plasmid DNA was isolated and sequenced to confirm the correct insert. The resulting plasmid was designated pMON13187.

E. coli strain JM101 was transformed with pMON13187 for protein expression and protein isolation from inclusion bodies.

The plasmid, pMON13187, contains the DNA sequence of (SEQ ID NO:99) which encodes the following amino acid sequence: Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg Pro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp Val Ser Ile Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu Ser Phe Val Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly Ile Glu Ala Ile Leu Arg Asn Leu Gln Pro Cys Leu Pro Ser Ala Thr Ala Ala Pro Ser Arg His Pro Ile Ile Ile Lys Ala Gly Asp Trp Gln Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu Gln Ala Gln Glu Gln Gln Tyr Val Glu Gly Gly Gly Gly Ser Pro Gly Glu Pro Ser Gly Pro Ile Ser Thr Ile Asn Pro Ser Pro Pro WO 97/12985 PCT/US96/15774 182 Ser Lys Glu Ser His Lys Ser Pro Asn Met Ala Met Ala Pro Ala Leu Gin Pro Thr Gin Gly Ala Met Pro Ala Phe Ala Ser Ala Phe Gin Arg Arg Ala Gly Gly Val Leu Val Ala Ser His Leu Gin Ser Phe Leu Glu Val Ser Tyr Arg Val Leu Arg His Leu Ala Gin Pro Ser Gly Gly Ser Gly Gly Ser Gin Ser Phe Leu Leu Lys Ser Leu Glu Gin Val Arg Lys Ile Gin Gly Asp Gly Ala Ala Leu Gln Glu Lys Leu Cys Ala Thr Tyr Lys Leu Cys His Pro Glu Glu Leu Val Leu Leu Gly His Ser Leu Gly Ile Pro Trp Ala Pro Leu Ser Ser Cys Pro Ser Gin Ala Leu Gin Leu Ala Gly Cys Leu Ser Gin Leu His Ser Gly Leu Phe Leu Tyr Gin Gly Leu Leu Gln-Ala Leu Glu Gly Ile Ser Pro Glu Leu Gly Pro Thr Leu Asp Thr Leu Gin Leu Asp Val Ala Asp Phe Ala Thr Thr Ile Trp Gin Gin Met Glu Glu Leu Gly (SEQ ID NO:171) EXAMPLE 59 Construction of pMON3188 The new N-terminus/C-terminus gene in pMON13188 was created using Method I as described in Materials and Methods. Fragment Start was created and amplified from G- CSF Serl 7 sequence in pMON13037 using the primer set, 133 start (SEQ ID NO:70) and L-ll start (SEQ ID Fragment Stop was created and amplified from G-CSF Ser 17 sequence in pMON13037 using the primer set, 132 stop (SEQ ID NO:71) and L-ll stop (SEQ ID NO:61). The full-length new N terminus/C-terminus G-CSF Serl 7 gene was created and amplified from the annealed Fragments Start and Stop using 133 start and 132 stop.

The resulting DNA fragment which contains the new gene was digested with restriction endonucleases NcoI and HindIII and purified using a Magic DNA Clean-up System kit (Promega, Madison, WI). The intermediate plasmid, pMON13180, was digested with restriction endonucleases HindIII and AflIII, resulting in a 4023 base pair vector fragment, and purified using a Magic DNA Clean-up System kit (Promega, Madison, WI). The purified restriction fragments were combined and ligated using T4 DNA ligase (Boehringer Mannheim, Indianapolis, IN). A portion of the ligation reaction was used to transform E. coli strain DH5a cells (Life Wn O 7/910Q VT v PCT/US96/15774 183 Technologies, Gaithersburg, MD). Transformant bacteria were selected on ampicillin-containing plates. Plasmid DNA was isolated and sequenced to confirm the correct insert. The resulting plasmid was designated pMON13188.

E. coli strain JM101 was transformed with pMON13188 for protein expression and protein isolation from inclusion bodies.

The plasmid, pMON13188, contains the DNA sequence of (SEQ ID NO:100) which encodes the following amino acid sequence: Asn Pro Val Ser Glu Ala Gin Gin Gly Met Leu Val Gin Gly Leu Ile Leu Gin Pro Thr Cys Pro Ser Phe Ala Ala Glu Ala Gly Pro Val Leu Ser Asp Cys Pro Ala Gly Thr Ile Ser Ala Ile Val Ile Pro Phe Gir Gly Ala Ala Arg Phe Gly His Trp Gly Leu Leu Trp Ile Met Pro Leu Leu Met Arg Ala Leu Arg Ser Arg Arg Glu Glu Gin Ser Gly Phe Ala Ser His His Leu Leu Leu Ala Ala Pro Glu Ala Pro Cys Leu Leu Gin Asp Thr Gin Gin ID NO:1 Ile Leu Asp Val Asn His Lys Gin Gly Ser Leu Ala Lys Leu Glu Leu Ser Ala Leu Met 72) Asp Glu Asp Pro Arg Asn Lys Asn Leu Gin Pro Ile Leu Thr Tyr Val Gly Ser Ala Phe Gin Ser Gin Pro Ser Leu Gin Glu Leu Val Ser Ser Gin Leu Leu Glu Gin Leu Glu Glu Ile Ile Asn Asn Leu Arg Leu Glu Pro Cys Ile Ile Phe Tyr Glu Gly Asn Met Gin Arg Phe Leu Ser Gly Glu Gin Lys Leu Leu Leu Cys Pro His Ser Gly Ile Asp Val Leu Gly His His Leu"Asn Leu Pro Asn Ala Leu Pro Lys Ala Leu Val Gly Gly Ala Thr Arg Ala Glu Val Gly Ser Val Arg Cys Ala Gly His Ser Gin Gly Leu Ser Pro Ala Asp Met Ala Leu Asp Asn Ser Ser Gly Thr Gly Gin Gly Ser Gly Lys Thr Ser Ala Phe Glu Phe Pro Lys Glu Leu Gly Ala Asp Leu Ser Gly Gly Tyr Gly Ile Tyr Leu Leu Leu Leu Ala Ala Arg Asp Glu Ile Thr Trp Glu Pro Ala Val Arg Ser Gin Lys Gly Gin Tyr Gly Thr Leu Gin Pro (SEC EXAMPLE Construction of pMONl3189 The new N-terminus/C-terminus gene in pMON13189 was created using Method I as described in Materials and Methods. Fragment Start was created and amplified from G- CSF Serl7 sequence in pMON13037 using the primer set, 133 start (SEQ ID NO:70) and L-11 start (SEQ ID WO 97/12985 PCT/US96/1 5 7 7 4 184 Fragment Stop was created and amplified from G-CSF Serl7 sequence in pMON13037 using the primer set, 132 stop (SEQ ID NO:71) and L-ll stop (SEQ ID NO:61). The full-length new N terminus/C-terminus G-CSF Serl 7 gene was created and amplified from the annealed Fragments Start and Stop using 133 start and 132 stop.

The resulting DNA fragment which contains the new gene was digested with restriction endonucleases NcoI and HindIII and purified using a Magic DNA Clean-up System kit (Promega Madison, WI). The intermediate plasmid, pMON13181, was digested with restriction endonucleases HindIII and AflIII, resulting in a 4068 base pair vector fragment, and purified using a Magic DNA Clean-up System kit (Promega, Madison, WI). The purified restriction fragments were combined and ligated using T4 DNA ligase (Boehringer Mannheim, Indianapolis, IN). A portion of the ligation reaction was used to transform E. coli strain DH5a cells (Life Technologies, Gaithersburg, MD). Transformant bacteria were selected on ampicillin-containing plates. Plasmid DNA was isolated and sequenced to confirm the correct insert. The resulting plasmid was designated pMON13189.

E. coli strain JM101 was transformed with pMON13189 for protein expression and protein isolation from inclusion bodies.

The plasmid, pMON13189, contains the DNA sequence of (SEQ ID NO:101) which encodes the following amino acid sequence: Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg Pro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp Val Ser Ile Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu Ser Phe Val Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly Ile Glu Ala Ile Leu Arg Asn Leu Gln Pro Cys Leu Pro Ser Ala Thr Ala Ala Pro Ser Arg His Pro Ile Ile Ile Lys Ala Gly Asp Trp Gln Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu Gln Ala Gln Glu Gln Gln Tyr Val Glu Gly Gly Gly Gly Ser Pro Gly Glu Pro Ser Gly Pro Ile Ser Thr Ile Asn Pro Ser Pro Pro WO 97/12985 PCT/US96/15774 185 Ser Lys Glu Ser His Lys Ser Pro Asn Met Ala Thr GlnGly Ala Met Pro Ala Phe Ala Ser Ala Phe Gin Arg Arg Ala Gly Gly Val Leu Val Ala Ser His Leu Gin Ser Phe Leu Glu Val Ser Tyr Arg Val Leu Arg His Leu Ala Gin Pro Ser Gly Gly Ser Gly Gly Ser Gin Ser Phe Leu Leu Lys Ser Leu Glu Gin Val Arg Lys Ile Gin Gly Asp Gly Ala Ala Leu Gin Glu Lys Leu Cys Ala Thr Tyr Lys Leu Cys His Pro Glu Glu Leu Val Leu Leu Gly His Ser Leu Gly Ile Pro Trp Ala Pro Leu Ser Ser Cys Pro Ser Gin Ala Leu Gin Leu Ala Gly Cys Leu Ser Gin Leu His Ser Gly Leu Phe Leu Tyr Gin Gly Leu Leu Gin Ala Leu Glu Gly Ile Ser Pro'Glu Leu Gly Pro Thr Leu Asp Thr Leu Gin Leu Asp Val Ala Asp Phe Ala Thr Thr Ile Trp Gin Gin Met Glu Glu Leu Gly Met Ala Pro Ala Leu Gin Pro (SEQ ID NO:173) EXAMPLE 61 Construction of DMON13190 The new N-terminus/C-terminus gene in pMON13190 was created using Method I as described in Materials and Methods. Fragment Start was created and amplified from G- CSF Serl 7 sequence in pMON13037 using the primer set, 142 start (SEQ ID NO:72) and L-ll start (SEQ ID Fragment Stop was created and amplified from G-CSF Ser 17 sequence in pMON13037 using the primer set, 141 stop (SEQ ID NO:73) and L-l1 stop (SEQ ID NO:61). The full-length new N terminus/C-terminus G-CSF Ser 17 gene was created and amplified from the annealed Fragments Start and Stop using 142 start and 141 stop.

The resulting DNA fragment which contains the new gene was digested with restriction endonucleases NcoI and HindIII and purified using a Magic DNA Clean-up System kit (Promega, Madison, WI). The intermediate plasmid, pMON13180, was digested with restriction endonucleases HindIII and AflIII, resulting in a 4023 base pair vector fragment, and purified using a Magic DNA Clean-up System kit (Promega, Madison, WI). The purified restriction fragments were combined and ligated using T4 DNA ligase (Boehringer Mannheim, Indianapolis, IN). A portion of the ligation reaction was used to transform E. coli strain DH5a cells (Life WO 97/12985 PCT/US96/15774 186 Technologies, Gaithersburg, MD). Transformant bacteria were selected on ampicillin-containing plates. Plasmid DNA was isolated and sequenced to confirm the correct insert. The resulting plasmid was designated pMON13190.

E. coli strain JM101 was transformed with pMON13190 for protein expression and protein isolation from inclusion bodies.

The plasmid, pMON13190, contains the DNA sequence of (SEQ ID NO:102) which encodes the following amino acid sequence: Asn Pro Val Ser Glu Ala Gin Gin Gly Arg Leu Gly Gin Leu Leu Pro Ser Ile Val Gly Phe Cys Pro Ser Phe Ala Ala Glu Ala Gly Arg Glu Gly Val Cys Gly Ser Gly Ser Ala Met Ala Ser Ile Ala Pro Ile Leu Val Arg Ile Leu Pro Ser Phe Arg Gin Glu Gly Ser Ala Gly Val Ser Ser Gly Arg Lys Ala Thr His Ser Gin Ala Leu Phe Pro Glu Asp Phe Ala Pro (SEQ ID Met Ile Leu Leu Met Asp Ala Val Arg Asn Arg His Glu Lys Gin Gin Gly Gly Gly Val Tyr Arg Gly Ser Ile Gin Tyr Lys Leu Gly Leu Gin Leu Tyr Leu Gly Ala Thr Ala Leu NO:174) Asp Asp Arg Lys Leu Pro Leu Tyr Gly Leu Val Gin Gly Leu Ile Leu Gin Pro Thr Gin Glu Ile Ile Pro Asn Asn Asn Leu Arg Asn Leu Glu Gin Pro Cys Ile Ile Ile Thr Phe Tyr Val Glu Gly Ser Asn Met Val Ala Ser Leu Arg His Ser Phe Leu Asp Gly Ala Cys His Pro Pro Trp Ala Ala Gly Cys Gly Leu Leu Thr Leu Asp Ile Trp Gin Pro Thr Gin His His Leu Leu Asn Asp Leu Pro Asn Asn Ala Ser Leu Pro Ser Lys Ala Gly Leu Val Thr Gly Gly Gly Ala Ser Ala His Leu Gin Leu Ala Gin Leu Lys Ser Ala Leu Gin Glu Glu Leu Pro Leu Ser Leu Ser Gin Gin Ala Leu Thr Leu Gin Gin Met Glu Gly Ala Met Lys Glu Leu Gly Ala Asp Leu Ser Phe Ser Pro Leu Glu Val Ser Leu Glu Leu Glu Pro Arg Asp Glu lie Thr Trp Glu Pro Gin Phe Ser Glu Lys Leu Cys His Gly Asp Leu Ala EXAMPLE 62 Construction of DMON3191 The new N-terminus/C-terminus gene in pMON13191 was created using Method I as described in Materials and Methods. Fragment Start was created and amplified from G- CSF Ser 17 sequence in pMON13037 using the primer set, 142 WO 97/12985 PCT/US96/15774 187 start (SEQ ID NO:72) and L-ll start (SEQ ID Fragment Stop was created and amplified from G-CSF Serl7 sequence in pMON13037 using the primer set, 141 stop (SEQ ID NO:73) and L-ll stop (SEQ ID NO:61). The full-length new N terminus/C-terminus G-CSF Serl 7 gene was created and amplified from the annealed Fragments Start and Stop using 142 start and 141 stop.

The resulting DNA fragment which contains the new gene was digested with restriction endonucleases NcoI and HindIII and purified using a Magic DNA Clean-up System kit (Promega, Madison, WI). The intermediate plasmid, pMON13181, was digested with restriction endonucleases HindIII and AflIII, resulting in a 4068 base pair vector fragment, and purified using a Magic DNA Clean-up System kit (Promega, Madison, WI). The purified restriction fragments were combined and ligated using T4 DNA ligase (Boehringer Mannheim, Indianapolis, IN). A portion of the ligation reaction was used to transform E. coli strain DH5a cells (Life Technologies, Gaithersburg, MD). Transformant bacteria were selected on ampicillin-containing plates. Plasmid DNA was isolated and sequenced to confirm the correct insert. The resulting plasmid was designated pMON13191.

E. coli strain JM101 was transformed with pMON13191 for protein expression and protein isolation from inclusion bodies.

The plasmid, pMON13191, contains the DNA sequence of (SEQ ID NO:103) which encodes the following amino acid sequence: Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg Pro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp Val Ser Ile Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu Ser Phe Val Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly Ile Glu Ala Ile Leu Arg Asn Leu Gln Pro Cys Leu Pro Ser Ala Thr Ala Ala Pro Ser Arg His Pro Ile Ile Ile Lys Ala Gly Asp Trp Gin Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu Gin Ala Gin Glu Gin Gin Tyr Val Glu Gly Gly Gly Gly Ser Pro WO 97/12985 PCTJUS96/15 7 74 Gly Glu Pro Ser Gly Pro Ser Lys Glu Ser His Lys Arg Arg Ala Gly Gly Val Leu Glu Val Ser Tyr Arg Gly Gly Ser Gly Gly Ser Gin Val Arg Lys Ile Gin Leu Cys Ala Thr Tyr Lys Leu Gly His Ser Leu Gly Pro Ser Gin Ala Leu Gin Ser Gly Leu Phe Leu Tyr Ile Ser Pro Glu Leu Gly Val Ala Asp Phe Ala Thr Gly Met Ala Pro Ala Leu Phe Ala (SEQ ID NO:175) lie Ser Leu Val Gin Gly Leu Ile Leu Gin Pro Thr Gin Ser Thr Ile Pro Asn Met Val Ala Ser Leu Arg His Ser Phe Leu Asp Gly Ala Cys His Pro Pro Trp Ala Ala Gly Cys Gly Leu Leu Thr Leu Asp Ile Trp Gin Pro Thr Gin Asn Pro Ser Pro Ala Ser Ala Phe His Leu Gin Ser Leu Ala Gin Pro Leu Lys Ser Leu Ala Leu Gin Glu Glu Glu Leu Val Pro Leu Ser Ser Leu Ser Gin Leu Gin Ala Leu Glu Thr Leu Gin Leu Gin Met Glu Glu Gly Ala Met Pro Pro Gin Phe Ser Glu Lys Leu Cys His Gly Asp Leu Ala EXAMPLE 63 Construction of pMONI3192 The new N-terminus/C-terminus gene in pMON13192 was created using Method II as described in Materials and Methods. Fragment Start was created and amplified from G- CSF sequence in pMON13037 using the primer set, 39 start (SEQ ID NO:64) and P-bl start (SEQ ID NO:62). Fragment Stop was created and amplified from G-CSF Serl 7 sequence in pMON13037 using the primer set, 38 stop (SEQ ID NO:65) and P-bl stop (SEQ ID NO:63). Fragment Start was digested with restriction endonuclease NcoI, and Fragment Stop was digested with restriction endonuclease HindIII. After purification, the digested Fragments Start and Stop were combined with and ligated to the approximately 3800 base pair NcoI-HindIII vector fragment of pMON3934.

The intermediate plasmid described above contained the full length new N-terminus/C-terminus G-CSF Serl 7 gene and was digested with restriction endonucleases NcoT and HindIII. The digested DNA was resolved on a 1% TAE gel, stained with ethidium bromide and the full-length new Nterminus/C-terminus G-CSF Serl 7 gene was isolated using Geneclean (BiolOl, Vista, CA). The intermediate plasmid, WO 97/12985 PCT/US96/15774 189 pMON13180, was digested with restriction endonucleases HindIII and AflIII, resulting in a 4023 base pair vector fragment, and purified using a Magic DNA Clean-up System kit (Promega, Madison, WI). The purified restriction fragments were combined and ligated using T4 DNA ligase (Boehringer Mannheim, Indianapolis, IN). A portion of the ligation reaction was used to transform E. coli strain DH5C cells (Life Technologies, Gaithersburg, MD). Transformant bacteria were selected on ampicillin-containing plates.

Plasmid DNA was isolated and sequenced to confirm the correct insertion of the new gene. The resulting plasmid was designated pMON13192.

E. coli strain JM101 was transformed with pMON13192 for protein expression and protein isolation from inclusion bodies.

The plasmid, pMON13192, contains the DNA sequence of (SEQ ID NO:104) which encodes the following amino acid sequence: 131 92 .Pept Asn Pro Val Ser Glu Ala Gin Gin Gly His Trp Gly Leu Leu Trp Thr Ala Val Gly Glu Lys Cys Ser Ile Met Ile Asp Glu Ile Pro Ala Pro Leu Leu Asp Pro Asn Ser Ile Leu Met Asp Arg Asn Leu Phe Val Arg Ala Val Lys Asn Leu Ala Ile Leu Arg Asn Leu Gin Pro Ala Pro Ser Arg His Pro Ile Ile Glu Phe Arg Glu Lys Leu Thr Phe Ala Gin Glu Gin Gin Tyr Val Glu Gly Gly Ser Gly Gly Gly Ser Asn Pro Glu Glu Leu Val Leu Leu Gly Ala Pro Leu Ser Ser Cys Pro Ser Cys Leu Ser Gin Leu His Ser Gly Leu Gin Ala Leu Glu Gly Ile Ser Asp Thr Leu Gin Leu Asp Val Ala Gin Gin Met Glu Glu Leu Gly Met Gin Gly Ala Met Pro Ala Phe Ala Gly Gly Val Leu Val Ala Ser His Ser Tyr Arg Val Leu Arg His Leu Pro Ala Ser Ser Leu Pro Gin Ser Gin Val Arg Lys Ile Gln Gly Asp Leu Cys Ala Thr (SEQ ID NO:176) Ile Asn Arg Glu Cys Ile Tyr Gly Met His Gin Leu Pro Asp Ala Ser Leu Ala Phe Gly His Leu Leu Asn Leu Lys Leu Gly Ala Ser Ala Phe Glu Phe Pro Ala Gin Gin Leu Ala His Leu Asn Asp Pro Asn Ala Ser Pro Ser Ala Gly Val Thr Gly Gly Tyr Lys Leu Gly Leu Gin Leu Tyr Leu Gly Ala Thr Ala Leu Phe Gln Ser Phe Pro Thr Leu Lys Ala Leu Lys Glu Leu Gly Ala Asp Leu Ser Leu Ile Leu Gin Pro Thr Gin Arg Leu Pro Ser Gln Arg Asp Glu Ile Thr Trp Glu Pro Cys Pro Ala Gly Thr Ile Pro Arg Glu Leu Leu Glu WO 97/12985 PCT/US96/1 5 7 7 4 190 EXAMPLE 64 Construction of pMON13193 The new N-terminus/C-terminus gene in pMON13193 was created using Method II as described in Materials and Methods. Fragment Start was created and amplified from G- CSF Ser 17 sequence in pMON13037 using the primer set, 39 start (SEQ ID NO:64) and P-bl start (SEQ ID NO:62).

Fragment Stop was created and amplified from G-CSF Serl7 sequence in pMON13037 using the primer set, 38 stop (SEQ ID and P-bl stop (SEQ ID NO:63). Fragment Start was digested with restriction endonuclease Ncol,. and Fragment Stop was digested with restriction endonuclease HindIII.

After purification, the digested Fragments Start and Stop were combined with and ligated to the approximately 3800 base pair IcoI-HindIII vector fragment of pMON3934.

The intermediate plasmid described above contained the full length new N-terminus/C-terminus G-CSF Serl 7 gene and was digested with restriction endonucleases NcoI and HindIII. The digested DNA was resolved on a 1% TAE gel, stained with ethidium bromide and the full-length new Nterminus/C-terminus G-CSF Serl 7 gene was isolated using Geneclean (BiolOl, Vista, CA). The intermediate plasmid, pMON13181, was digested with restriction endonucleases HindIII and AflIII, resulting in a 4068 base pair vector fragment, and purified using a Magic DNA Clean-up System kit (Promega, Madison, WI). The purified restriction fragments were combined and ligated using T4 DNA ligase (Boehringer Mannheim, Indianapolis, IN). A portion of the ligation reaction was used to transform E. coli strain DH5a cells (Life Technologies, Gaithersburg, MD). Transformant bacteria were selected on ampicillin-containing plates.

Plasmid DNA was isolated and sequenced to confirm the WO 97/12985 PCT/US96/15774 191 correct insertion of the new gene. The resulting plasmid was designated pMON13193.

E. coli strain JM101 was transformed with pMON13193 for protein expression and protein isolation from inclusion bodies.

The plasmid, pMON13193, contains the DNA sequence of (SEQ ID NO:105) encodes the following amino acid sequence: Asn Pro Val Ser Glu Ala Gin Gln Gly Ser His Trp Gly Leu Leu Trp Thr Ala Val Gly Glu Lys Cys Pro Ser Phe Ala Ala Glu Ala Glu Lys Pro Ala Cys Leu Asp Gin Gin Gly Ser Pro Gin Leu Ser Ala lie Val Ile Pro Phe Gin Pro Glu Glu Pro Leu Gin Thr Gin Gly Gly Tyr Ala Val Cys Ile Met Pro Leu Leu Met Arg Ala Leu Arg Ser Arg Arg Glu Glu Gin Ser Gly Ser His Glu Leu Leu Ser Ser Gin Ala Leu Leu Gin Met Glu Ala Met Val Leu Arg Val Ser Ser Arg Lys Ala Thr Ile Asp Glu Leu Asp Pro Asp Arg Asn Val Lys Asn Asn Leu Gin His Pro Ile Lys Leu Thr Gin Tyr Val Pro Ile Ser Lys Ser Pro Val Leu Leu Ser Cys Pro Leu His Ser Glu Gly Ile Leu Asp Val Glu Leu Gly Pro Ala Phe Val Ala Ser Leu Arg His Leu Pro Gin Ile Gin Gly (SEQ ID NO:1 Ile Ile Asn Asn Leu Arg Leu Glu Pro Cys Ile Ile Phe Tyr Glu Gly Thr Ile Asn Met Gly His Ser Gin Gly Leu Ser Pro Ala Asp Met Ala Ala Ser His Leu Leu Ala Ser Phe Asp Gly 77) His His Leu Asn Leu Pro Asn Ala Leu Pro Lys Ala Leu Val Gly Gly Asn Pro Ala Tyr Ser Leu Ala Leu Phe Leu Glu Leu Phe Ala Pro Ala Ala Phe Gin Ser Gin Pro Leu Leu Ala Ala Leu Lys Arg Asp Glu Asp Asn Leu Glu Ser Gly Ile Ser Ala Thr Gly Asp Trp Thr Leu Glu Gly Ser Pro Ser Pro Pro Lys Leu Cys Gly Ile Pro Gin Leu Ala Tyr Gin Gly Gly Pro Thr Thr Thr Ile Leu Gin Pro Gin Arg Arg Phe Leu Glu Thr Pro Leu Lys Ser Leu Leu Gin Glu EXAMPLE Construction of MON25190 The new N-terminus/C-terminus gene in pMON25190 was created using Method II as described in Materials and Methods. Fragment Start was created and amplified from G- CSF sequence in pMON13037 using the primer set, 97 start (SEQ ID NO:66) and P-bl start (SEQ ID NO:62). Fragment Stop was created and amplified from G-CSF Serl 7 sequence in WO 97/12985 PCT/US96/15 7 7 4 192 pMON13037 using the primer set, 96 stop (SEQ ID NO:'67) and P-bl stop (SEQ ID NO:63). Fragment Start was digested with restriction endonuclease NcoI, and Fragment Stop was digested with restriction endonuclease HindlII. After purification, the digested Fragments Start and Stop were combined with and ligated to the approximately 3800 base pair NcoI-HindIII vector fragment of pMON3934. The intermediate plasmid described above contained the full length new N-terminus/C-terminus G-CSF Ser l7 gene and was digested with restriction endonucleases Ncol and HindIII. The digested DNA was resolved on a 1% TAE gel, stained with ethidium bromide and the full-length new Nterminus/C-terminus G-CSF Ser 17 gene was isolated using Geneclean (BiolOl, Vista, CA). The intermediate plasmid, pMON13180, was digested with restriction endonucleases HindIII and AflIII, resulting in a 4023 base pair vector fragment, and purified using a Magic DNA Clean-up System kit (Promega, Madison, WI). The purified restriction fragments were combined and ligated using T4 DNA ligase (Boehringer Mannheim, Indianapolis, IN). A portion of the ligation reaction was used to transform E. coli strain DH5X cells (Life Technologies, Gaithersburg, MD). Transformant bacteria were selected on ampicillin-containing plates.

Plasmid DNA was isolated and sequenced to confirm the correct insertion of the new gene. The resulting plasmid was designated pMON25190.

E. coli strain JM101 was transformed with pMON25190 for protein expression and protein isolation from inclusion bodies.

The plasmid, pMON25190, contains the DNA sequence of (SEQ ID NO:106) which encodes the following amino acid sequence: Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg Pro Pro Ala Pro Leu LeuAsp Pro Asn Asn Leu Asn Asp Glu Asp WO 97/12985 PCT/US96/15774 Val Ser lie Ser Phe Val Glu Ala Ile Ala Ala Pro Gin Glu Phe Gin Ala Gin Gly Gly Gly Pro Thr Leu Thr Ile Trp Gin Pro Thr Arg Arg Ala Leu Glu Val Pro Leu Gly Ser Leu Glu Gin Glu Lys Leu Val Leu Ser Ser Cys Gin Leu His Leu Glu Gly Leu Met Arg Ala Leu Arg Ser Arg Arg Glu Glu Gin Ser Gly Asp Thr Gin Gin Gin Gly Gly Gly Ser Tyr Pro Ala Gin Val Leu Cys Leu Gly Pro Ser Ser Gly Asp Val Asn His Lys Gin Gly Leu Met Ala Val Arg Ser Arg Ala His Gin Leu Arg Asn Lys Asn Leu Gin Pro Ile Leu Thr Tyr Val Gly Ser Gin Leu Glu Glu Met Pro Leu Val Val Leu Ser Leu Lys Ile Thr Tyr Ser Leu Ala Leu Phe Leu Leu Arg Leu Pro Asn- Leu Leu Glu Asn Ala Ser Gly Pro Cys Leu Pro Ser Ala Ile Ile Lys Ala Gly Asp Phe Tyr Leu Val Thr Leu Glu Gly Gly Gly Gly Ser Asn Met Ala Pro Glu Leu Asp Val Ala Asp Phe Ala Leu Gly Met Ala Pro Ala Ala Phe Ala Ser Ala Phe Ala Ser His Leu Gin Ser Arg His Leu Ala Gin Pro Pro Gin Ser Phe Leu Leu Gin Gly Asp Gly Ala Ala Lys Leu Cys His Pro Glu Gly Ile Pro Trp Ala Pro Gin Leu Ala Gly Cys Leu Tyr Gin Gly Leu Leu Gin 178) Glu lie Thr Trp Glu Pro Gly Thr Leu Gin Phe Thr Lys Leu Glu Leu Ser Ala Ile Ser (SEQ ID NO: EXAMPLE 66 Construction of pMON25I91 The new N-terminus/C-terminus gene in pMON25191 was created using Method II as described in Materials and Methods. Fragment Start was created and amplified from G- CSF Ser 17 sequence in pMON13037 using the primer set, 97 start (SEQ ID NO:66) and P-bl start (SEQ ID NO:62).

Fragment Stop was created and amplified from G-CSF Serl7 sequence in pMON13037 using the primer set, 96 stop (SEQ ID NO:98) and P-bl stop (SEQ ID NO:63). Fragment Start was digested with restriction endonuclease NcoI, and Fragment Stop was digested with restriction endonuclease HindIII.

After purification, the digested Fragments Start and Stop were combined with and ligated to the approximately 3800 base pair NcoI-HindIII vector fragment of pMON3934.

The intermediate plasmid described above contained the full length new N-terminus/C-terminus G-CSF Serl 7 gene and was digested with restriction endonucleases NcoI and WO 97/12985 PCTIUS96/15774 194 HindIII. The digested DNA was resolved on a 1% TAE gel, stained with ethidium bromide and the full-length new Nterminus/C-terminus G-CSF Serl 7 gene was isolated using Geneclean (BiolOl, Vista, CA). The intermediate plasmid, pMON13181, was digested with restriction endonucleases HindIII and AflIII, resulting in a 4068 base pair vector fragment, and purified using a Magic DNA Clean-up System kit (Promega, Madison, WI). The purified restriction fragments were combined and ligated using T4 DNA ligase (Boehringer Mannheim, Indianapolis, IN). A portion of the ligation reaction was used to transform E. coli strain DH5a cells (Life Technologies, Gaithersburg, MD). Transformant bacteria were selected on ampicillin-containing plates.

Plasmid DNA was isolated and sequenced to confirm the correct insertion of the new gene. The resulting plasmid was designated pMON25191.

E. coli strain JM101 was transformed with pMON25191 for protein expression and protein isolation from inclusion bodies.

The plasmid, pMON25191, contains the DNA sequence of (SEQ ID NO:107) which encodes the following amino acid sequence: Asn Cys Ser Ile Met Ile Asp Glu lie lie His His Leu Lys Arg Pro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp Val Ser Ile Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu Ser Phe Val Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly Ile Glu Ala Ile Leu Arg Asn Leu Gin Pro Cys Leu Pro Ser Ala Thr Ala Ala Pro Ser Arg His Pro Ile Ile Ile Lys Ala Gly Asp Trp Gin Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu Gin Ala Gin Glu Gin Gin Tyr Val Glu Gly Gly Gly Gly Ser Pro Gly Glu Pro Ser Gly Pro Ile Ser Thr Ile Asn Pro Ser Pro Pro Ser Lys Glu Ser His Lys Ser Pro Asn Met Ala Pro Glu Leu Gly Pro Thr Leu Asp Thr Leu Gin Leu Asp Val Ala Asp Phe Ala Thr Thr Ile Trp Gin Gin Met Glu Glu Leu Gly Met Ala Pro Ala Leu Gin Pro Thr Gin Gly Ala Met Pro Ala Phe Ala Ser Ala Phe Gin Arg Arg Ala Gly Gly Val Leu Val Ala Ser His Leu Gin Ser Phe Leu Glu Val Ser Tyr Arg Val Leu Arg His Leu Ala Gin Pro Thr Pro Leu Gly Pro Ala Ser Ser Leu Pro Gin Ser Phe Leu Leu Lys Ser Leu Glu Gin Val Arg Lys Ile Gin Gly Asp Gly Ala Ala Leu WO 97/12985 PCT/US96/15774 195 Gln Glu Lys Leu Cys Ala Thr Tyr Lys Leu Cys His Pro'Glu Glu Leu Val Leu Leu Gly His Ser Leu Gly Ile Pro Trp Ala Pro Leu Ser Ser Cys Pro Ser Gin Ala Leu Gin Leu Ala Gly Cys Leu Ser Gin Leu His Ser Gly Leu Phe Leu Tyr Gin Gly Leu Leu Gln Ala Leu Glu Gly Ile Ser (SEQ ID NO:179) EXAMPLE 67 Construction of pMON13194 The new N-terminus/C-terminus gene in pMON13194 was created using Method II as described in Materials and Methods. Fragment Start was created and amplified from G- CSF Ser 17 sequence in pMON13037 using the primer set, 126 start (SEQ ID NO:68) and P-bl start (SEQ ID NO:62).

Fragment Stop was created and amplified from G-CSF Ser 17 sequence in pMON13037 using the primer set, 125 stop (SEQ ID NO:67) and P-bl stop (SEQ ID NO:63). Fragment Start was digested with restriction endonuclease NcoI, and Fragment Stop was digested with restriction endonuclease HindIII.

After purification, the digested Fragments Start and Stop were combined with and ligated to the approximately 3800 base pair NcoI-HindIII vector fragment of pMON3934.

The intermediate plasmid described above contained the full length new N-terminus/C-terminus G-CSF Ser 17 gene and was digested with restriction endonucleases NcoI and HindIII. The digested DNA was resolved on a 1% TAE gel, stained with ethidium bromide and the full-length new Nterminus/C-terminus G-CSF Ser 17 gene was isolated using Geneclean (BiolOl, Vista, CA). The intermediate plasmid, pMON13180, was digested with restriction endonucleases HindIII and AflIII, resulting in a 4023 base pair vector fragment, and purified using a Magic DNA Clean-up System kit (Promega, Madison, WI). The purified restriction fragments were combined and ligated using T4 DNA ligase (Boehringer WO 97/12985 PCT/US96/15774 196 Mannheim, Indianapolis, IN). A portion of the ligation reaction was used to transform E. coli strain DH5a cells (Life Technologies, Gaithersburg, MD). Transformant bacteria were selected on ampicillin-containing plates.

Plasmid DNA was isolated and sequenced to confirm the correct insertion of the new gene. The resulting plasmid was designated pMON13194.

E. coli strain JM101 was transformed with pMON13194 for protein expression and protein isolation from inclusion bodies.

The plasmid, pMON13194, contains the DNA sequence of (SEQ ID NO:108) which encodes the following amino acid sequence: Asn Cys Pro Pro Val Ser Ser Phe Glu Ala Ala Ala Gin Glu Gin Ala Gly Gly Leu Gin Gin Arg Phe Leu Thr Pro Lys Ser Leu Gin Glu Leu Leu Ser Ser Gin Ala Leu Leu Gin Met Glu Ser Ala Ile Val Ile Pro Phe Gin Gly Pro Arg Glu Leu Leu Glu Val Ser Leu Glu Leu Glu Ile Met Pro Leu Leu Met Arg Ala Leu Arg Ser Arg Arg Glu Glu Gin Ser Gly Thr Gin Ala Gly Val Ser Gly Pro Glu Gin Lys Leu Leu Leu Cys Pro His Ser Gly Ile Asp Val Leu Gly Ile Asp Glu Leu Asp Pro Asp Arg Asn Val Lys Asn Asn Leu Gin His Pro Ile Lys Leu Thr Gin Tyr Val Gly Gly Ser Gly Ala Met Gly Val Leu Tyr Arg Val Ala Ser Ser Val Arg Lys Cys Ala Thr Gly His Ser Ser Gin Ala Gly Leu Phe Ser Pro Glu Ala Asp Phe (SEQ ID NO:1 Ile Ile Asn Asn Leu Arg Leu Glu Pro Cys Ile Ile Phe Tyr Glu Gly Asn Met Pro Ala Val Ala Leu Arg Leu Pro Ile Gin Tyr Lys Leu Gly Leu Gin Leu Tyr Leu Gly Ala Thr His Leu Leu Asn Leu Lys Leu Gly Ala Phe Ser His Gin Gly Leu Ile Leu Gin Pro Thr His Asn Pro Ala Pro Ala Val Gly Met Ala His Leu Ser Asp Cys Pro Ala Gly Thr Ile Leu Asp Asn Ser Ser Gly Thr Gly Ala Ser Leu Ala Phe Gly His Trp Gly Leu Leu Trp Lys Glu Leu Gly Ala Asp Leu Ser Pro Ala Gin Gin Leu Ala Pro Ala Cys Leu Asp Gin Arg Asp Glu Ile Thr Trp Glu Pro Ala Phe Ser Pro Leu Ala Glu Pro Leu Gin Thr Gin EXAMPLE 68 Construction of pMON13195 The new N-terminus/C-terminus gene in pMON13195 was created using Method II as described in Materials and WO 97/12985 PCT/US96/15774 197 Methods. Fragment Start was created and amplified from G- CSF Ser 17 sequence in pMON13037 using the primer set, 126 start (SEQ ID NO:68) and P-bl start (SEQ ID NO:62).

Fragment SLop was created and amplified from G-CSF Serl7 sequence in pMON13037 using the primer set, 125 stop (SEQ ID NO:69) and P-bl stop (SEQ ID NO:63). Fragment Start was digested with restriction endonuclease NcoI, and Fragment Stop was digested with restriction endonuclease HindIII.

After purification, the digested Fragments Start and Stop were combined with and ligated to the approximately 3800 base pair NcoI-HindIII vector fragment of pMON3934.

The intermediate plasmid described above contained the full length new N-terminus/C-terminus G-CSFSerl 7 gene and was digested with restriction endonucleases NcoI and HindIII. The digested DNA was resolved on a 1% TAE gel, stained with ethidium bromide and the full-length new Nterminus/C-terminus G-CSF Ser 17 gene was isolated using Geneclean (BiolOl, Vista, CA). The intermediate plasmid, pMON13181, was digested with restriction endonucleases HindIII and AflIII, resulting in a 4068 base pair vector fragment, and purified using a Magic DNA Clean-up System kit (Promega, Madison, WI). The purified restriction fragments were combined and ligated using T4 DNA ligase (Boehringer Mannheim, Indianapolis, IN). A portion of the ligation reaction was used to transform E. coli strain DH5a cells (Life Technologies, Gaithersburg, MD). Transformant bacteria were selected on ampicillin-containing plates.

Plasmid DNA was isolated and sequenced to confirm the correct insertion of the new gene. The resulting plasmid was designated pMON13195.

E. coli strain JM101 was transformed with pMON13195 for protein expression and protein isolation from inclusion bodies.

WO 97/12985 PCT/US96/15774 The plasmid, pMON13195, contains the DNA sequence of (SEQ ID NO:109) which encodes the following amino acid sequence: Asn Cys Pro Pro Val Ser Ser Phe Glu Ala Ala Ala Gln Glu Gin Ala Gly Glu Ser Lys Leu Gin Gin Arg Phe Leu Thr Pro Lys Ser Leu Gin Glu Leu Leu Ser Ser Gin Ala Leu Leu Gin Met Glu Ser Ala Ile Val Ile Pro Phe Gin Pro Glu Pro Arg Glu Leu Leu Glu Val Ser Leu Glu Leu Glu lie Pro Leu Arg Leu Ser Arg Glu Ser Ser Thr Ala Val Gly Glu Lys Leu Cys His Gly Asp Leu Met Leu Met Ala Arg Arg Glu Gin Gly His Gin Gly Ser Pro Gin Leu Leu Pro Ser Ile Val Gly Ile Asp Leu Asp Asp Arg Val Lys Asn Leu His Pro Lys Leu Gin Tyr Pro Ile Lys Ser Gly Ala Gly Val Tyr Arg Ala Ser Val Arg Cys Ala Gly His Ser Gin Gly Leu Ser Pro Ala Asp (SEQ ID Glu Ile Pro Asn Asn Leu Asn Leu Gin Pro Ile Ile Thr Phe Val Glu Ser Thr Pro Asn Met Pro Leu Val Val Leu Ser Leu Lys Ile Thr Tyr Ser Leu Ala Leu Phe Leu Glu Leu Phe Ala NO:181) Ile Asn Arg Glu Cys Ile Tyr Gly Ile Met Ala Ala Arg Pro Gin Lys Gly Gin Tyr Gly Thr His His Leu Leu Asn Asp Leu Pro Asn Asn Ala Ser Leu Pro Ser Lys Ala Gly Leu Val Thr Gly Gly Gly Asn Pro Ser Ala Met Ala Phe Ala Ser Ser His Leu His Leu Ala GlrI Ser Phe Gly Asp Gly Leu Cys His Ile Pro Trp Leu Ala Gly Gin Gly Leu Pro Thr Leu Thr Ile Trp Lys Glu Leu Gly Ala Asp Leu Ser Pro Pro Ala Gin Gin Leu Ala Pro Ala Cys Leu Asp Gin Arg Asp Glu Ile Thr Trp Glu Pro Pro Ala Phe Ser Pro Leu Ala Glu Pro Leu Gin Thr Gin EXAMPLE 69 Construction of DMON13196 The new N-terminus/C-terminus gene in pMON13196 was created using Method II as described in Materials and Methods. Fragment Start was created and amplified from G- CSF sequence in pMON13037 using the primer set, 133 start (SEQ ID NO:70) and P-bl start (SEQ ID NO:62). Fragment Stop was created and amplified from G-CSF Ser 17 sequence in pMON13037 using the primer set, 132 stop (SEQ ID NO:71) and P-bl stop (SEQ ID NO:63). Fragment Start was digested with restriction endonuclease NcoI, and Fragment Stop was digested with restriction endonuclease HindIII. After purification, the digested Fragments Start and Stop were WO 97/12985 PCT/US96/15774 199 combined with and ligated to the approximately 3800 base pair NcoI-HindIII vector fragment of pMON3934.

The intermediate plasmid described above contained the full length new N-terminus/C-terminus G-CSF Ser 17 gene and was digested with restriction endonucleases NcoI and HindIII. The digested DNA was resolved on a 1% TAE gel, stained with ethidium bromide and the full-length new Nterminus/C-terminus G-CSF Ser 17 gene was isolated using Geneclean (BiolOl, Vista, CA). The intermediate plasmid, pMON13180, was digested with restriction endonucleases HindIII and AflIII, resulting in a 4023 base pair vector fragment, and purified using a Magic DNA Clean-up System kit (Promega, Madison, WI). The purified restriction fragments were combined and ligated using T4 DNA ligase (Boehringer Mannheim, Indianapolis, IN). A portion of the ligation reaction was used to transform E. coli strain DH5a cells (Life Technologies, Gaithersburg, MD). Transformant bacteria were selected on ampicillin-containing plates.

Plasmid DNA was isolated and sequenced to confirm the correct insertion of the new gene. The resulting plasmid was designated pMON13196.

E. coli strain JM101 was transformed with pMON13196 for protein expression and protein isolation from inclusion bodies.

The plasmid, pMON13196, contains the DNA sequence of (SEQ ID NO:110) which encodes the following amino acid sequence: Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg Pro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp Val Ser Ile Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu Ser Phe Val Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly Ile Glu Ala Ile Leu Arg Asn Leu Gln Pro Cys Leu Pro Ser Ala Thr Ala Ala Pro Ser Arg His Pro Ile Ile Ile Lys Ala Gly Asp Trp Gin Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu Gin Ala Gin Glu Gin Gin Tyr Val Glu Gly Gly Gly Gly Ser Pro Gly Gly Gly Ser Gly Gly Gly Ser Asn Met Ala Thr Gin Gly Ala WO 97/12985 PCT/US96/15774 200 Met Pro Ala Phe Ala Ser Ala Phe Gin Arg Arg Ala Gli Gly Val Leu Val Ala Ser His Leu Gin Ser Phe Leu Glu Val Ser Tyr Arg Val Leu Arg His Leu Ala Gin Pro Thr Pro Leu Gly Pro Ala Ser Ser Leu Pro Gin Ser Phe Leu Leu Lys Ser Leu Glu Gin Val Arg Lys Ile Gln Gly Asp Gly Ala Ala Leu Gln Glu Lys Leu Cys Ala Thr Tyr Lys Leu Cys His Pro Glu Glu Leu Val Leu Leu Gly His Ser Leu Gly Ile Pro Trp Ala Pro Leu Ser Ser Cys Pro Ser Gln Ala Leu Gin Leu Ala Gly Cys Leu Ser Gin Leu His Ser Gly Leu Phe Leu Tyr Gln Gly Leu Leu Gln Ala Leu Glu Gly Ile Ser Pro Glu Leu Gly Pro Thr Leu Asp Thr Leu Gin Leu As Val Ala Asp Phe Ala Thr Thr Ile Trp Gin Gin Met Glu Glu Leu Gly Met Ala Pro Ala Leu Gln Pro (SEQ ID NO:182) EXAMPLE Construction of pMON13197 The new N-terminus/C-terminus gene in pMON13197 was created using Method II as described in Materials and Methods. Fragment Start was created and amplified from G- CSF Serl 7 sequence in pMON13037 using the primer set, 133 start (SEQ ID NO:70) and P-bl start (SEQ ID NO:62).

Fragment Stop was created and amplified from G-CSF Serl7 sequence in pMON13037 using the primer set, 132 stop (SEQ

ID

NO:71) and P-bl stop (SEQ ID NO:63). Fragment Start was digested with restriction endonuclease NcoI, and Fragment Stop was digested with restriction endonuclease HindIII.

After purification, the digested Fragments Start and Stop were combined with and ligated to the approximately 3800 base pair NcoI-HindIII vector fragment of pMON3934.

The intermediate plasmid described above contained the full length new N-terminus/C-terminus G-CSF Serl 7 gene and was digested with restriction endonucleases NcoI and HindIII. The digested DNA was resolved on a 1% TAE gel, stained with ethidium bromide and the full-length new Nterminus/C-terminus G-CSF Serl 7 gene was isolated using Geneclean (BiolOl, Vista, CA). The intermediate plasmid, pMON13181, was digested with restriction endonucleases WO 97/12985 PCT/US96/15774 201 HindIII and AflIII, resulting in a 4068 base pair vector fragment, and purified using a Magic DNA Clean-up System kit (Promega, Madison, WI). The purified restriction fragments were combined and ligated using T4 DNA ligase (Boehringer Mannheim, Indianapolis, IN). A portion of the ligation reaction was used to transform E. coli strain DH5a cells (Life Technologies, Gaithersburg, MD). Transformant bacteria were selected on ampicillin-containing plates.

Plasmid DNA was isolated and sequenced to confirm the correct insertion of the new gene. The resulting plasmid was designated pMON13197.

E. coli strain JM101 was transformed with OMON11Q7

F-

protein expression and protein isolation from inclusion bodies.

J

The plasmid, pMON13197, contains the DNA sequence of (SEQ ID NO:111) which encodes the following amino acid sequence: Asn Cys Pro Pro Val Ser Ser Phe Glu Ala Ala Ala Gin Glu Gin Ala Gly Gly His Pro Trp Ala Gly Cys Leu Leu Leu Asp Trp Gin Thr Gin Ala Gly Val Ser Gly Pro Glu Gin Lys Leu Ser Ile Met Ala Pro Leu lile Leu Met Val Arg Ala Ile Leu Arg Pro Ser Arg Phe Arg Glu Gin Glu Gin Gly Ser Gly Glu Glu Leu Pro Leu Ser Leu Ser Gin Gin Ala Leu Thr Leu Gin Gin Met Glu Gly Ala Met Gly Val Leu Tyr Arg Val Ala Ser Ser Val Arg Lys Cys Ala Thr Ile Asp Glu Ile Leu Asp Pro Asn Asp Arg Asn Leu Val Lys Asn Leu Asn Leu Gin Pro His Pro Ile Ile Lys Leu Thr Phe Gin Tyr Val Glu Gly Gly Ser Asn Val Leu Leu Gly Ser Cys Pro Ser Leu His Ser Gly Glu Gly Ile Ser Leu Asp Val Ala Glu Leu Gly Met Pro Ala Phe Ala Val Ala Ser His Leu Arg His Leu Leu Pro Gin Ser Ile Gin Gly Asp (SEQ ID NO:183) Ile His Asn Leu Arg Leu Glu Asn Cys Leu Ile Lys Tyr Leu Gly Gly Met Ala His Ser Gin Ala Leu Phe Pro Glu Asp Phe Ala Pro Ser Ala Leu Gin Ala Gin Phe Leu Gly Ala His Leu Asn Asp Pro Asn Ala Ser Pro Ser Ala Gly Val Thr Gly Gly Tyr Lys Leu Gly Leu Gin Leu Tyr Leu Gly Ala Thr Ala Leu Phe Gin Ser Phe Pro Thr Leu Lys Ala Leu Lys Glu Leu Gly Ala Asp Leu Ser Leu Ile Leu Gin Pro Thr Gin Arg Leu Pro Ser Gin Arg Asp Glu Ile Thr Trp Glu Pro Cys Pro Ala Gly Thr Ile Pro Arg Glu Leu Leu Glu WO 97/12985 PCT/US96/1 5 7 7 4 202 EXAMPLE 71 Construction of DMON1I319 The new N-terminus/C-terminus gene in pMON13198 was created using Method II as described in Materials and Methods. Fragment Start was created and amplified from

G-

CSF sequence in pMON13037 using the primer set, 142 start (SEQ ID NO:72) and P-bl start (SEQ ID NO:62). Fragment Stop was created and amplified from G-CSF Serl 7 sequence in pMON13037 using the primer set, 141 stop (SEQ ID NO:73) and P-bl stop (SEQ ID NO:63). Fragment Start was digested with restriction endonuclease NcoI, and Fragment. Stop was digested with restriction endonuclease HindIII. After purification, the digested Fragments Start and Stop were combined with and ligated to the approximately 3800 base pair NcoI-HindIII vector fragment of pMON3934.

The intermediate plasmid described above contained the full length new N-terminus/C-terminus G-CSF Serl 7 gene and was digested with restriction endonucleases NcoI and HindIII. The digested DNA was resolved on a 1% TAE gel, stained with ethidium bromide and the full-length new

N-

terminus/C-terminus G-CSF Serl 7 gene was isolated using Geneclean (BiolOl, Vista, CA). The intermediate plasmid, pMON13180, was digested with restriction endonucleases HindIII and AflIII, resulting in a 4023 base pair vector fragment, and purified using a Magic DNA Clean-up System kit (Promega, Madison, WI). The purified restriction fragments were combined and ligated using T4 DNA ligase (Boehringer Mannheim, Indianapolis, IN). A portion of the ligation reaction was used to transform E. coli strain DH5a cells (Life Technologies, Gaithersburg, MD). Transformant bacteria were selected on ampicillin-containing plates.

Plasmid DNA was isolated and sequenced to confirm the WO 97/12985 PCTIUS96/15774 203 correct insertion of the new gene. The resulting plasmid was designated pMON13198.

E. coli strain JM101 was transformed with nMOni-1oo 4protein expression and protein isolation from inclusion bodies.

The plasmid, pMON13198, contains the DNA sequence of (SEQ ID NO:112) which encodes the following amino acid oLUr sequence: Asn Pro Val Ser Glu Ala Gin Gin Gly Arg Leu Pro Ser Gin Leu Ser Gin Leu Gin Glu Met Cys Pro Ser Phe Ala Ala Glu Ala Gly Arg Glu Leu Leu Glu Val Ser Leu Glu Leu Glu Pro Ser Ala Ile Val lie Pro Phe Gin Gly Ala Val Gly Glu Lys Leu Cys His Gly Asp Leu Ala Ile Pro Leu Arg Leu Ser Arg Glu Ser Gly Ser Pro Gin Leu Leu Pro Ser Ile Val Gly Phe Met Leu Met Ala Arg Arg Glu Gin Gly Gly Tyr Ala Val Cys Gly Ser Gly Ser Ala Met Ala Ile Asp Leu Asp Asp Arg Val Lys Asn Leu His Pro Lys Leu Gin Tyr Gly Gly Val Leu Arg Val Ser Ser Arg Lys Ala Thr His Ser Gin Ala Leu Phe Pro Glu Asp Phe Ala Pro (SEQ ID Glu Ile Pro Asn Asn Leu Asn Leu Gin Pro Ile Ile Thr Phe Val Glu Ser Asn Val Ala Leu Arg Leu Pro Ile Gin Tyr Lys Leu Gly Leu Gin Leu Tyr Leu Gly Ala Thr Ala Leu NO:184) lie Asn Arg Glu Cys Ile Tyr Gly Met Ser His Gin Gly Leu Ile Leu Gin Pro Thr Gin His His Leu Asn Leu Pro Asn Ala Leu' Pro Lys Ala Leu Val Gly Gly Ala Ser His Leu Leu Ala Ser Phe Asp Gly Cys His Pro Trp Ala Gly Gly Leu Thr Leu Ile Trp Pro Thr Leu Asp Asn Ser Ser Gly Thr Gly Ala Gin Gin Leu Ala Pro Ala Cys Leu Asp Gin Gin Lys SGlu Leu Gly Ala Asp Leu Ser Phe Ser Pro Leu Ala Glu Pro Leu Gin Thr Gin Gly Arg Asp Glu Ile Thr Trp Glu Pro Gin Phe Thr Lys Leu Glu Leu Ser Ala Leu Met Ala EXAMPLE 72 Construction of M0N13199 The new N-terminus/C-terminus gene in pMON13199 was created using Method II as described in Materials and Methods. Fragment Start was created and amplified from G- A A 'u us" Seri- sequence in pMON13037 using the primer set, 142 start (SEQ ID NO:72) and P-bl start (SEQ ID NO:62).

Fragment Stop was created and amplified from G-CSF Serl7 WO 97/12985 PCT/US96/15774 204 sequence in pMON13037 using the primer set, 141 stop (SEQ

ID

NO:73) and P-bl stop (SEQ ID NO:63). Fragment Start was digested with restriction endonuclease NcoI, and Fragment Stop was digested with restriction endonuclease HindII.

After purification, the digested Fragments Start and Stop were combird with and ligated to the approximately 3800 base pair NcoI-HindIII vector fragment of pMON3934.

The intermediate plasmid described above contained the full length new N-terminus/C-terminus G-CSF Serl 7 gene and was digested with restriction endonucleases NcoI and HindIII. The digested DNA was resolved on a 1% TAE gel, stained with ethidium bromide and the full-length new Nterminus/C-terminus G-CSF Serl 7 gene was isolated using Geneclean (BiolOl, Vista, CA). The intermediate plasmid, pMON13181, was digested with restriction endonucleases HindIII and AflIII, resulting in a 4068 base pair vector fragment, and purified using a Magic DNA Clean-up System kit (Promega, Madison, WI). The purified restriction fragments were combined and ligated using T4 DNA ligase (Boehringer Mannheim, Indianapolis, IN). A portion of the ligation reaction was used to transform E. coli strain DH5a cells (Life Technologies, Gaithersburg, MD). Transformant bacteria were selected on ampicillin-containing plates.

Plasmid DNA was isolated and sequenced to confirm the correct insertion of the new gene. The resulting plasmid was designated pMON13199.

E. coli strain JM101 was transformed with pMON13199 for protein expression and protein isolation from inclusion bodies.

The plasmid, pMON13199, contains the DNA sequence of (SEQ ID NO:113) which encodes the following amino acid sequence: Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg Pro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp WO 97/12985 PCT/US96/15774 205 Val Ser Ser Phe Glu Ala Ala Ala Gin Glu Gin Ala Gly Glu Ser Lys Arg Arg Leu Glu Pro Leu Ser Leu Gin Glu Leu Val Ser Ser Gin Leu Leu Glu Gin Leu Glu Glu Met Pro Ile Leu Met Val Arg Ala lie Leu Arg Pro Ser Arg Phe Arg Glu Gin Glu Gin Pro Ser Gly Glu Ser His Ala Gly Gly Val Ser Tyr Gly Pro Ala Glu Gin Val Lys Leu Cys Leu Leu Gly Cys Pro Ser His Ser Gly Gly Ile Ser Asp Val Ala Leu Gly Met Ala Phe Ala Asp Arg Val Lys Asn Leu His Pro Lys Leu Gin Tyr Pro Ile Lys Ser Val Leu Arg Val Ser Ser Arg Lys Ala Thr His Ser Gin Ala Leu Phe Pro Glu Asp Phe Ala Pro (SEQ ID As] As] Glr Il( Th Va Sei Prc Val Lei Lei Ile Tyr Leu Leu Leu Leu Ala Ala

NO:

n Leu n Leu n Pro e Ile r Phe L Glu r Thr Asn L Ala Arg i Pro Gin Lys SGly Gin Tyr SGly Thr Leu 185) Arg Leu Pro Glu Asn Ala Cys Leu Pro Ile Lys Ala Tyr Leu Val Gly Gly Gly Ile Asn Pro Met Ala Ser Ser His Leu His Leu Aij Gin Ser Phe Gly Asp Gly Leu Cys His Ile Pro Trp Leu Ala Gly 3Gn Gly Leu Pro Thr Leu rhr Ile Trp G1n Pro Thr Asri Ser Ser Gly Thr Gly Ser Ala Gin Gin Leu Ala Pro Ala Cys Leu Asp Gin Gin Leu Gly Ala Asp Leu Ser Pro Phe Ser Pro Leu Ala Glu Pro Leu Gin Thr Gin Gly Glu Ile Thr Trp Glu Pro Pro Gin Phe Thr Lys Leu Glu Leu Ser Ala Leu Met Ala EXAMPLE 73 Cnstrctin of tandemlv-dulicated iamid tempite Svntanl To create the tandemly-duplicated hIL-3 receptor agonist pMON13416 template, Syntanl, three DNAs were joined by means of ligation using T4 DNA ligase (Boehringer Mannheim). The three DNAs are: 1) pMON13046, containing hIL-3 receptor agonist pMON13416, digested with BstEII and SnaBI; 2) the annealed complimentary pair of synthetic oligonucleotides, Llsyn.for (SEQ ID NO:48) and Llsyn.rev (SEQ ID NO:49), which contain sequence encoding the linker that connects the C-terminal and N-terminal ends of the original protein and a small amount of surrounding pMON13416 sequence and which when properly assembled result in BstEII and ClaI ends; and 3) a portion of hIL-3 receptor agonist PMON13416 digested from pMON13046 with Clal (DNA had been grown in the dam- cells, DM1 (Life Technologies)) and SnaBI.

WO 97/12985 PCTIUS96/1 5 7 7 4 206 The digested DNAs were resolved on a 0.9% TAE gel, stained with ethidium bromide and isolated using Geneclean (Biol0).

A portion cf the ligation reaction was used to transform

E.

coli strain DH5a cells (Life Technologies, Gaithersburg, MD). Miniprep DNA was isolated from the transformants, and the transformants were screened using a PCR based assay.

Plasmid DNA from selected transformants was sequenced to obtain the correct template. The resulting plasmid was designated syntanl and contains the DNA sequence of (SEQ

ID

NO:84).

EXAMPLE 74 Cnstruction of tandmlv-duliated tmae. snt To create the tandemly-duplicated hIL-3 receptor agonist pMON13416 template, syntan3, three DNAs were joined by means of ligation using T4 DNA ligase (Boehringer Mannheim). The three DNAs are: 1) pMON13046, containing hIL-3 receptor agonist pMON13416, digested with BstEII and SnaBI; 2) the annealed complimentary pair of synthetic oligonucleotides, L3syn.for (SEQ ID NO:50) and L 3 syn.rev (SEQ ID NO:51), which contain sequence encoding the linker that connects the C-terminal and N-terminal ends of the original protein and a small amount of surrounding pMON13416 sequence and which when properly assembled result in BstEII and SnaBI ends; and 3) a portion of hIL-3 receptor agonist pMON13416 digested from pMON13046 with Clal (DNA had been grown in the dam- cells, DM1 (Life Technologies)) and SnaBI.

The digested DNAs were resolved on a 0.9% TAE gel, stained with ethidium bromide and isolated using Geneclean (BiolOl).

A portion of the ligation reaction was used to transform

E.

coli strain DH5a cells (Life Technologies, Gaithersburg, WO 97/12985 PCT/US96/15774 207 MD). Miniprep DNA was isolated from the transformahts, and the transformants were screened using a PCR based assay.

Plasmid DNA from selected transformants was sequenced to obtain the correct template. The resulting plasmid was designated syntan3 and contains the DNA sequence of (SEQ ID EXAMPLE Construction of DMON31104 The new N-terminus/C-terminus gene in pMON31104 was created using Method III as described in Materials and Methods. The full length new N-terminus/C-terminus gene of hIL-3 receptor agonist pMON13416 was created and amplified from the intermediate plasmid, Syntanl, using the primer set start (SEQ ID NO:52) and 34 rev (SEQ ID NO:53).

The resulting DNA fragment which contains the new gene was digested with restriction endonucleases NcoI and SnaBI.

The digested DNA fragment was resolved on a 1% TAE gel, stained with ethidium bromide and isolated using Geneclean (BiolOl, Vista, CA). The purified digested DNA fragment was ligated into the expression vector,pMON13189, using T4 DNA ligase (Boehringer Mannheim, Indianapolis, IN). The pMON13189 DNA had been previously digested with Ncol and SnaBI to remove the hIL3 receptor agonist pMON13416 coding sequence and the 4254 base pair vector fragment was isolated using Geneclean (BiolOl, Vista, CA) after resolution on a 0.8% TAE gel and staining with ethidium bromide. A portion of the ligation reaction was used to transform E. coli strain DH5a cells (Life Technologies, Gaithersburg,

MD).

Transformant bacteria were selected on ampicillin-containing plates. Plasmid DNA was isolated and sequenced to confirm the correct insert. The resulting plasmid was designated pMON31104.

WO 97/12985 PCT/US96/15774 208 E. coli strain JM101 was transformed with pMON31104 for protein expression and protein isolation from inclusion bodies.

The plasmid, pMON31104, contains the DNA sequence of (SEQ

ID

NO:86) which encodes the following amino acid sequence: Leu Asp Pro Asp Val Asn His Lys Gin His Gly Pro Thr Ala Val Ser Arg Ala His Gin Leu Pro Asp Ala Arg Lys Leu Pro Leu Gly His Gly Ser Gin Gly Ser Gly Lys Thr Ser Ala Phe Glu Phe Pro Asn Asn Gin Ile Thr Gly Leu Ser Pro Gly Gly Tyr Gly Ile Tyr Leu Leu Leu Leu Ala Ala Asn Asn Leu Arg Leu Glu Pro Cys Ile Ile Phe Tyr Gly Ser Lys Arg Pro Gly Pro Ser Ala Met Val Leu Arg Val Ser Gin Gin Gly Lys Leu Gly Ile Gin Leu Tyr Gin Gly Pro Thr Thr Leu Gin Leu Leu Asn Leu Lys Leu Asn Pro Glu Lys Pro Val Leu Ser Asp Cys Pro Ala Gly Thr Ile Pro Asn Asp Pro Asn Ala Ser Pro Ser Ala Gly Val Thr Cys Ser Pro Ala Pro Ser Glu Ser Ala Phe Ala Ser Arg His Phe Leu Gly Ala His Pro Trp Ala Gly Cys Leu Leu Leu Asp Trp Gin (SEQ ID Glu Leu Gly Ala Asp Leu Ile Pro Gly His Ala His Leu Leu Ala Glu Pro Leu Gin Thr Gin

NO:I

Asp Glu Ile Thr Trp Glu Met Leu Pro Lys Ser Leu Ala Lys Leu Glu Leu Ser Ala Leu Met 86) Val Ser Ile Ser Phe Val Glu Ala Ile Ala Ala Pro Gin Glu Phe Gin Ala Gin Ile Asp Glu Tyr Val Glu Ile Ser Thr Ser Pro Asn Ala Phe Gin Gin Ser Phe Gin Pro Ser Ser Leu Glu Gin Gu Lys Leu Val Leu Ser Ser Cys Gin Leu His Leu Glu Gly Gin Leu Asp Glu Giu Leu Leu Arg Leu Ser Arg Glu Ile Gly Ile Met Arg Leu Gly Gin Leu Leu Pro Ser Ile Val Gly Met Ala Arg Arg Glu Gin Ile Gly Asn Ala Arg Glu Gly Val Cys Gly Ser Gly Ser Ala Met EXAMPLE 76 Construction of DMON31105 The new N-terminus/C-terminus gene in pMON31105 was created using Method III as described in Materials and Methods. The full length new N-terminus/C-terminus gene of hIL-3 receptor agonist pMON13416 was created and amplified from the intermediate plasmid, Syntani, using the primer set 70 start (SEQ ID NO:54) and 69 rev (SEQ ID The resulting DNA fragment which contains the new gene was digested with restriction endonucleases NcoI and SnaBI.

WO 97/12985 PCT/US96/15774 209 The digested DNA fragment was resolved on a 1% TAE gel, stained with ethidium bromide and isolated using Geneclean (BiolOl, Vista, CA). The purified digested DNA fragment was ligated into the expression vector pMON13189, using T4 DNA ligase (Boehringer Mannheim, Indianapolis, IN). The pMON13189 DNA had been previously digested with NcoI and SnaBI to remove the hIL3 receptor agonist pMON13416 coding sequence and the 4254 base pair vector fragment was isolated using Geneclean (BiolOl, Vista, CA) after resolution on a 0.8% TAE gel and staining with ethidium bromide. A portion of the ligation reaction was used to transform E. coli strain DH5a cells (Life Technologies, Gaithersburg,

MD).

Transformant bacteria were selected on ampicillin-containing plates. Plasmid DNA was isolated and sequenced to confirm the correct insert. The resulting plasmid was designated pMON31105.

E. coli strain JM101 was transformed with pMON31105 for protein expression and protein isolation from inclusion bodies.

The plasmid, pMON31105, contains the DNA sequence of (SEQ ID NO:87) which encodes the protein with the following amino acid sequence: Asn Leu Lys Leu Asn Pro Val Ser Gly Pro Thr Ala Val Ser Arg Ala His Ala Pro Ala Val Cys Pro Ser Phe Gly Ser Gin Gly Ser Gly Lys Thr Ser Ser Gly Ile Glu Ser Ala Thr Ala Gly Asp Trp Gln Thr Leu Glu Gin Ser Ile Met Ile Ala Pro Leu Leu Ile Leu Met Asp Val Arg Ala Val Ser Pro Gly Glu Pro Pro Ser Lys Gly Ala Met Pro Gly Val Leu Val Tyr Arg Val Leu Gly Ser Gin Ser Ile Gin Gly Asp Tyr Lys Leu Cys Leu Gly Ile Pro Ala Ile Leu Ala Pro Ser Glu Phe Arg Ala Gin Glu Asp Glu Ile Asp Pro Asn Arg Asn Leu Lys Asn Leu Pro Ser Gly Glu Ser His Ala Phe Ala Ala Ser His Arg His Leu Phe Leu Leu Gly Ala Ala His Pro Glu Trp Ala Pro Arg Arg Glu Gin Ile Asn Arg Glu Pro Lys Ser Leu Ala Lys Leu Glu Leu Asn Leu His Pro Lys Leu Gin Gly His His Leu Asn Leu Pro Tyr Val Ile Ser Ser Pro Ala Phe Gin Ser Gin Pro Ser Leu Gin Glu Leu Val Ser Ser Gin Ile Thr Gly Leu Asp Asn Glu Thr Asn Gin Phe Ser Glu Lys Leu Cys Pro Cys Ile Ile Phe Tyr Gly Ser Lys Arg Glu Asp Leu Glu Gly Gly Ile Asn Met Ala Arg Arg Leu Glu Gly Gly Gin Val Leu Cys Leu Gly Pro Ser WO 97/12985 PCT/US96/1577 4 210 Gin Ala Leu Gin Leu Ala Gly Cys Leu Ser Gin Leu His Ser Gly Leu Phe Leu Tyr Gin Gly Leu Leu Gin Ala Leu Glu Gly Ile Ser Pro Glu Leu Gly Pro Thr Leu Asp Thr Leu Gin Leu Asp Val Ala Asp Phe Ala Thr Thr Ile Trp Gin Gin Met Glu Glu Leu Gly Met Ala Pro Ala Leu Gin Pro (SEQ ID NO:187) EXAMPLE 77 Construction of DMON31106 The new N-terminus/C-terminus gene in pMON31106 was created using Method III as described in Materials and Methods. The full length new N-terminus/C-terminus gene of hIL-3 receptor agonist pMON13416 was created and amplified from the intermediate plasmid, Syntanl, using the primer set 91 start (SEQ ID NO:56) and 90 rev (SEQ ID NO:57).

The resulting DNA fragment which contains the new gene was digested with restriction endonucleases NcoI and SnaBI.

The digested DNA fragment was resolved on a 1% TAE gel, stained with ethidium bromide and isolated using Geneclean (BiolOl, Vista, CA). The purified digested DNA fragment was ligated into the expression vector pMON13189, using T4 DNA ligase (Boehringer Mannheim, Indianapolis, IN). The pMON13189 DNA had been previously digested with NcoI and SnaBI to remove the hIL3 receptor agonist pMON13416 coding sequence and the 4254 base pair vector fragment was isolated using Geneclean (BiolOl, Vista, CA) after resolution on a 0.8% TAE gel and staining with ethidium bromide. A portion of the ligation reaction was used to transform E. coli strain DH5a cells (Life Technologies, Gaithersburg,

MD).

Transformant bacteria were selected on ampicillin-containing plates. Plasmid DNA was isolated and sequenced to confirm the correct insert. The resulting plasmid was designated pMON31106.

WO 97/12985 PCT/US96/15774 211 E. coli strain JM101 was transformed with pMON-31106 for protein expression and protein isolation from inclusion bodies.

The plasmid, pMON31106, contains the DNA sequence of (SEQ ID which encodes the protein with the following amino acid sequence: Ala Glu Ala Asp Asp Arg Lys Leu Gly Pro Thr Ala Val Ser Arg Ala His Gin Leu Pro Asp Ala Pro Phe Gin Glu Pro Asn Asn Gin Gly Ser Gin Gly Ser Gly Lys Thr Ser Ala Phe Glu Phe Pro Sei Arg Glu Ile Asn Leu Leu Pro Ser Pro Gly Gly Tyr Gly Ile Tyr Leu Leu Leu Leu Ala Ala Arg Glu Gin Ile Asn Arg Glu Cys Pro Pro Ala Val Arg Ser Gin Lys Gly Gin Tyr Gly Thr Leu His Lys Gin His Leu Leu Asn Leu Gly Ser Met Leu Val Gin Gly Leu Ile Leu Gin Pro Thr Gin Pro Leu Gly His Asn Pro Ala Pro Glu Lys Pro Val Leu Ser Asp Cys Pro Ala Gly Thr Ile Pro Ile Ile Thr Phe Gly Gly Leu Lys Asp Glu Asn Leu Ser Gly Ser Ala Pro Ser Glu Ser Ala Phe Ala Ser Arg His Phe Leu Gly Ala His Pro Trp Ala Gly Cys Leu Leu Leu Asp Trp Gin Ile Lys Ala Gly Tyr Leu Val Thr Ser Asn Cys Ser Arg Pro Pro Ala Asp Val Ser Ile Glu Ser Phe Val Ile Glu Ala Ile Thr Ala Tyr-Val Gly Pro Ile Ser His Lys Ser Pro Ala Ser Ala Phe His Leu Gin Ser Leu Ala Gin Pro Leu Lys Ser Leu Ala Leu Gin Glu Glu Glu Leu Val Pro Leu Ser Ser Leu Ser Gin Leu Gin Ala Leu Glu Thr Leu Gin Leu Gin Met Glu Glu Asp Trp Gin Leu Glu Gin Ile Met Ile Pro Leu Leu Leu Met Asp Arg Ala Val Leu Arg Asn Glu Gly Gly Thr Ile Asn Asn Met Ala Gin Arg Arg Phe Leu Glu Ser Gly Gly Glu Gin Val Lys Leu Cys Leu Leu Gly Cys Pro Ser His Ser Gly Gly Ile Ser Asp Val Ala Leu Gly Met (SEQ ID NO:188) EXAMPLE 78 Construction of pMON31107 The new N-terminus/C-terminus gene in pMON31107 was created using Method III as described in Materials and Methods. The full length new N-terminus/C-terminus gene of hIL-3 receptor agonist pMON13416 was created and amplified from the intermediate plasmid, Syntanl, using the primer set 101 start (SEQ ID NO:58) and 100 rev (SEQ ID NO:59).

WO 97/12985 PCT/TJS96/15774 212 The resulting DNA fragment which contains the-new gene was digested with restriction endonucleases NcoI and SnaBI.

The digested The DNA fragment was resolved on a 1% TAE gel stained with ethidium bromide and isolated using Geneclean (BiolOl, Vista, CA). The purified digested DNA fragment was ligated into the expression vector pMON13189, using T4 DNA ligase (Boehringer Mannheim, Indianapolis, IN) The pMON13189 DNA had been previously digested with NcoI and SnaBI to remove the hIL3 receptor agonist pMON13416 coding sequence and the 4254 base pair vector fragment was isolated using Geneclean (BiolOl, Vista, CA) after resolution on a 0.8% TAE gel and staining with ethidium bromide. A portion of the ligation reaction was used to transform E. coli strain DH5a cells (Life Technologies, Gaithersburg,

MD).

Transformant bacteria were selected on ampicillin-containing plates. Plasmid DNA was isolated and sequenced to confirm the correc: insert. The resulting plasmid was designated pMON31107.

E. coli strain

JM

1 01 was transformed with pMON31107 for protein expression and protein isolation from inclusion bodies.

The plasmid, pMON31107, contains the DNA sequence of (SEQ

ID

NO:89) which encodes the following amino acid sequence: Ala Gly Asp Trp Gin Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu Gln Ala Gin Glu Gln Gin Gly Gly Gly Ser Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg Pro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp Val Ser Ile Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu Ser Phe Val Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly Ile Glu Ala Ile Leu Arg Asn Leu Gln Pro Cys Leu Pro Ser Ala Thr Ala Ala Pro Ser Arg His Pro Ile Ile Ile Lys Tyr Val Glu Gly Gly Gly Gly Ser Pro Gly Glu Pro Ser Gly Pro Ile Ser Thr Ile Asn Pro Ser Pro Pro Ser Lys Glu Ser His Lys Ser Pro Asn Met Ala Thr Gin Gly Ala Met Pro Ala Phe Ala Ser Ala Phe Gin Arg Arg Ala Gly Gly Val Leu Val Ala Ser His Leu Gin Ser Phe Leu Glu Val Ser Tyr Arg Val Leu Arg His Leu Ala Gin Pro Ser Gly Gly Ser Gly Gly Ser Gin Ser Phe Leu Leu Lys Ser Leu Glu Gin Val Arg Lys Ile Gin Gly Asp Gly Ala Ala Leu Gin Glu Lys Leu Cys

I

WO 97/12985 PCT/US96/15774 213 Ala Thr Tyr Lys Leu Cys His Pro Glu Glu Leu Val Leu Leu Gly His Ser Leu Gly Ile Pro Trp Ala Pro Leu Ser Ser Cys Pro Ser Gin Ala Leu Gin Leu Ala Gly Cys Leu Ser Gin Leu His Ser Gly Leu Phe Leu Tyr Gin Gly Leu Leu Gin Ala Leu Glu Gly Ile Ser Pro Glu Leu Gly Pro Thr Leu Asp Thr Leu Gin Leu Asp Val Ala Asp Phe Ala Thr Thr Ile Trp Gin Gin Met Glu Glu Leu Gly Met Ala Pro Ala Leu Gin Pro (SEQ ID NO:189) EXAMPLE 79 Construction of pMON311 8 The new N-terminus/C-terminus gene in pMON31108 was created using Method III as described in-Materials and Methods. The full length new N-terminus/C-terminus gene of hIL-3 receptor agonist pMON13416 was created and amplified from the intermediate plasmid, Syntan3, using the primer set start (SEQ ID NO:52) and 34 rev (SEQ ID NO:53) The resulting DNA fragment which contains the new gene was digested with restriction endonucleases NcoI and SnaBI.

The digested DNA fragment was resolved on a 1% TAE gel, stained with ethidium bromide and isolated using Geneclean (Biol01, Vista, CA). The purified digested DNA fragment was ligated into the expression vector pMON13189, using T4 DNA ligase (Boehringer Mannheim, Indianapolis, IN). The PMON13189 DNA had been previously digested with NcoI and SnaBI to remove the hIL3 receptor agonist pMON13416 coding sequence and the 4254 base pair vector fragment was isolated using Geneclean (BiolOl, Vista, CA) after resolution on a 0.8% TAE gel and staining with ethidium bromide. A portion of the ligation reaction was used to transform E. coli strain DH5a cells (Life Technologies, Gaithersburg,

MD).

Transformant bacteria were selected on ampicillin-containing plates. Plasmid DNA was isolated and sequenced to confirm the correct insert. The resulting plasmid was designated pMON31108.

WO 97/12985 PCT/US96/157 7 4 214 E. coli strain JM101 was transformed with pMON31108 for protein expression and protein isolation from inclusion bodies.

The plasmid, pMON31108, contains the DNA sequence of (SEQ ID which encodes the following amino acid sequence: Leu Asp Pro Asp Arg Asn Val Lys Asn Asn Leu Gin His Pro Ile Lys Leu Thr Gin Gly Gly Ser Ile Met Ala Pro Leu Ser Gly Pro Ser His Lys Phe Ala Ser Ser His Leu His Leu Ala Leu Leu Lys Ala Ala Leu Pro Glu Glu Ala Pro Leu Cys Leu Ser Leu Gin Ala Asp Thr Leu Gln Gin Met ID NO:190) Asn Asn Leu Arg Leu Glu Pro Cys Ile Ile Phe Tyr Gly Ser Ile Asp Tyr Val Ile Ser Ser Pro Ala Phe Gin Ser Gin Pro Ser Leu Gin Glu Leu Val Ser Ser Gin Leu Leu Glu Gin Leu Glu Glu Leu Asn Asp Leu Pro Asn Asn Ala Ser Leu Pro Ser Lys Ala Gly Leu Val Thr Gly Gly Gly Glu Ile Ile Glu Gly Gly Thr Ile Asn Asn Met Ala Gin Arg Arg Phe Leu Glu Ser Gly Gly Glu Gin Val Lys Leu Cys Leu Leu Gly Cys Pro Ser His Ser Gly Gly Ile Ser Asp Val Ala Leu Gly Met Glu Asp Leu Glu Gly Ile Ala Thr Asp Trp Leu Glu Ser Gly His His Gly Gly Pro Ser Thr Gin Ala Gly Val Ser Ser Gly Arg Lys Ala Thr His Ser Gin Ala Leu Phe Pro Glu Asp Phe Ala Pro Val Ser Ser Phe Glu Ala Ala Ala Gin Glu Gin Ala Gly Gly Leu Lys Ser Pro Pro Pro Gly Ala Gly Val Tyr Arg Gly Ser Ile Gin Tyr Lys Leu Gly Leu Gin Leu Tyr Leu Gly Ala Thr Ala Leu Ile Val Ile Pro Phe Gin Ser Arg Gly Ser Met Leu Val Gin Gly Leu Ile Leu Gin Pro Thr Gin Leu Arg Leu Ser Arg Glu Asn Pro Glu Lys Pro Val Leu Ser Asp Cys Pro Ala Gly Thr Ile Pro Met Ala Arg Arg Glu Gin Cys Pro Pro Glu Ala Ala Arg Phe Gly His Trp Gly Leu Leu Trp

(SEQ

EXAMPLE Construction of pMON31109 The new N-terminus/C-terminus gene in pMON31109 was created using Method III as described in Materials and Methods. The full length new N-terminus/C-terminus gene of hIL-3 receptor agonist pMON13416 was created and amplified from the intermediate plasmid, Syntan3, using the primer set start (SEQ ID NO:54) and 69 rev (SEQ ID WO 97/12985 PCT/US96/15774 215 The resulting DNA fragment which contains the hew gene was digested with restriction endonucleases NcoI and SnaBI.

The digested DNA fragment was resolved on a 1% TAE gel, stained with ethidium bromide and isolated using Geneclean (BiolOl, Vista, CA). The purified digested DNA fragment was ligated into the expression vector pMON13189, using T4 DNA ligase (Boehringer Mannheim, Indianapolis, The pMON13189 DNA had been previously digested with NcoI and SnaBI to remove the hIL3 receptor agonist pMON13416 coding sequence and the 4254 base pair vector fragment was isolated using Geneclean (BiolOl, Vista, CA) after resolution on a 0.8% TAE gel and staining with ethidium bromide. A portion of the ligation reaction was used to transform E. coli strain DH5a cells (Life Technologies, Gaithersburg,

MD).

Transformant bacteria were selected on ampicillin-containing plates. Plasmid DNA was isolated and sequenced to confirm the correct insert. The resulting plasmid was designated pMON31109.

E. coli strain JM101 was transformed with pMON31109 for protein expression and protein isolation from inclusion bodies.

The plasmid, pMON31109, contains the DNA sequence of (SEQ ID NO:91) which encodes the following amino acid sequence: Asn Leu Lys Leu Gly Glu Pro Asn Asn Ser Ser Phe Ser His Leu Ala Ser Gly Pro Ser Ala Ala Gly Asp Val Thr Leu Gly Gly Ser Ile Ile His Asn Asn Leu Leu Arg Leu Leu Glu Tyr Gly Pro Ile His Lys Ser Ala Ser Ala His Leu Gln Leu Ala Gin Leu Lys Ser Ile Glu Ala Thr Ala Ala Trp Gin Glu Glu Gin Ala Gly Gly Gly His Leu Lys Asn Asp Glu Pro Asn Leu Val Glu Gly Ser Thr Ile Pro Asn Met Phe Gin Arg Ser Phe Leu Pro Ser Gly Leu Glu Gin Ile Leu Arg Asn Pro Ser Arg His Phe Arg Glu Lys Gin Glu Gin Gin Ser Asn Cys Ser Arg Pro Pro Ala Asp Val Ser Ile Glu Ser Phe Val Gly Gly Gly Ser Asn Pro Ser Pro Ala Thr Gin Gly Arg Ala Gly Gly Glu Val Ser Tyr Gly Ser Gly Gly Val Arg Lys Ile Leu Gin Pro Pro Ile Ile Leu Thr Phe Gly Gly Gly Ile Met Ile Pro Leu Leu Leu Met Asp Arg Ala Val Pro Gly Glu Pro Ser Lys Ala Met Pro Val Leu Val Arg Val Leu Ser Gin Ser Gin Gly Asp Cys Ile Tyr Ser Asp Asp Arg Lys Pro Glu Ala Ala Arg Phe Gly WO 97/12985 PCTUS96/ 1 5 7 7 4 216 Ala Ala Leu Gin Glu Lys Leu Cys Ala Thr Tyr Lys Leu Cys His Pro Glu GIu Leu Val Leu Leu Gly His Ser Leu Gly Ile Pro Trp Ala Pro Leu Ser Ser Cys Pro Ser Gin Ala Leu Gln Leu Ala Gly Cys Leu Ser Gin Leu His Ser Gly Leu Phe Leu Tyr Gin Gly Leu Leu Gin Ala Leu Glu Gly Ile Ser Pro Glu Leu Gly Pro Thr Leu Asp Thr Leu Gin Leu Asp Val Ala Asp Phe Ala Thr Thr Ile Trp n Gn Met Glu Glu Leu Gly Met Ala Pro Ala Leu Gin Pro (SEQ ID NO:191) EXAMPLE 81 Construction of DMON3110 The new N-terminus/C-terminus gene in pMON31110 was created using Method III as described in Materials and Methods. The full length new N-terminus/C-terminus gene of hIL-3 receptor agonist pMON13416 was created and amplified from the intermediate plasmid, Syntan3, using the primer set 91 start (SEQ ID NO:56) and 90 rev (SEQ ID NO:57) The resulting DNA fragment which contains the new gene was digested with restriction endonucleases NcoI and SnaBI.

The digested DNA fragment was resolved on a 1% TAE gel stained with ethidium bromide and isolated using Geneclean (Biol0, Vista, CA). The purified digested DNA fragment was ligated into the expression vector pMON13189, using T4 DNA ligase (Boehringer Mannheim, Indianapolis, IN). The pMON13189 DNA had been previously digested with NcoI and SnaBI to remove the hIL3 receptor agonist pMON13416 coding sequence and the 4254 base pair vector fragment was isolated using Geneclean (Biol01, Vista, CA) after resolution on a 0.8% TAE gel and staining with ethidium bromide. A portion of the ligation reaction was used to transform E. coli strain DH5a cells (Life Technologies, Gaithersburg,

MD).

Transformant bacteria were selected on ampicillin-containing plates. Plasmid DNA was isolated and sequenced to confirm WO 97/12985 PCT/US96/I 5774 the correct insert. The resulting plasmid was designated pMON3 1110.

E. coli strain JMl0l was transformed with vm1-111 L, -L -L 1 1 protein expression and protein isolation from inclusion 0 for 1R Vk.uJe3 The plasmid, pMON3llio, contains the DNA sequen~fe of (SEQ

ID

N0:92) which encodes the following amino acid sequence: Ala Pro Ser Glu Phe Arg Ala Gin Giu Gly Ser Asn Lys Arg Pro Glu Asp Val Leu Giu Ser Gly Ile Glu Ala Thr Ala Ser Gly Pro Ser His Lys Phe Ala Ser Ser His Leu His Leu Ala Leu Leu Lys Ala Ala Leu Pro Giu Glu Ala Pro Leu Cys Leu Ser Leu Gin Ala Asp Thr Leu Gin Gin Met ID NO:192) Arg Giu Gin Cys Pro Ser Phe Ala Tyr Ile Ser Ala Gin Gin Ser Gin Leu Ser Gin Leu Gin Glu His *Lys *Gin Ser Ala Ile Val le Val Ser Pro Phe Ser Pro Leu Giu Val Ser Leu Giu Leu Glu Pro Leu Gly Ile Pro Leu Arg Leu Giu Thr Asn Gin Phe Ser Glu Lys Leu Cys His Gly Asp Leu Ile Thr Giy Met Leu Met Ala Arg Gly Ile Met Arg Leu Gly Gin Leu Leu Pro Ser Ile Val Gly Ile Phe Giy Ile Leu Asp Val Asn Gly Asn Ala Arg Glu Gly Vai Cys Gly Ser Gly Ser Al a Met Ile Tyr Ser Asp Asp Arg Lys Leu Gly Pro Thr Ala Val Ser Arg Ala His Gin Leu Pro Asp Ala Lys *Leu Gly Glu Pro Asn Asn Gin Gly Ser Gin Gly Ser Gly Lys Thr S er Ala Phe Giu Phe Pro Ala Gly Val Thr Gly Gly Ile Ile Asn Asn Leu.Arg Leu Giu Pro Cys Ser Pro Pro Pro Giy Ala Gly Val Tyl Arg Gly Ser Ile Gin Tyr Lys Leu Gly Leu Gin Leu Tyr Leu Gly Ala Thr Ala Leu Asp Leu Ser His Leu Leu Asni Leu Gly Ser Met Leu Val Gin Gly L eu Ile Leu Gin Pro Thr Gin *Trp Giu Gly His Asn Pro Ala Pro Giu Lys Pro Val Leu Ser Asp Cys Pro Ala Giy Thr Ile Pro Gin Gin Gly Leu Asp Asn Ser Ser Pro Glu Ala Ala Arg Phe G ly His Trp Gly Leu Leu Trp

(SEQ

EXAMPLE 82 The new N-terminus/C-terminus gene in pMON3illl was created using Method III as described in Materials and methods. The full length new N-terminus/C-terminus gene of hIL-3 receptor agonist pM0N13416 was created and amplified WO 97/12985 PCT/US96/15774 218 from the intermediate plasmid, Syntan3, using the primer set 101 start (SEQ ID NO:58) and 100 rev (SEQ ID NO:59) The resulting DNA fragment which contains the new gene was digested with restriction endonucleases NcoI and SnaBI.

The digested DNA fragment was resolved on a 1% TAE gel, stained with ethidium bromide and isolated using Geneclean (Biol01, Vista, CA). The purified digested DNA- fragment was ligated into the expression vector pMON13189, using T4 DNA ligase (Boehringer Mannheim, Indianapolis, IN). The pMON13189 DNA had been previously digested with NcoI and SnaBI to remove the hIL3 receptor agonist pMON13416 coding sequence and the 4254 base pair vector fragment was isolated using Geneclean (BiolOl, Vista, CA) after resolution on a 0.8% TAE gel and staining with ethidium bromide. A portion of the ligation reaction was used to transform E. coli strain DH5a cells (Life Technologies, Gaithersburg,

MD).

Transformant bacteria were selected on ampicillin-containing plates. Plasmid DNA was isolated and sequenced to confirm the correct insert. The resulting plasmid was designated pMON31111.

E. coli strain JM101 was transformed with pMON31111 for protein expression and protein isolation from inclusion bodies.

The plasmid, pMON31111, contains the DNA sequence of (SEQ ID NO:93) which encodes the following amino acid sequence: Ala Gly Asp Trp Gin Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu Gin Ala Gln Glu Gln Gin Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg Pro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp Val Ser Ile Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu Ser Phe Val Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly Ile Glu Ala Ile Leu Arg Asn Leu Gsn Pro Cys Leu Pro Ser Ala Thr Ala Ala Pro Ser Arg His Pro Ile Ile Ile Lys Tyr Val Glu Gly Gly Gly Gly Ser Pro Gly Glu Pro Ser Gly Pro Ile Ser Thr Ile Asn Pro Ser Pro Pro Ser Lys Glu Ser His Lys Ser Pro Asn Met Ala Thr Gln Gly Ala Met Pro Ala Phe Ala Ser Ala Phe Gin Arg Arg Ala Gly Gly Val Leu Val Ala WO 97/12985 PCT/US96/15774 219 Ser His Leu Gin Ser Phe Leu Glu Val Ser Tyr Arg Val Leu Arg His Leu Ala Gin Pro Ser Gly Gly Ser Gly Gly Ser Gin Ser Phe Leu Leu Lys Ser Leu Glu Gin Val Arg Lys Ile Gin Gly Asp Gly Ala Ala Leu Gin Glu Lys Leu Cys Ala Thr Tyr Lys Leu Cys His Pro Glu Glu Leu Val Leu Leu Gly His Ser Leu Gly Ile Pro Trp Ala Pro Leu Ser Ser Cys Pro Ser Gin Ala Leu Gin Leu Ala Gly Cys Leu Ser Gin Leu His Ser Gly Leu Phe Leu Tyr Gln Gly Leu Leu Gin Ala Leu Glu Gly Ile Ser Pro Glu Leu Gly Pro Thr Leu Asp Thr Leu Gin Leu Asp Val Ala Asp Phe Ala Thr Thr Ile Trp Gn Gln Met Glu Glu Leu Gly Met Ala Pro Ala LeuGln Pro (SEQ ID NO:193) EXAMPLE 83 Construction of PMON31112 Construction of pMON31112, a plasmid containing

DNA

sequence encoding a multi-functional hematopoietic receptor agonist which activates the hIL-3 receptor and G-CSF receptor. Plasmid, pMON13189 DNA was digested with restriction enzymes Ncol and XmaI resulting in an NcoI, XmaI vector fragment that was isolated and purified from a 0.8% agarose gel. The DNA from a second plasmid, pMON13222

(WO

94/12639, US serial 08/411,796) was digested with NcoI and EcoRI resulting in a 281 base pair NcoI, EcoRI fragment.

This fragment was isolated and purified from a 1.0% agarose gel. Two oligonucleotides SYNNOXA1.REQ (SEQ ID NO:240) and SYNNOXA2.REQ (SEQ ID NO:241) were annealed and ligated with the 281 base pair DNA fragment from pMON13222 to the DNA vector fragment from pMON13189. A portion of the ligation mixture was then transformed into E. coli K-12 strain JM101.

Transformant bacteria were selected on ampicillin-containing plates. Plasmid DNA was isolated, analyzed by restriction analysis to show the presence of an EcoRV fragment, and sequenced to confirm the correct inserts.

WO 97/12985 PCT/US96,l 5774 220 The plasmid, pMON3ll12, contains the DNA sequence of (SEQ ID NO:114) which encodes the following amino acid sequence: MetAlaAsnCysSerAsrietIieAspClIlIlehise~s~nr~o Ala le lu~r~ eLeuLYSAsnLeuLeuProCysLeuPrL eu l r l a r SerPro~lyGluProSerGlProlShrlsnoerororysu LysLeuCysAlaThrTyrLysLeuCysliProl~ue~le~ul~se CLeul~ero~rnleaHiLeuSerSeCYsPrOSerGlnAlaLeulnLeuAlaGly GiyIleSerProGluLeuGlyProThrLeuAsTr~LnuGYnLeueuplAla~eu~he (SEQ ID NO:199)Gl lue ly tlar lLl Constuctio of DO 1-1l3 Construction of pMON3lll3, a plasmid containing DNA sequence encoding a multi-functional hematopoietic receptor agonist which activates the hIL-3 receptor and G-CSF receptor, Plasmid, pMONl3l97 DNA was digested with restriction enzymes NcoI and XmaI resulting in an NcoI, XmaI vector fragment that was isolated and purified from a 0.8% agarose gel. The DNA from a second plasmid, pM0N13239 (WO 94/12639, US serial 08/411,796) was digested with NcoI and EcoRI resulting in a 281 base pair NcoI, EcoRI fragment. This fragment was isolated and purified from a 1.0% agarose gel. Two oligonucleotides SYNNOXA1.REQ (SEQ ID NO:240) and SYNNOXA2.REQ (SEQ ID NO:241) were annealed and ligated with the 281 base pair DNA fragment from pMON13239 to the DNA vector fragment from pMON13197. A portion of the ligation mixture was then transformed into E. coli K-12 strain JMl0l.

Transformant bacteria were selected on ampicillin-containing WO 97/1 2985 PCTIUS96/1 5774 221 Plates. Plasrnid DNA was isolated, analyzed by restriction analysis to show the presence of an EcoRV fragment, and sequenced to confirm the correct inserts.

The plasmid, pMON3lll3, contains the DNA sequence of

(SEQ

ID NO:115) which encodes the following amino acid sequence: MetAlaAsnCys SerAsnMet IleAspGluIleI leThrflisLeuLysGlnProProLe ProLeuLeuAspPheAsnAsnLeuAsnGlyGlu~sp~l~sp 1 leLeuMetGluAsnsn PheTyrLeuLye~u~nl~n~al~nyra~ulyl 1 yl SerHisLysSerProAsnMetAlaThrGlnGlyAlaMetProAlaPheAlaelah TyrArgValLeuArg~i~ujalnr r~oeul r~aerSerLeuPro GlnSerPheLeubeuLys e~ul~na~gy~l~nl~pl~al LeuGlnGluLy cLeuCysAlaThrTyrLysLeuCy~isProlulueualeue GlyHisSer~euGlyIler~pPro~aLSeeryrorlnaeun LeuAlaGlyCysLeuSerl~iSerl~ui~GlLheuyrllyueun AlaLeuGluGyIleSerProGluLeGlPhr~us~re~ne~p Glnro(SEQ ID NO:200) EXAMPLE Constrcto of-O3114 Construction of pMON311l4, a plasmid containing DNA sequence encoding a multi-functional hematopoietic receptor agonist which activates the hIL-3 receptor and C-CSF receptor.

Plasmid, pM0N13189 DNA was digested with restriction enzymes NcoI and Xmal resulting in an NcoI, XmaI vector fragment that was isolated and purified from a 0.8% agarose gel. The DNA from a second plasmid, pMON13239 (Wa 94/12639, US serial 08/411,796), was digested with NcoI and EcoRI resulting in a 281 base pair NcoI, EcoRI fragment. This fragment was isolated and purified from a 1.0% agarose gel. Two oligonucleotides SYNNOXA1.REQ (SEQ ID NO:240) and SYNNOXA2.REQ (SEQ ID NO:241) were annealed and ligated with WO 97/12985 PCT/US96/15774 222 the 281 base pair DNA fragment from pMON13239 to th-e DNA vector fragment from pMON13189. A portion of the ligation mixture was then transformed into E. coi K-12 strain jMl0l.

Transformant bacteria were selected on arnpicillin-containing plates. Plasmid DNA was isolated, analyzed by restriction analysis to show the presence of an EcoRV fragment, and sequenced to confirm the correct inserts.- The plasmid, pMON3lll4, contains the DNA sequence of (SEQ ID NO:ll6) which encodes the following amino acid sequence: MetAlaAsnCysSerAsnMetleAsp~lulllTh.se~slnr~oe Pr~ue~ph~ns~e nl~us~ns~ eLeuMetcluAsnAsn LeuArgArgProAsnLeuG uAlsnrpl~l~sere~l~n 1 ae PheTyrLeuLysThrLeuGuAsnAaGnAaGlnGlnyalulyyly Se~ol~ur~rl~ol~r~rl~nr~rr~oe~sl Se~sy~rr~ne~ah~n~yl~tr~ah~ae~ah Gl~gr~al~ya~ua~a~ri~ul~rh~ul~le LeuLeyseeullnargy lel lyslyl lae ln u Ly~uy~ah~ry~uy~s~ol~ue~le~ul~se Le~yl~or~ar~ue~r~sr~rl~ae~ne~al CysLeuS erGlnLeuHis SerGlyLeuPheLeu~yrGlnGlyLeuLeuGlnAlaL euGlu Glyl leSerr ue~yr~h~us~re~n~us~ll~ph Al~rh~er~nlie~ulue~ye~ar~ae~nr (SEQ ID NO:201) EXAMPLE 86 Construction of DMON31S Construction of pMON3l1l5, a plasmid containing DNA sequence encoding a multi-functional hematopoietic receptor agonist which activates the hIL-3 receptor and G-CSF receptor.

Plasmid, pMON13197 DNA was digested with restriction enzymes WO 97/12985 PCTIUS96/15774 223 NcoI and XmaI resulting in an NcoI, Xmal vector fragment that was isolated and purified from a 0.8% agarose gel. The DNA from a second plasmid, pMON13222, was digested with Ncoj and EcoRI resulting in a 281 base pair NcoI, EcoRI fragment.

This fragment was isolated and purified from a 1.0% agarose gel. Two oligonucleotides SYNNOXAl.REQ (SEQ ID NO:240) and SYNNOXA2.REQ (SEQ ID NO:241) were annealed and ligated with the 281 base pair DNA fragment from pMON13222 to the DNA vector fragment from pMON13197. A portion of the ligation mixture was then transformed into E. coli K-12 strain Jmlol.

Transformant bacteria were selected on ampicillin-containing plates. Plasmid DNA was isolated, analyzed by restriction analysis to show the presence of an EcoRV fzagment, and sequenced to confirm the correct inserts.

The plasmid, pMON3lll5, contains the DNA sequence of (SEQ ID NO:117) which encodes the following amino acid sequence: Me~as~se~ne~es~u~el~ri~uy~nr~oe ProLeuLeuAspPheAsnAsnLeuAsnGlyGluAspGlnspI leLeuMetAspAsnAsn Le~gr~os~e~ul es~g~aa~se~ulnAsnAlaSer Al~el~rl~uy~ne~u~oy~ur~ul~rl~ar Th~gi~ol~sl~ss~y~pr~nl~er~gy~uh PheTyrLeuLysThrLeuGluAsnAlaGlnAlaGlnGlnyrValGluGlyGlyGlyGly SerProGlyGluProSerclyPro~ leSerThrlleAsnProSerProProSerLysGlu SerHisLysSerProAsnMetAlaThrGlnyAla et~lPAlahAlalhe Gl~gr~al~ya~ua~a~ri~ul~rh~ul~le TyrArgvalLeuArgHl sLeuAlaGlnProThrProL euGlyProAlaS erSerLeuPro Gl~rh~ue~se~ul~n~lr~sl~nl~pl~al LeuGlnGluLysLeuCysAlaThrTyrLysLeuCy 5 sj 5 ProGluGluLeuValLeuLeu GlyliisSerLeuGlyle or~ar~e~re~sr~e~nl~u LeuAlaGlyCysLeuSerGlnLeuHisSerGl beuph~eu~y GlLLGln Al~ul~yl~rr~ue~y~oh~us~re~ne~pa AlaAspPheAlaThrThrlleTrpGlnGlnMetGluluLeulyMtAlaPrAlaLe GlnPro (SEQ ID NO:202) EXAMPLE 87 WO 97/12985 PCT/US96/15774 224 Determination of the in vitro activity of multi-fucton hematopoietic recentor aaonist nroteins The protein concentration of the multi-functional hematopoietic receptor agonist protein can be determined using a sandwich ELISA based on an affinity purified polyclonal antibody. Alternatively the protein concentration can be determined by amino acid composition analysis. The bioactivity of the multi-functional hematopoietic receptor agonist can be determined in a number of in vitro assays.

For example a multi-functional hematopoietic receptor agonist which binds the hIL-3 receptor and G-CSF receptor can be assayed in cell proliferation assays using cell lines expressing the hIL-3 and/or G-CSF receptors. One such assay is the AML-193 cell proliferation assay. AML-193 cells respond to IL-3 and G-CSF which allows for the combined bioactivity of the IL-3/G-CSF multi-functional hematopoietic receptor agonist to be determined. Another such assay is the TF1 cell proliferation assay.

In addition other factor dependent cell lines, such as (ATCC. CRL 1838) or 32D which are murine IL-3 dependent cell line, may be used. The activity of IL-3 is species specific whereas G-CSF is not, therefore the bioactivity of the G-CSF component of the IL-3/G-CSF multifunctional hematopoietic receptor agonist can be determined independently. Cell lines, such as BHK or murine Baf/3, which do not express the receptor for a given ligand can be transfected with a plasmid containing a gene encoding the desired receptor. An example of such a cell line is BaF3 transfected with the hG-CSF receptor (BaF3/hG-CSF). The activity of the multi-functional hematopoietic receptor agonist in these cell lines can be compared with hIL-3 or G- CSF alone or together. The bioactivity of examples of multifunctional hematopoietic receptor agonists of the present invention assayed in the BaF3/hG-CSF cell proliferation and WO 97/12985 PCTUS96/15774 225 TF1 cell proliferation assays is shown in Table 5 and Table 6. The bioactivity of the multi-functional hematopoietic receptor agonist is expressed as relative activity compared with a standard protein pMON13056 (WO 95/21254). The bioactivity of examples of multi-functional hematopoietic receptor agonists of the present invention assayed in the BaF3/c-mpl cell proliferation and TF1 cell proliferation assays is shown in Table 7 and Table 8.

WO 97/12985 PCTJUS96,1 5774

PMON~

.13182 13183 13184 13185 13186 13187 13188 13189 13190 13191 13192 13193 25190 25191 13194 13195 13196 13197 13198 13199 15982 -15981 15965 15966 15967 TABLE CELL PROLIFERATIVE

ACTIVITY

OF DUAL IL-3/G-CsF RECEPTOR

AGONISTS

BaF3/ha-csF receptor TF1 cell proliferation Cell Proliferation assayasy relative activity reatv aa elati--e acivit 0.015 1.- 0.021.

0.7 0.8 0.364 1.8 0.62 1. 37 nd =not determined *The bioactivity of the multi-functional hematopojetic receptor agonist is expressed as relative activity compared with a standard protein pMON13056. n=3 or greater WO 97/12985 PCT/US96/15774 227 TABLE 6 CELL PROLIFERATIVE

ACTIVITY

OF DUAL IL-3/G-CSF RECEPTOR

AGONISTS

PMON BaF3/hG-CSF receptor TF1 cell proliferation cell proliferation assay assay relative activity relative activity 31104 31105 31106 31107 nd nd 31108 31109 31110 nd nd 31111 nd nd 31112 31113 31114 31115 31116 nd nd 31117 nd nd nd not determined t The bioactivity (n=l or 2) of the multi-functional hematopoietic receptor agonist is expressed as relative activity compared with a standard protein pMON13056.

indicates that the molecule was comparable to pMON13056.

WO 97/12985 PTU9/57 228 TABLE 7 CELL PROLIFERATION

ACTIVITY

Baf3/c-MPl receptor TF1 PHON cell Proliferation cell Proliferation assay assay -activitv* act ivrI~t 28505 28506- 280 +4 T*5 A c i v t m e s r d i h a e l i e t a s e t d w t th 2 8 5 0 r c p o r e a i et9c m l l g nd 5 78civt- m a ur d reaiv o0MN1-6 WO 97/12985 PCT/US96/15774 229 In a similar manner other factor dependent cell lines known to those skilled in the art can be used to measure the bioactivity of the desired multi-functional hematopoietic receptor agonist. The methylcellulose assay can be used to determine the effect of the multi-functional hematopoietic receptor agonists on the expansion of the hematopoietic progenitor cells and the pattern of the different types of hematopoietic colonies in vitro. The methylcellulose assay can provide an estimate of precursor frequency since one measures the frequency of progenitors per 100,000 input cells. Long term, stromal dependent cultures have been used to delineate primitive hematopoietic progenitors and stem cells. This assay can be used to determine whether the multi-functional hematopoietic receptor agonist stimulates the expansion of very primitive progenitors and/or stem cells. In addition, limiting dilution cultures can be performed which will indicate the frequency of primitive progenitors stimulated by the multi-functional hematopoietic receptor agonist.

WO 97/12985 PCTIUS96/1 5 7 7 4 Table8 PMON IL-3 agonist activity c-mol reecptor agonist (AML cell activity proliferation assay) (Baf/3-c-rmpj cell roliferation assay 28505 28506 28507 28508 28509 28510 28511 2852 28524 28525 28526 28527 28522 28529 WO 97/12985 PCT/US96/157 74 28535 28539 28540 28541 28542 28545 28551 28571 Table 8 (cont) EXAMPLE 88 G-CSF variants which contain single or multiple amino acid substitutions were made using PCR mutagenesis techniques as described in WO 94/12639 and WO 94/12638.

These and other variants amino acid substitutions insertions or deletions and N-terminal or C-terminal extensions) could also be made, by one skilled in the art, using a variety of other methods including synthetic gene assembly or site-directed mutagenesis (see Taylor et al., Nucl. Acids Res., 13: 7864-8785 [1985]; Kunkel et al., Proc.

Natl. Acad. Sci. USA, 82: 488-492 [1985]; Sambrook et al., Molecular Cloning: A Laboratory Manual, 2nd ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, [1989],

(WO

94/12639) and (WO 94/12638)). These substitutions can be made one at a time or in combination with other amino acid substitutions, and/or deletions, and/or insertions and/or extensions. After sequence verification of the changes, the plasmid DNA can be transfected into an appropriate mammalian cell, insect cell or bacterial strain such as E. coli for production. Known variants of G-CSF, which are active, include substitutions at positions 1 (Thr to Ser, Arg or WO 97/12985 WO 912985 PCT/US96/15774 232 Gly, 2 (Pro to Leu), 3 (Leu to Arg or Ser) and 17 (cys to Ser) and deletions of amino acids 1-11 (Kuga et al.

Biochemicla and Biophysical Research Comm. 159:103-111 (1989)). These G-CSF amino acid substitution variants can be used as the template to create the G-CSF receptor agonists in which a new N-terminus and new C-terminys are created.

Examples of G-CSF amino acid substitution variants are shown in Table 9.

EXAMPLE 89 Biacivitv determination of G-CSF min id sustittion variants The G-CSF amino acid substitution variants can be assayed for cell proliferation activity using the Baf/3 cell line transtected with the human G-CSF receptor. The bioactvity of examples of G-CSF amino acid substitution variants is shown in Table 9 relative to native human

G-CSF.

indicates a comparable activity to native and a Iindicates significantly reduced or no measurable activity.

WO 97/12985 PCTIUS96/I 5774 233 TABLE 9 CELL. PROLIFV ER IN ACT'IVITY OF G-CSF VARIAMNS IN BAF3

CELL

L NE TRA7\SFEC~mTED WITH THE H M NG-CSF REC EPTO aa positic-1 n-ative aa mutant aa activit, 13 Phe Ser 13 Phe His+ 13 Phe Thr 13 Phe Pro 16 Lys Pro 16 Lys Ser 16 Lys Thr 16 Lys His 18 Leu Pro 18 Leu Thr 18 Leu His 18 Leu Cys+ 18 Leu Ile 19 Glu Ala 19 Glu Thr 19 Clu Arg 19 Glu Pro 19 Glu Leu 19 Glu Ser 22 Arg Ty~r 22 Arg Ser 22 Arg Ala 22 Arg Thr 24 Ile Pro 24 Ile Leu 24 le T r WO 97/12985 PCTJUS96I1 5774 234 TABLE 9 cont.

WO 97/12985 PCTIUS96/1 5774 235 TABLE 8 cont.

WO 97/12985 PCTIUS96/1 5774 236 TABLE 8 cont.

activity relative to native hG-CSF nd =not determined WO 97/12985 PCT/US96/15774 237 Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following preferred specific embodiments are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.

More details concerning the molecular biology techniques, protein purification and bioassays can be found in WO 94/12639, WO 94/12638, WO 9 5/20976, WO 95/21197,

WO

95/20977, WO 95/21254, are hereby incorporated by reference in their entirety.

All references, patents or applications cited herein are incorporated by reference in their entirety as if written herein.

Various other examples will be apparent to the person skilled in the art after reading the present disclosure without departing from the spirit and scope of the invention. It is intended that all such other examples be included within the scope of the appended claims.

WO 97/12985 WO 912985 PCT/US96/1 5774 238 SEQUENCE

LISTING

GENERAL

INFORMATION:

APPLICANT:

NAME: G. D. Searle Co.

STREET: P. O. Box 5110 CITY: Chicago STATE: Illinois COUNTRY: United States of America POSTAL CODE (ZIP): 60680 TELEPHONE: (708)470-6501 TELEFAX: (708)470-6881 NAME: Monsanto Company STREET: 800 North Lindbergh Boulevard CITY: St. Louis STATE: Missouri COUNTRY: United States of America POSTAL CODE (ZIP): 63167 TELEPHONE: (314)647-3131 TELEFAX: (314)694-5435 (ii) TITLE OF INVENTION: Multi-Functional Hematopoetic Receptor Agonistsopoietic Receptor (iii) NUMBER OF SEQUENCES: 258 (iv) COMPUTER READABLE

FORM:

MEDIUM TYPE: Floppy disk COMPUTER: IBM PC compatible OPERATING SYSTEM:

PC-DOS/MS-DOS

SOFTWARE: PatentIn Release Version #1.30

(EPO)

CURRENT APPLICATION

DATA:

APPLICATION NUMBER: US 2910 (vi) PRIOR APPLICATION

DATA:

APPLICATION NUMBER: US 60/004,834 FILING DATE: 0 5-OCT-1995 INFORMATION FOR SEQ ID NO: 1: SEQUENCE

CHARACTERISTICS:

LENGTH: 174 amino acids TYPE: amino acid STRANDEDNESS: unknown TOPOLOGY: unknown (ii) MOLECULE TYPE: protein (ix) FEATURE: WO 97/12985 PCT/US96/15774 239 NAME/KEY: Modified-site LOCATION:1 OTHER INFORMATION:/note= "Xaa at position 1 is Thr, Ser, Arg, Tyr or Gly;" (ix) FEATURE: NAME/KEY: Modified-site LOCATION:2 OTHER INFORMATION:/note= "Xaa at position 2 is Pro or Leu;" (ix) FEATURE: NAME/KEY: Modified-site LOCATION:3 OTHER INFORMATION:/note= "Xaa at position 3 is Leu, Arg, Tyr or Ser;" (ix) FEATURE: NAME/KEY: Modified-site LOCATION:13 OTHER INFORMATION:/note= "Xaa at position 13 is Phe, Ser, His, Thr or Pro;" (ix) FEATURE: NAME/KEY: Modified-site LOCATION:16 OTHER INFORMATION:/note= "Xaa at position 16 is Lys, Pro, Ser, thr or His;" (ix) FEATURE: NAME/KEY: Modified-site LOCATION:17 OTHER INFORMATION:/note= "Xaa at position 17 is Cys, Ser, Gly, Ala, Ile, Tyr or Arg;" (ix) FEATURE: NAME/KEY: Modified-site LOCATION:18 OTHER INFORMATION:/note= "Xaa at position 18 is Leu, Thr, Pro, His, Ile or Cys;" (ix) FEATURE: NAME/KEY: Modified-site LOCATION:22 OTHER INFORMATION:/note= "Xaa at position 22 is Arg, Tyr, Ser, Thr or Ala;" (ix) FEATURE: NAME/KEY: Modified-site LOCATION:24 OTHER INFORMATION:/note= "Xaa at position 24 is Ile, Pro, Tyr or Leu;" (ix) FEATURE: WO 97/12985 PCTIUS96/1 5774 NAME/KEY: Modified-site LOCATION:27 OTHER INFORMATION:/note or Gly;- (ix) FEATURE: NAME/KEY: Modified-site OTHER INFORMATION:/note= Ile, Leu or Gly;"- (ix) FEATURE: NAME/KEY: Modified-site LOCATION:34 OTHER INFORMATION:/note= or Ser;", (ix) FEATURE: NAME/KEY: Modified-site LOCATION:36 OTHER INFORMATION:/note= or Ser;11 (ix) FEATURE: NAME/KEY: Modified-site LOCATION:42 OTHER INFORMATION:/note=.

or Ser;11 "Xaa at Position 27 is Asp, "Xaa at Position 30 is Ala, "Xaa at Position 34 is Lys "Xaa at Position 36 is Cys "Xaa at Position 42 is Cys (ix) FEATURE: NAME/KEY: Modified-site LOCATION:43 OTHER INFORMATION:/note= "Xaa at Position 43 is His, Thr, Giy, Vai, Lys, Trp, Ala, Arg, Cys, or Leu;" (ix) FEATURE: NAME/KEY: Modified-site LOCATION:44 OTHER INFORMATION:/note=. "Xaa at position 44 is Pro, Gly, Arg, Asp, Val, Ala, His, Trp, Gin, or Thr;' (ix) FEATURE: NAME/KEY: Modified-site LOCATION:46 OTHER INFORMATION:/note= "Xaa at position 46'is Giu, Arg, Phe, Arg, Ile or Ala;" (ix)

FEATURE:

NAME/KEY: Modified-site LOCATION:47 OTHER INFORMATION:/note= "Xaa at position 47 is Leu or Thr;" (ix) FEATURE: WO 97/12985 PCT/US96/1 5774 NAME/KEY: Modified-site LOCATION:49 OTHER INFORMATION:/note; Phe, Arg or Ser;1- (ix) FEATURE: NAME/KEY: Modified-site OTHER INFORMATION:/note= Ile, His, Pro or Tyr; (ix) FEATURE: NAME/KEY: Modified-site LOCATION:54 OTHER INFORMATION:/note= or His;" (ix) FEATURE: NAME/KEY: Modified-site LOCATION:64 OTHER INFORMATION:/note= or Ser;", (ix) FEATURE: NAME/KEY: Modified-site LOCATION:67 OTHER INFORMATION:/note= Lys, Leu or Cys;", (ix) FEATURE: NAME/KEY: Modified-site OTHER INFORNATION:/note= Pro, Leu, Arg or Ser;' (ix) FEATURE: NAME/KEY: Modified-site LOCATION:74 OTHER INFORMATION:/note= or Ser;"1 (ix) FEATURE: NAME/KEY: Modified-site LOCATION:104 OTHER INFORMATION:/note= Gly or Val;,- "Xaa at Position 49 is Leu, Xaa at Position 50 -is Leu, "Xaa at position 54 is Leu "Xaa at position 64 is Cys "Xaa at position 67 is Gin, "Xaa at position 70 is Gin, 'Xaa at position 74 is Cys "Xaa at position 104 is Asp, (ix) FEATURE: NAME/KEY: Modified-site LOCATION:108 OTHER INFORMATION:/note= "Xaa at Position 108 is Leu, Ala, Val, Arg, Trp, Gin or Gly;"1 (ix) FEATURE: WO 97/12985 PCT/US96/1577 4 NAME/KEY: Modified-site LOCATION:115 OTHER INFORMATION:/note= His, Leu or Ala;' (ix) FEATUJRE: NAME/KEY: Modified-site LOCATION:120 OTHER INFORMATION:/note= Gly, Arg, Lys or His" (ix) FEATURE: NAME/KEY: Modified-site LOCATION:123 OTHER INFORMATION:/note=~ Arg, Phe or Thr" "Xaa at position 115 is Thr, "Xaa at Position 120 is Gin, "Xaa at position 123 is Glu, (ix) FEATURE: NAME/KEY: Modified-site LOCATION:144 OTHER INFORMATION:/note, "Xaa at Position 144 is Phe, His, Arg, Pro, Leu, Gin or Glu;" (ix) FEATURE: NAME/KEY: Modified-site LOCATION:146 OTHER INFOIRNATION:/note= or Gin;"1 (ix) FEATURE: NAME/KEY: Modified-site LOCATION:147 OTHER INFORMATION: /note= or Gin;" (ix) FEATURE: NAME/KEY: Modified-site LOCATION:156 OTHER INFORMATION: /note= Gly or Ser;11 (ix) FEATURE: NAME/KEY: Modified-site LOCATION:159 OTHER INFORMATION:/note= Arg, Thr, Tyr, Val or (ix) FEATURE: NAME/KEY: Modified-site LOCATION:162 OTHER INFORI4ATION:/note= Leu, Gly or Trp;" "Xaa at Positioni46 is Arg "Xaa ap position 147 is Arg "Xaa at position 156 is His, "Xaa at position 159 is Ser, Giy;" "Xaa at Position 162 is Giu, (ix) FEATURE: WO 97/12985 PCT/US96/157 7 4 NAME/KEY: Modified-site LOCATION:i63 OTHER INFORMATION:/note= "Xaa at Position 163 is Val, Gly, Arg or Ala;" (ix) FEATURE: NAME/KEY: Modified-site LOCATION:169 OTHER INFORMATION:/note= "Xaa at Position 169- is Arg, Ser, Leu, Arg or Cys;" (ix) FEATURE: NAME/KEY: Modified-site OTHER INFORMATION:/note= "Xaa at position 170 is His, Arg or Ser;" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 1:- Xaa Xaa Xaa Gly Pro Ala Ser Ser Leu Pro Gin Ser Xaa Leu Leu Xaa 1 5 1 A Xaa Giu Xaa Pro Gly Pro Phe Ala Xaa Xaa Xaa Ser Leu Glu Ala Leu Glu Leu Gly Xaa Phe Leu Xaa 115 Gin Gin Xaa His Ala Leu Gly 100 Thr Pro Val Ala Ser Leu Tyr Pro Ile Thr Xaa Thr Xaa Xaa 70 Gin Thr Trp Gin Lys Xaa Tyr Lys 40 Gly Ile 55 Leu Ala Gly Leu Leu Xaa Gin Gin 120 Gly Ala 135 Gin 25 Leu Pro Gly Leu Thr 105 Met Met *Gly Xaa Xaa Xaa Trp Ala Xaa Leu 75 Gin Ala 90 Leu Gin Giu Xaa Pro Ala Gly Xaa Pro Ser Leu Xaa Xaa Phe 140 Ala Glu Leu Gin Glu Asp Giy 125 Ala Xaa Xaa Ser Leu Gly Val1 110 Met Ser Leu Xaa Ser His Ile Ala Ala Ala Xaa Gin Val Xaa Ser Ser Asp Pro Xaa Phe 130 Gin Xaa Xaa Ala Gly Gly Val Leu Val Ala 145 150 Leu Xaa Xaa Ser Tyr Arg Val Leu Xaa Xaa 165 170 INFORMATION FOR SEQ ID NO: 2: Ser 155 Leu Ala Gin Pro WO 97/12985 PCTJUS96/157 7 4 244 Wi SEQUENCE

CHARACTERISTICS:

LENGTH: 133 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: protein (ix) FEATURE: NAME/KEY: Modified-site LOCATION:17 OTHER INFORMATION:/note= 'Xaa at Position 17 is Ser, Lys, Gly, Asp, Met, Gln, or Arg;11 (ix) FEATURE: CA) NAME/KEY: Modified-site LOCATION:18 OTHER INFORMATION:/note= "Xaa at Position 18 is Asn, His, Leu, Ile, Phe, Arg, or Gin;"1 (ix) FEATURE: NAME/KEY: Modified-site LOCATION:19 OTHER INFORMATION:/note=, "Xaa at position 19 is Met, Phe, Ile, Arg, Gly, Ala, or Cys;" Cix) FEATURE: CA) NAME/KEY: Modified-site OTHER INFORMATION:/note= "Xaa at position 20 is Ile, Cys, Gln, Giu, Arg, Pro, or Ala;" (ix) FEATURE: NAME/KEY: Modified-site LOCATION:21 OTHER INFORMATION:/note= "Xaa at position 21 is Asp, Phe, Lys, Arg, Ala, Gly, Glu, Gln, Asn, Thr, Ser or Val;" (ix) FEATURE: NAME/KEY: Modified-site LOCATION:22 OTHER INFORMATION:/note= "Xaa at position 22 is Glu, Trp, Pro, Ser, Ala, His, Asp, Asn, Gin, Leu, Val or Gly;" (ix) FEATURE: NAME/KEY: Modified-site LOCATION:23 OTHER INFORMATION:/note= "Xaa at position 23 is Ile, Val, Ala, Gly, Trp, Lys, Phe, Leu, Ser, or Arg;" WO 97/12985 PCT/US96,'1577 4 245 (ix) FEATURE: NAME/KEY: Modified-site LOCATION:24 OTHER INFORMATION:/note= "Xaa at Position 24 is Ile, Gly, Val, Arg, Ser, Phe, Leu; (ix) FEATURE: NAME/KEY: Modified-site OTHER INFORMAJTION:/note= "Xaa at position 25 is Thr, His, Gly, Gin, Arg, Pro, or Ala;" (ix) FEATURE: NAME/KEY: Modified-site LOCATION:26 OTHER INFORM~ATION:/note= "Xaa at Position 26 is His, Thr, Phe, Gly, Arg, Ala, Trp;" (ix) FEATURE: NAME/KEY: Modified-site LOCATION:27 OTHER INFORMATION:/note= "Xaa at Position 27 is Leu, Gly, Arg, Thr, Ser, or Ala;" (ix) FEATURE: NAME/KEY: Modified-site LOCATION:28 OTHER INFORMATION:/note= "Xaa at position 28 is Lys, Arg, Leu, Gin, Gly, Pro, Val or Trp;" (ix) FEATURE: NAME/KEY: Modified-site LOCATION:29 OTHER INFORMATION:/note= "Xaa at position 29 is Gin, Asn, Leu, Pro, Arg, or Val;" (ix) FEATURE: NAME/KEY: Modified-site OTHER INFORMATION-./note= "Xaa at position 30 is Pro, His, Thr, Gly, Asp, Gin, Ser, Leu, or (ix) FEATURE: NAME/KEY: Modified-site LOCATION:31 OTHER INFORMATION:/note= "Xaa at position 31 is Pro, Asp, Gly, Ala, Arg, Leu, or Gin;" (ix) FEATURE: NAME/KEY: Modified-site LOCATION:32 OTHER INFORMATION:/note= 'Xaa at position 32 is Leu, Val, Arg, Gin, Asn, Gly, Ala, or Glu;" WO 97/12985 PCT/US96/I 5774 246 (ix) FEATURE: NAME/KEY: Modified-site LOCATION:33 OTHER INFORMATION:/note= 'Xaa at Position 33 is pro, Leu, Gin, Ala, Thr, or Glu;"1 (ix) FEATURE: NAME/KEY: Modified-site LOCATION:34 OTHER INFORMATION:/note= "Xaa at position 34 is Leu, Val, Gly, Ser, Lys, Glu, Gin, Thr, Arg, Ala, Phe, Ile or Met;" (ix) FEATURE: NAME/KEY: Modified-site OTHER INFORMATION:/note= "Xaa at position 35 is Leu, Ala, Gly, Asn, Pro, Gin, or Val;" (ix) FEATURE: NAME/KEY: Modified-site LOCATION:36 OTHER INFORMATION:/note= Leu, or Val;" (ix) FEATURE: NAME/KEY: Modified-site LOCATION:37 OTHER INFORMATION:/note= Ser, Pro, Trp, or Ile; "Xaa at position 36 is Asp, 'Xaa at Position 37 is Phe, (ix) FEATURE: NAME/KEY: Modified-site LOCATION:38 OTHER INFORMATION:/note= or Ala;" (ix) FEATURE: NAME/KEY: Modified-site OTHER INFORMATIoN:/note= Trp, or Arg;11 "Xaa at Position 38 is Asn, "Xaa at Position 40 is Leu, (ix) FEATURE: NAME/KEY: Modified-site LOCATION:41 OTHER INFORMATION:/note= "Xaa at Position 41 is Asn, Cys, Arg, Leu, His, Met, or pro;" (ix) FEATURE: NAME/KEY: Modified-site LOCATION:42 OTHER INFORMATION:/note= "Xaa at position 42 is Giy, WO 97/12985 PCT/US96/1 5774 247 Ile, MetAsp, Ser, Cys, Asn, Lys, Thr, Leu, Val, Gu, Ph e, Tyr, or Ala;" (ix) FEATURE: NAME/KEY: Modified-site LOCATION:43 OTHER INFORMATION:/note= "Xaa at position 43 is Glu, or Ser;"Asn, Tyr, Leu, Phe, Asp, Ala, Cys, Gin, Arg, Thr, Gly, (ix) FEATURE: NAME/KEY: Modified-site LOCATION:44 OTHER INFORMATION:/note= "Xaa at Position 44 is Asp, Ser, Leu, Arg, Lys, Thr, Met, Trp, Glu, Asn, Gin, Ala or Pro;" (ix) FEATURE: NAME/KEY: Modified-site OTHER INFORMATION:/note= "Xaa at position 45 is Gin, Pro, Phe, Val, Met, Leu, Thr, Lys, Trp, Asp, Asn, Arg, Ser, Ala, Ile, Giu or His;" (ix) FEATURE: NAME/KEY: Modified-site LOCATION:46 OTHER INFORMATION:/note= "Xaa at position 46 is Asp, Phe, Ser, Thr, Cys, Glu, Asn, Gin, Lys, His, Ala, Tyr, Ile, Vai or Gly;" (ix) FEATURE: NAME/KEY: Modified-site LOCATION:47 OTHER INFORMATION:/note= "Xaa at position 47 is Ile, Gly, Val, Ser, Arg, Pro, or His;" (ix) FEATURE: NAME/KEY: Modified-site LOCATION:48 OTHER INFORMATION:/note= "Xaa at position 48 is Leu, Ser, Cys, Arg, Ile, His, Phe, Giu, Lys, Thr, Ala, Met, Vai or Asn;" (ix) FEATURE: NAME/KEY: Modified-site LOCATION:49 OTHER INFORMATION:/note= "Xaa at position 49 is Met, Arg, Ala, Gly, Pro, Asn, His, or Asp;" WO 97/12985 PCTIUS96,1 5774 248 (ix) FEATURE: NAME/KEY: Modified-site OTHER INFORMATION:/note= "Xaa at Position 50 is Giu, Phe, MetLeu, Thr, Asp, Tyr, Lys, Asn, Ser, Ala, Ile, Val, His, or Gin;" (ix) FEATURE: NAME/KEY: Modified-site LOCATION:51 OTHER INFORMATION:/note= "Xaa at Position 51 is Asn, Arg, Met, Pro, Ser, Thr, or his;,, (ix) FEATURE: NAME/KEY: Modified-site LOCATION:52 OTHER INFORMATION:/note= "Xaa at position 52 is Asn, His, Arg, Leu, Gly, Ser, or Thr;"- (ix) FEATURE: NAME/KEY: Modified-site LOCATION:53 OTHER INFORMATION:/note=. "Xaa at position 53 is Leu, Thr, Ala, Gly, Giu, Pro, Lys, Ser, or M..

(ix) FEATURE: NAME/KEY: Modified-site LOCATION:54 OTHER INFORMATION:/note= "Xaa at position 54 is Arg, Asp, Ile, Ser, Val, Thr, Gin, Asn, Lys, His, Ala or Leu;' (ix) FEATURE: NAME/KEY: Modified-site OTHER INFORMATION:/note= "Xaa at position 55 is Arg, Thr, Val, Ser, Leu, or Gly;' (ix) FEATURE: NAME/KEY: Modified-site LOCATION:56 OTHER INFORMATION:/note= "Xaa at position 56 is Pro, Gly, Cys, Ser, Gin, Giu, Arg, His, Thr, Ala, Tyr, Phe, Leu, Val or Lys;" (ix) FEATURE: NAME/KEY:-Modified-site LOCATION:57 OTHER INFORMATION:/note= "Xaa at position 57 is Asn or Gly;" (ix) FEATURE: WO 97/12985 PCT/US96/15774 249 NAME/KEY: Modified-site LOCATION:58 OTHER INFORMATION:/note= "Xaa at position 58 is Leu, Ser, Asp, Arg, Gin, Val, or Cys;' (ix) FEATURE: NAME/KEY: Modified-site LOCATION:59 OTHER INFORMATION:/note= "Xaa at position 59 is Glu, Tyr, His, Leu, Pro, or Arg;'' (ix) FEATURE: NAME/KEY: Modified-site OTHER INFORI4ATION:/note= "Xaa at position 60 is Ala, Ser, Pro, Tyr, Asn, or Thr;"' (ix) FEATURE: NAME/KEY: Modified-site LOCATION:61 OTHER INFORMATION:/note= "Xaa at position 61 is Phe, Asn, Glu, Pro, Lys, Arg, or Ser;" (ix) FEATURE: NAME/KEY: Modified-site LOCATION:62 OTHER INFORMATION:/note= "Xaa at position 62 is Asn, His, Val, Arg, Pro, Thr, Asp, or Ile;" (ix) FEATURE: NAME/KEY: Modified-site LOCATION:63 OTHER INFORMATION:/note= "Xaa at position 63 is Arg, Tyr, Trp, Lys, Ser, His, Pro, or Val;" (ix) FEATURE: NAME/KEY: Modified-site LOCATION:64 OTHER INFORMNJ2ION:/note= "Xaa at position 64 is Ala, Asn, Pro, Ser, or Lys;'' (ix) FEATURE: NAME/KEY: Modified-site OTHER INFORMATION:/note= "Xaa at position 65 is Val, Thr, Pro, His, Leu, Phe, or Ser;" (ix) FEATURE: NAME/KEY: Modified-site LOCATION:66 OTHER INFORMATION:/note= "Xaa at position 66 is Lys, Ile, Arg, Val, Asn, Glu, or Ser;" (ix) FEATURE: WO 97/12985 PCT/US96/157 7 4 250 NAME/KEY: Modified-site LOCATION:67 OTHER INFORMATION:/note= "Xaa at postion 67 is Ser, Ala, Phe, Val, Gly, Asn, Ile, Pro, or His;" (ix) FEATURE: NAME/KEY: Modified-site LOCATION:68 OTHER INFORNATION:/note= "Xaa at position 68_is Leu, Val, Trp, Ser, Ile, Phe, Thr, or His;" (ix) FEATURE: NAME/KEY: Modified-site LOCATION:69 OTHER INFORMATION:/note= "Xaa at position 69 is Gin, Ala, Pro, Thr, Glu, Arg, Trp, Gly, or L." (ix) FEATURE: NAME/KEY: Modified-site OTHER INFORMATION:/note= "Xaa at position 70 is Asn, Leu, Val, Trp, pro, or Ala;" (ix) FEATURE: NAME/KEY: Modified-site LOCATION:71 OTHER INFORMATION:/note= "Xaa at position 71 is Ala, Met, Leu, Pro, Arg, Giu, Thr, Gin, Trp, or Asn;" (ix) FEATURE: NAME/KEY: Modified-site LOCATION:72 OTHER INFORMATION:/note= "Xaa at position 72 is Ser, Giu, Met, Ala, His, Asn, Arg, or Asp;" (ix) FEATURE: NAME/KEY: Modified-site LOCATION:73 OTHER INFORMATION:/note= "Xaa at position 73 is Ala, Giu, Asp, Leu, Ser, Gly, Thr, or Arg;" (ix) FEATURE: NAME/KEY: Modified-site LOCATION:74 OTHER INFOPMATION:/note= "Xaa at position 74'is Ile, Met, Thr, Pro, Arg, Gly, Ala;" (ix) FEATURE: NAME/KEY: Modified-site OTHER INFORMATION:/note= "Xaa at position 75 is Giu, Lys, Gly, Asp, Pro, Trp, Arg, Ser, Gin, or Leu;" (ix) FEATURE: WO 97/12985 PCTIUS96/15774 251 NAME/KEY: Modified-site LOCATION:76 OTHER INFORMATION:/note= "Xaa at position 76 is Ser, Val, Ala, Asn, Trp, Glu, Pro, Gly, or (ix) FEATURE: NAME/KEY: Modified-site LOCATION:77 OTHER INFORMATIQN:/note, "Xaa at Position 77-is Ile, Ser, Arg, Thr, or Leu;" (ix) FEATURE: NAME/KEY: Modified-site LOCATION:78 OTHER INFORMATION:/note= "Xaa at position 78 is Leu, Ala, Ser, Glu, Phe, Gly, or Arg;" (ix) FEATURE: NAME/KEY: Modified-site LOCATION:79 OTHER INFORMATION:/note= "Xaa at position 79 is Lys, Thr, Asn, Met, Arg, Ile, Gly, or Asp;" (ix) FEATURE: NAME/KEY: Modified-site OTHER INFORMATION:/note= "Xaa position at 80 is Asn, Trp, Val, Gly, Thr, Leu, Glu, or Arg;" (ix) FEATURE: NAME/KEY: Modified-site LOCATION:81 OTHER INFORMATION:/note= "Xaa at position 81 is Leu, Gin, Gly, Ala, Trp, Arg, Val, or Lys;" (ix) FEATURE: NAME/KEY: Modified-site LOCATION:82 OTHER INFORMATION:/note= "Xaa at position 82 is Leu, Gin, Lys, Trp, Arg, Asp, Giu, Asn, His, Thr, Ser, Ala, Tyr, Phe, Ile, Met or Val;" (ix) FEATURE: NAME/KEY: Modified-site LOCATION:83 OTHER INFORMATION:/note= "Xaa at position 83 is Pro, Ala, Thr, Trp, Arg, or Met;" (ix) FEATURE: NAME/KEY: Modified-site LOCATION:84 OTHER INFORMATION:/note= 'Xaa at position 84 is Cys, Glu, Gly, Arg, Met, or Val;" WO 97/12985 PCT/UJS96/15 7 7 4 252 (ix) FEATURE: NAME/KEY: Modified-site OTHER INFORMATION:/note= "Xaa at Position 85 is Leu, Asn, Val, or Gin;" (ix) FEATURE: NAME/KEY: Modified-site LOCATION:86 OTHER INFORMATION:/note= "Xaa at Position 86 is Pro, Cys, Arg, Ala, or Lys;,, (ix) FEATURE: NAME/KEY: Modified-site LOCATION:87 OTHER INFORMATION:/note= "Xaa at Position 87 is Leu, Ser, Trp, or Gly;" (ix) FEATURE: NAME/KEY: Modified-site LOCATION:88 OTHER INFORMATION:/note= "Xaa at position 88 is Ala, Lys, Arg, Val, or Trp;" (ix) FEATURE: NAME/KEY: Modified-site LOCATION:89 OTHER INFORMATION:/note= "Xaa at position 89 is Thr, Asp, Cys, Leu, Val, Glu, His, Asn, or (ix) FEATURE: NAME/KEY: Modified-site OTHER INFORMATION:/note= "Xaa at position 90 is Ala, Pro, Ser, Thr, Gly, Asp, Ile, or ,Met;" (ix) FEATURE: NAME/KEY: Modified-site LOCATION:91 OTHER INFORMATION:/note= "Xaa at position 91 is Ala, Pro, Ser, Thr, Phe, Leu, Asp, or His;' (ix) FEATURE: NAME/KEY: modified-site LOCATION:92 OTHER INFORMATION:/note= "Xaa at position 92 is Pro, Phe, Arg, Ser, Lys, His, Ala, Gly, Ile or Leu;" (ix) FEATURE: NAME/KEY: Modified-site LOCATION:93 OTHER INFORMATION:/note= "Xaa at position 93 is Thr, Asp, Ser, Asn, Pro, Ala, Leu, or Arg;" WO 97/1 2985 PCTIUS96/15774 253 (ix) FEATURE: NAME/KEY: Modified-site LOCATION:94 OTHER INFORMATION:/note= "Xaa at Position 94 is Arg, Ile, Ser, Glu, Leu, Val, Gin, Lys, His, Ala, or Pro;" (ix) FEATURE: NAME/KEY: Modified-site OTHER INFORMATION:/niote= "Xaa at position 95 is His, Gin, Pro, Arg, Val, Leu, Giy, Thr, Asn, Lys, Ser, Ala, Trp, Phe, Ile, or Tyr;" (ix) FEATURE: NAME/KEY: Modified-site LOCATION:96 CD) OTHER INFORMATION:/note= "Xaa at Position 96 is Pro, Lys, Tyr, Gly, Ile, or Thr;" (ix) FEATURE: NAME/KEY: Modified-site LOCATION:97 OTHER INFORMATION:/note= 'Xaa at position 97 is Ile, Vai, Lys, Ala, or Asn;" (ix) FEATURE: NAME/KEY: Modified-site LOCATION:98 OTHER INFORMATION:/note= 'Xaa at position 98 is His, Ile, Asn, Leu, Asp, Ala, Thr, Giu, Gin, Ser, Phe, Met, Vai, Lys, Arg, Tyr, or Pro;" (ix) FEATURE: NAME/KEY: Modified-site LOCATION:99 OTHER INFORMATION:/note= "Xaa at position 99 is Ile, Leu, Arg, Asp, Val, Pro, Gin, Gly, Ser, Phe, or His;" (ix) FEATURE: NAME/KEY: Modified-site LOCATION:lOO OTHER INFORMATION:/note= 'Xaa at position 100 is Lys, Tyr, Leu, His, Arg, Ile, Ser, Gin, or (ix) FEATURE: NAME/KEY: Modified-site LOCATION:i0i OTHER INFORMATION:/note= "Xaa at position is Asp, Pro, Met, Lys, His, Thr, Val, Tyr, Giu, Asn, Ser, Ala, Gly, Ile, Leu, or Gin;" WO 97/12985 PCTIUS96/15774 254 (ix) FEATURE: NAME/KEY: Modified-site LOCATION:102 OTHER INFORMATION:/note= "Xaa at position 102 is Gly, Leu, Glu, Lys, Ser, Tyr, or Pro;" (ix) FEATURE: NAME/KEY: Modified-site LOCATION:103 OTHER INFORMATION:/note= "Xaa at position 103 is Asp, or Ser;" (ix) FEATURE: NAME/KEY: Modified-site LOCATION:104 OTHER INFORMATION:/note= "Xaa at position 104 is Trp, Val, Cys, Tyr, Thr, Met, Pro, Leu, Gin, Lys, Ala, Phe, or Gly;" (ix) FEATURE: NAME/KEY: Modified-site LOCATION:105 OTHER INFORMATION:/note= "Xaa at position 105 is Asn, Pro, Ala, Phe, Ser, Trp, Gin, Tyr, Leu, Lys, Ile, Asp, or His;" (ix) FEATURE: NAME/KEY: Modified-site LOCATION:106 OTHER INFORMATION:/note= "Xaa at position 106 is Glu, Ser, Ala, Lys, Thr, Ile, Gly, or Pro;" (ix) FEATURE: NAME/KEY: Modified-site LOCATION:108 OTHER INFORMATION:/note= "Xaa at position 108 is Arg, Lys, Asp, Leu, Thr, Ile, Gin, His, Ser, Ala or Pro;" (ix) FEATURE: NAME/KEY: Modified-site LOCATION:109 OTHER INFORMATION:/note= "Xaa at position 109 is Arg, Thr, Pro, Glu, Tyr, Leu, Ser, or Gly;" (ix) FEATURE: NAME/KEY: Modified-site LOCATION:110 OTHER INFORMATION:/note= "Xaa at position 110 is Lys, Ala, Asn, Thr, Leu, Arg, Gin, His, Glu, Ser, or Trp;" (ix) FEATURE: NAME/KEY: Modified-site LOCATION:111 WO 97/12985 PCTIUS96/1 5774 255 OTHER INFORMATION:/note= "Xaa at position 111 is Leu, Ile, Arg, Asp, or Met;" (ix) FEATURE: NAME/KEY: Modified-site LOCATION:112 OTHER INFORMATION:/note= "Xaa at position 112 is Thr, Val, Gin, Tyr, Glu, His, Ser, or Phe;" (ix) FEATURE: NAME/KEY: Modified-site LOCATION:113 OTHER INFORMATION:/note= "Xaa at position 113 is Phe, Ser, Cys, His, Gly, Trp, Tyr, Asp, Lys, Leu, Ile, Val or Asn;" (ix) FEATURE: NAME/KEY: Modified-site LOCATION:114 OTHER INFORMATION:/note= "Xaa at position 114 is Tyr, Cys, His, Ser, Trp, Arg, or Leu;" (ix) FEATURE: NAME/KEY: Modified-site LOCATION:115 OTHER INFORMATION:/note= "Xaa at position 115 is Leu, Asn, Val, Pro, Arg, Ala, His, Thr, Trp, or Met;" (ix) FEATURE: NAME/KEY: Modified-site LOCATION:116 OTHER INFORMATION:/note= "Xaa at position 116 is Lys, Leu, Pro, Thr, Met, Asp, Val, Glu, Arg, Trp, Ser, Asn, His, Ala, Tyr, Phe, Gin, or Ile;" (ix) FEATURE: NAME/KEY: Modified-site LOCATION:117 OTHER INFORMATION:/note= "Xaa at position 117 is Thr, Ser, Asn, Ile, Trp, Lys, or Pro;" (ix) FEATURE: NAME/KEY: Modified-site LOCATION:118 OTHER INFORMATION:/note= "Xaa at position 118 is Leu, Ser, Pro, Ala, Glu, Cys, Asp, or Tyr;" (ix) FEATURE: NAME/KEY: Modified-site LOCATION:119 OTHER INFORMATION:/note= "Xaa at position 119 is Glu, Ser, Lys, Pro, leu, Thr, Tyr, or Arg;" WO 97/12985 PCTIUS96/1 5774 256 (ix) FEATURE: NAME/KEY: Modified-site OTHER INFORMATION:/note= "Xaa at position 120 is Asn, Ala, Pro, Leu, His, Val, or Gin;" (ix) FEATURE: NAME/KEY: Modified-site LOCATION:121 OTHER INFORMATION:/note= 'Xaa at position 121 is Ala, Ser, Ile, Asn, Pro, Lys, Asp, or Gly;" (ix) FEATURE: NAME/KEY: Modified-site LOCATION:122 OTHER INFORMATION:/note= "Xaa at position 122 is Gin, Ser, Met, Trp, Arg, Phe, Pro, His, Ile, Tyr, or Cys;" (ix) FEATURE: NAME/KEY: Modified-site LOCATION:123 OTHER INFORMATION:/note= "Xaa at position 123 is Aia, Met, Glu, His, Ser, Pro, Tyr, or Leu;" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 2: Ala Pro Met Thr Gin Thr Thr Ser Leu Lys Thr Ser Trp Val Asn Cys 1 5 10 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 25 Xaa Xaa Xaa Xaa Xaa Xaa Asn Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 40 Xaa Xaa Xaa Xaa Xaa Xaa *Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 55 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 70 75 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 90 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Phe Xaa Xaa Xaa Xaa Xaa 100 105 110 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Gin Gin Thr Thr Leu 115 120 125 Ser Leu Ala Ile Phe 130 WO 97/12985 PCT/US96/15774 257 INFORMATION FOR SEQ ID NO: 3: SEQUENCE CHARACTERISTICS: LENGTH: 332 amino acids TYPE: amino acid STRANDEDNESS: unknown TOPOLOGY: unknown (ii) MOLECULE TYPE: protein (ix) FEATURE: NAME/KEY: Modified-site LOCATION:112 OTHER INFORMATION:/note= "position 112 is deleted or Leu, Ala, Val, Ile, Pro, Phe, Trp, or (ix) FEATURE: NAME/KEY: Modified-site LOCATION:113 OTHER INFORMATION:/note= "position 113 is deleted or Pro, Phe, Ala, Leu, Ile, Trp, or Met" (ix) FEATURE: NAME/KEY: Modified-site LOCATION:114 OTHER INFORMATION:/note= "position 114 is deleted or Pro, Phe, Ala, Val, Leu, Ile, Trp or Met" (ix) FEATURE: NAME/KEY: Modified-site LOCATION:115 OTHER INFORMATION:/note= "position 115 is deleted or Gin, Gly, Ser, Thr, Tyr or Asn" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 3: Ser Pro Ala Pro Pro Ala Cys Asp Leu Arg Val Leu Ser Lys Leu Leu 1 5 10 Arg Asp Ser His Val Leu His Ser Arg Leu Ser Gin Cys Pro Glu Val 25 His Pro Leu Pro Thr Pro Val Leu Leu Pro Ala Val Asp Phe Ser Leu 40 Gly Glu Trp Lys Thr Gin Met Glu Glu Thr Lys Ala Gin Asp Ile Leu 55 Gly Ala Val Thr Leu Leu Leu Glu Gly Val Met Ala Ala Arg Gly Gin 70 75 Leu Gly Pro Thr Cys Leu Ser Ser Leu Leu Gly Gln Leu Ser Gly Gin WO 97/12985 WO 97/ 2985PCT/US96/15774 Val Arg Leu Leu Leu Gly Ala Leu Gin Ser Leu Leu Xaa Leu Val1 145 Val Arg Thr Pro Tyr 225 Pro Thr Pro Pro Asp 305 Ser Xaa Ser 130 Gly Pro Thr Gly Gly 210 Leu Gly Ser Ser Pro 290 Pro Tyr Xaa 115 Phe Gly Ser Ser Ser 195 Leu Asn Pro Asp Pro 275 Thr Ser Thr 100 Gly Gin Ser Arg Gly 180 Gly Leu Arg Ser Thr 260 Thr Leu Ala His Arg His Thr Thr 165 Leu Leu Asn Ile Arg 245 Gly His Pro Pro Ser Thr Leu Leu 150 Ser Leu Leu Gin His 230 Arg Ser Pro Thr Thr 310 Gin Thr Leu 135 Cys Leu Glu Lys Thr 215 Glu Thr Leu Pro Pro 295 Pro Asn Ala 120 Arg Val1 Val Thr Trp 200 Ser Leu Leu Pro Thr 280 Val Thr Leu 105 His Gly Arg Leu Asn 185 Gin Arg Leu Gly Pro 265 Gly Val Pro Lys Lys Arg Thr 170 Phe Gin Ser Asn Ala 250 Asn Gin Gin Thr Asp Val Ala 155 Leu Thr Gly Leu Gly 235 Pro Leu Tyr Leu Ser 315 Pro Arg 140 Pro Asn Ala Phe Asp 220 Thr Asp Gin Thr His 300 Pro Gly Thr 110 Asn Ala 125 Phe Ireu Pro Thr Giu Leu Ser Ala 190 Arg Ala 205 Gin Ile Arg Gly Ile Ser Pro Gly 270 Leu Phe 285 Pro Leu Leu Leu Gin Ile Met Thr Pro 175 Arg Lys Pro Leu Ser 255 Tyr Pro Leu Asn Xaa Phe Leu Ala 160 Asri Thr Ile Gly Phe 240 Gly Ser Leu Pro Thr 320 Ser Gin Glu Gly INFORMATION FOR SEQ ID NO: 4: SEQUENCE CHARACTERISTICS: LENGTH: 1 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear WO 97/12985 PCTIUS96/15774 259 (ii) MOLECULE TYPE: protein (ix) FEATURE: NAME/KEY: Protein LOCATION:1 OTHER INFORMATION:/note= "where x=(glyglyglyser)n and where n is an integer" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 4: Xaa 1 INFORMATION FOR SEQ ID NO: SEQUENCE CHARACTERISTICS: LENGTH: 1 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: protein (ix) FEATURE: NAME/KEY: Peptide LOCATION:1 OTHER INFORMATION:/note= "where x=(glyglyglyglyser)n and where n is an integer" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: Xaa 1 INFORMATION FOR SEQ ID NO: 6: SEQUENCE CHARACTERISTICS: LENGTH: 1 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: protein (ix) FEATURE: NAME/KEY: Protein LOCATION:1 OTHER INFORMATION:/note= "where x= WO 97/12985 PCT/US96/15774 260 (glyglyglyglyglyser)n and where n is an integer" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 6: Xaa 1 INFORMATION FOR SEQ ID NO: 7: SEQUENCE CHARACTERISTICS: LENGTH: 1 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: protein (ix) FEATURE: NAME/KEY: Protein LOCATION:1 OTHER INFORMATION:/note= "where x= (gly n ser)n and where n is an integer" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 7: Xaa 1 INFORMATION FOR SEQ ID NO: 8: SEQUENCE CHARACTERISTICS: LENGTH: 1 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: protein (ix) FEATURE: NAME/KEY: Protein LOCATION:1 OTHER INFORMATION:/note= "where x=(alaglyser)n and where n is an integer" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 8: WO 97/12985 PCT/US96/15774 261 INFORMATION FOR SEQ ID NO: 9: SEQUENCE CHARACTERISTICS: LENGTH: 35 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) Gly 1 Glu SEQUENCE DESCRIPTION: SEQ ID NO: 9: Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser Glu Gly Gly Ser 5 10 Gly Gly Gly Ser Glu Gly Gly Gly Ser Glu Gly Gly Gly Ser Gly 25 Gly Gly Ser INFORMATION FOR SEQ ID NO: SEQUENCE CHARACTERISTICS: LENGTH: 24 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO: Ile Ser Glu Pro Ser Gly Pro Ile Ser Thr Ile Asn Pro Ser Pro Thr 1 5 10 Ser Lys Glu Ser His Lys Ser Pro INFORMATION FOR SEQ ID NO: 11: SEQUENCE CHARACTERISTICS: LENGTH: 28 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: protein WO 97/12985 PCTIUS96/15774 262 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 11: Ile Glu Gly Arg Ile Ser Glu Pro Ser Gly Pro Ile Ser Thr Ile Asn 1 5 10 Pro Ser Pro Pro Ser Lys Glu Ser His Lys Ser Pro INFORMATION FOR SEQ ID NO: 12: SEQUENCE

CHARACTERISTICS:

LENGTH: 4 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 12: Gly Gly Gly Ser 1 INFORMATION FOR SEQ ID NO: 13: SEQUENCE

CHARACTERISTICS:

LENGTH: 45 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 13: ACGTCCATGG CNTCNCCNGC NCCNCCTGCT TGTGCACTCC

GAGTC

INFORMATION FOR SEQ ID NO: 14: SEQUENCE

CHARACTERISTICS:

LENGTH: 30 base pairs TYPE: nucleic acid WO 97/12985 PCT/US96/15774 263 STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 14: ATGCACGAAT TCCCTGACGC

AGAGGGTGGA

INFORMATION FOR SEQ ID NO: SEQUENCE CHARACTERISTICS: LENGTH: 33 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: TGACAAGCTT ACCTGACGCA GAGGGTGGAC

CCT

33 INFORMATION FOR SEQ ID NO: 16: SEQUENCE CHARACTERISTICS: LENGTH: 10 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 16:

AATTCGGCAA

INFORMATION FOR SEQ ID NO: 17: WO 97/12985 PCT/US96/15774 264 SEQUENCE CHARACTERISTICS: LENGTH: 10 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 17:

CATGTTGCCG

INFORMATION FOR SEQ ID NO: 18: SEQUENCE CHARACTERISTICS: LENGTH: 13 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 18: AATTCGGCGG

CAA

13 INFORMATION FOR SEQ ID NO: 19: SEQUENCE

CHARACTERISTICS:

LENGTH: 13 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 19: CATGTTGCCG

CCG

13 WO 97/12985 PCT/US96/15774 265 INFORMATION FOR SEQ ID NO: SEQUENCE CHARACTERISTICS: LENGTH: 22 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: AATTCGGCGG CAACGGCGGC

AA

22 INFORMATION FOR SEQ ID NO: 21: SEQUENCE

CHARACTERISTICS:

LENGTH: 22 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 21: CATGTTGCCG CCGTTGCCGC

CG

22 INFORMATION FOR SEQ ID NO: 22: SEQUENCE

CHARACTERISTICS:

LENGTH: 27 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 22: WO 97/12985 PCT/US96/15774 266 CGATCCATGG AGGTTCACCC

TTTGCCT

27 INFORMATION FOR SEQ ID NO: 23: SEQUENCE CHARACTERISTICS: LENGTH: 29 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 23: GATCAAGCTT ATGGGCACTG

GCTCAGTCT

29 INFORMATION FOR SEQ ID NO: 24: SEQUENCE CHARACTERISTICS: LENGTH: 27 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 24: CGATACATGT TGCCTACACC

TGTCCTG

27 INFORMATION FOR SEQ ID NO: SEQUENCE CHARACTERISTICS: LENGTH: 29 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)" WO 97/12985 PCT/US96/15774 267 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: GATCAAGCTT AAGGGTGAAC CTCTGGGCA 29 INFORMATION FOR SEQ ID NO: 26: SEQUENCE CHARACTERISTICS: LENGTH: 27 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 26: CGATCCATGG TCCTGCTGCC TGCTGTG 27 INFORMATION FOR SEQ ID NO: 27: SEQUENCE CHARACTERISTICS: LENGTH: 29 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 27: GATCAAGCTT AAGGTGTAGG CAAAGGGTG 29 INFORMATION FOR SEQ ID NO: 28: SEQUENCE CHARACTERISTICS: LENGTH: 30 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid WO 97/12985 PCT/US96/15774 268 DESCRIPTION: /desc "DNA (synthetic)" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 28: CGATCCATGG CTGTGGACTT

TAGCTTGGGA

INFORMATION FOR SEQ ID NO: 29: SEQUENCE

CHARACTERISTICS:

LENGTH: 29 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 29: GATCAAGCTT AAGGCAGCAG

GACAGGTGT

29 INFORMATION FOR SEQ ID NO: SEQUENCE

CHARACTERISTICS:

LENGTH: 27 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: CGATCCATGG ACTTTAGCTT

GGGAGAA

27 INFORMATION FOR SEQ ID NO: 31: SEQUENCE CHARACTERISTICS: LENGTH: 29base pairs TYPE: nucleic acid STRANDEDNESS: single WO 97/12985 PCT/US96/15774 269 TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 31: GATCAAGCTT ACACAGCAGG CAGCAGGAC 29 INFORMATION FOR SEQ ID NO: 32: SEQUENCE CHARACTERISTICS: LENGTH: 27 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 32: CGATCCATGG GAGAATGGAA AACCCAG 27 INFORMATION FOR SEQ ID NO: 33: SEQUENCE CHARACTERISTICS: LENGTH: 29 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 33: GATCAAGCTT ACAAGCTAAA

GTCCACAGC

29 INFORMATION FOR SEQ ID NO: 34: SEQUENCE CHARACTERISTICS: WO 97/12985 PCT/US96/157 7 4 270 LENGTH: 27 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 34: CGATCCATGG GACCCACTTG

CCTCTCA

27 INFORMATION FOR SEQ ID NO: SEQUENCE CHARACTERISTICS: LENGTH: 29 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: GATCAAGCTT ACAGTTGTCC

CCGTGCTGC

29 INFORMATION FOR SEQ ID NO: 36: SEQUENCE

CHARACTERISTICS:

LENGTH: 27 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 36: CAGTCCATGG GAACCCAGCT

TCCTCCA

27 WO 97/12985 PCT/US96/15774 271 INFORMATION FOR SEQ ID NO: 37: SEQUENCE CHARACTERISTICS: LENGTH: 29 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 37: GATCAAGCTT AAAGGAGGCT

CTGCAGGGC

29 INFORMATION FOR SEQ ID NO: 38: SEQUENCE

CHARACTERISTICS:

LENGTH: 27 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 38: CGATCCATGG GCAGGACCAC

AGCTCAC

27 INFORMATION FOR SEQ ID NO: 39: SEQUENCE CHARACTERISTICS: LENGTH: 30 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 39: WO 97/12985 PCTIUS96/1 5774 272 GATCAAGCTT ACTGTGGAGG AAGCTGGGTT INFORMATION FOR SEQ ID NO: SEQUENCE CHARACTERISTICS: LENGTH: 30 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: CGATCCATGG CTCACAAGGA TCCCAATGCC INFORMATION FOR SEQ ID NO: 41: SEQUENCE CHARACTERISTICS: LENGTH: 29 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 41: GATCAAGCTT ATGTGGTCCT GCGCTGTGG 29 INFORMATION FOR SEQ ID NO: 42: SEQUENCE CHARACTERISTICS: LENGTH: 30 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)" WO 97/12985 PCT/US96/15774 273 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 42: CGATCCATGG ATCCCAATGC CATCTTCCTG INFORMATION FOR SEQ ID NO: 43: SEQUENCE CHARACTERISTICS: LENGTH: 29 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 43: GATCAAGCTT ACTTGTGAGC TGTGGTCCT 29 INFORMATION FOR SEQ ID NO: 44: SEQUENCE CHARACTERISTICS: LENGTH: 30 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 44: CGATCCATGG CCATCTTCCT GAGCTTCCAA INFORMATION FOR SEQ ID NO: SEQUENCE CHARACTERISTICS: LENGTH: 32 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)" WO 97/12985 PCT/US96/15774 274 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: GATCAAGCTT AATTGGGATC CTTGTGAGCT

GT

32 INFORMATION FOR SEQ ID NO: 46: SEQUENCE CHARACTERISTICS: LENGTH: 83 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic); (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 46: AATTCCGTCG TAAACTGACC TTCTATCTGA AAACCTTGGA GAACGCGCAG

GCTCAACAGT

ACGTAGAGGG CGGTGGAGGC TCC 83 INFORMATION FOR SEQ ID NO: 47: SEQUENCE CHARACTERISTICS: LENGTH: 83 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 47: CCGGGGAGCC TCCACCGCCC TCTACGTACT GTTGAGCCTG CGCGTTCTCC

AAGGTTTTCA

GATAGAAGGT CAGTTTACGA

CGG

83 INFORMATION FOR SEQ ID NO: 48: WO 97/12985 PCT/US96/1 5774 275 SEQUENCE CHARACTERISTICS: LENGTH: 59 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 48: GTTACCCTTG AGCAAGCGCA GGAACAACAG GGTGGTGGCT CTAACTGCTC TATAATGAT 59 INFORMATION FOR SEQ ID NO: 49: SEQUENCE CHARACTERISTICS: LENGTH: 56 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 49: CGATCATTAT AGAGCAGTTA GAGCCACCAC CCTGTTGTTC CTGCGCTTGC TCAAGG 56 INFORMATION FOR SEQ ID NO: SEQUENCE CHARACTERISTICS: LENGTH: 80 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: WO 97/12985 PCT/US96/15774 276 GTTACCCTTG AGCAAGCGCA GGAACAACAG GGTGGTGGCT CTGGCGGTGG

CAGCGGCGGC

GGTTCTAACT GCTCTATAAT INFORMATION FOR SEQ ID NO: 51: SEQUENCE CHARACTERISTICS: LENGTH: 80 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 51: CGATCATTAT AGAGCAGTTA GAACCGCCGC CGCTGCCACC GCCAGAGCCA

CCACCCTGTT

GTTCCTGCGC TTGCTCAAGG INFORMATION FOR SEQ ID NO: 52: SEQUENCE CHARACTERISTICS: LENGTH: 30 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 52: GATCGACCAT GGCTCTGGAC CCGAACAACC INFORMATION FOR SEQ ID NO: 53: SEQUENCE CHARACTERISTICS: LENGTH: 28 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear WO 97/12985 PCT/US96/15774 277 (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 53: CTCGATTACG TACAAAGGTG

CAGGTGGT

28 INFORMATION FOR SEQ ID NO: 54: SEQUENCE CHARACTERISTICS: LENGTH: 32 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 54: GATCGACCAT GGCTAATGCA TCAGGTATTG

AG

32 INFORMATION FOR SEQ ID NO: SEQUENCE CHARACTERISTICS: LENGTH: 28 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: CTCGATTACG TATTCTAAGT

TCTTGACA

28 INFORMATION FOR SEQ ID NO: 56: SEQUENCE CHARACTERISTICS: LENGTH: 32 base pairs WO 97/12985 PCT/US96/15774 278 TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 56: GATCGACCAT GGCTGCACCC TCTCGACATC

CA

32 INFORMATION FOR SEQ ID NO: 57: SEQUENCE

CHARACTERISTICS:

LENGTH: 28 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 57: CTCGATTACG TAGGCCGTGG

CAGAGGGC

28 INFORMATION FOR SEQ ID NO: 58: SEQUENCE

CHARACTERISTICS:

LENGTH: 32 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 58: GATCGACCAT GGCTGCAGGT GACTGGCAAG

AA

32 INFORMATION FOR SEQ ID NO: 59: WO 97/12985 PCT/US96/15774 279 SEQUENCE CHARACTERISTICS: LENGTH: 28 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 59: CTCGATTACG TACTTGATGA

TGATTGGA

28 INFORMATION FOR SEQ ID NO: SEQUENCE CHARACTERISTICS: LENGTH: 54 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: GCTCTGAGAG CCGCCAGAGC CGCCAGAGGG CTGCGCAAGG TGGCGTAGAA

CGCG

54 INFORMATION FOR SEQ ID NO: 61: SEQUENCE

CHARACTERISTICS:

LENGTH: 54 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 61: WO 97/12985 PCT/US96/15774 280 CAGCCCTCTG GCGGCTCTGG CGGCTCTCAG AGCTTCCTGC TCAAGTCTTT

AGAG

54 INFORMATION FOR SEQ ID NO: 62: SEQUENCE

CHARACTERISTICS:

LENGTH: 18 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 62: GGGCTGCGCA

AGGTGGCG

18 INFORMATION FOR SEQ ID NO: 63: SEQUENCE CHARACTERISTICS: LENGTH: 21 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 63: ACACCATTGG GCCCTGCCAG

C

21 INFORMATION FOR SEQ ID NO: 64: SEQUENCE

CHARACTERISTICS:

LENGTH: 32 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)" WO 97/12985 PCT/US96/15774 281 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 64: GATCGACCAT GGCTTACAAG CTGTGCCACC

CC

32 INFORMATION FOR SEQ ID NO: SEQUENCE CHARACTERISTICS: LENGTH: 36 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: CGATCGAAGC TTATTAGGTG GCACACAGCT

TCTCCT

36 INFORMATION FOR SEQ ID NO: 66: SEQUENCE CHARACTERISTICS: LENGTH: 32 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 66: GATCGACCAT GGCTCCCGAG TTGGGTCCCA

CC

32 INFORMATION FOR SEQ ID NO: 67: SEQUENCE CHARACTERISTICS: LENGTH: 36 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)" WO 97/12985 PCT/US96/15774 282 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 67: CGATCGAAGC TTATTAGGAT ATCCCTTCCA

GGGCCT

36 INFORMATION FOR SEQ ID NO: 68: SEQUENCE

CHARACTERISTICS:

LENGTH: 32 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic) (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 68: GATCGACCAT GGCTATGGCC CCTGCCCTGC

AG

32 INFORMATION FOR SEQ ID NO: 69: SEQUENCE

CHARACTERISTICS:

LENGTH: 36 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 69: CGATCGAAGC TTATTATCCC AGTTCTTCCA

TCTGCT

36 INFORMATION FOR SEQ ID NO: SEQUENCE

CHARACTERISTICS:

LENGTH: 32 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear WO 97/12985 PCT/US96/15774 283 (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: GATCGACCAT GGCTACCCAG GGTGCCATGC

CG

32 INFORMATION FOR SEQ ID NO: 71: SEQUENCE CHARACTERISTICS: LENGTH: 36 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 71: CGATCGAAGC TTATTAGGGC TGCAGGGCAG

GGGCCA

36 INFORMATION FOR SEQ ID NO: 72: SEQUENCE CHARACTERISTICS: LENGTH: 36 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 72: CGATCGAAGC TTATTAGGGC TGCAGGGCAG

GGGCCA

36 INFORMATION FOR SEQ ID NO: 73: SEQUENCE CHARACTERISTICS: LENGTH: 36 base pairs WO 97/12985 PCT/US96/15774 284 TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 73: CGATCGAAGC TTATTAGGCG AAGGCCGGCA

TGGCAC

36 INFORMATION FOR SEQ ID NO: 74: SEQUENCE CHARACTERISTICS: LENGTH: 21 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 74: GTAGAGGGCG GTGGAGGCTC

C

21 INFORMATION FOR SEQ ID NO: SEQUENCE CHARACTERISTICS: LENGTH: 25 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: CCGGGGAGCC TCCACCGCCC

TCTAC

INFORMATION FOR SEQ ID NO: 76: WO 97/12985 PCT/US96/15774 285 SEQUENCE CHARACTERISTICS: LENGTH: 53 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 76: TTCTACGCCA CCTTGCGCAG CCCGGCGGCG GCTCTGACAT GTCTACACCA

TTG

53 INFORMATION FOR SEQ ID NO: 77: SEQUENCE CHARACTERISTICS: LENGTH: 53 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 77: CAATGGTGTA GACATGTCAG AGCCGCCGCC GGGCTGCGCA AGGTGGCGTA

GAA

53 INFORMATION FOR SEQ ID NO: 78: SEQUENCE CHARACTERISTICS: LENGTH: 439 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 78: WO 97/12985 PCT/US96/1577 4 OCTAACTGCT CTATAATGAT CGATGAATT ATACATCACT TAAAGAGACC

ACCTGCACCT

TTGCTGGACC CGAACAACCT CAATGACGAJA GACGTCTCTA TCCTGATGGA

CCGAAACCTT

120 CGACTTCCAA ACCTGGAGAG CTTCGTAAGG GCTGTCAAGA ACTTAGAAA

TGCATCAGGT

180 ATTGAGGCAA TTCTTCGTAA TCTCCAJACCA TGTCTGCCCT CTGCCACGGC

CGCACCCTCT

240 CGACATCCAA TCATCATCA GGCAGGTGAC TGGCAAGAAT TCCGGGAAA

ACTGACGTTC

300 TATCTGGTTA CCCTTGAGCA AGCGCAGGAA CAACAGTACG TAGAGGGCGG

TGGAGGCTCC

360 CCGGGTGAAC CGTCTGGTCC AATCTCTACT ATCAACCCGT CTCCTCCGtt-

TAAAGAATCT

420 CATAAATCTC

CAAACATGT

439 INFORMATION FOR SEQ ID NO: 79: SEQUENCE

CHARACTERISTICS:

LENGTH: 465 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 79: TCCCCAGCTC CACCTGCTTG TGACCTCCGA GTCCTCAGTA

AACTGCTTCG

GTCCTTCACA GCAGACTGAG CCAGTGCCCA GAGGTTCACC

CTTTGCCTAC

120 CTGCCTGCTG TGGACTTTAG CTTGGGAGAA TGGAAAACCC

AGATGGAGGA

180 CAGGACATTC TGGGAGCAGT GACCCTTCTG CTGGAGGGAG

TGATGGCAGC

240 CTGGGACCCA CTTGCCTCTC ATCCCTCCTG GGGCAGCTTT

CTGGACAGGT

300 TGACTCC

CAT

ACCTGTCCTG

GACCAAGGCA

ACGGGGACAA

CCGTCTCCTC

WO 97/12985 PCTIUS96/15774 287 CTTGGGGCCC TGCAGAGCCT CCTTGGAACC CAGCTTCCTC CACAGGOCAG

GACCACAGCT

360 CACAAGGATC CCAATGCCAT CTTCCTGA.GC TTCCAACACC TGCTCCGAGG

AAAGGTGCGT

420 TTCCTGATGC TTGTAGGAGG GTCCACCCTC TGCGTCAGGG

AATTC

465 INFORMATION FOR SEQ ID NO: W(i SEQUENCE

CHARACTERISTICS:

LENGTH: 927 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: TCCCCAGCTC CACCTGCTTG TGACCTCCGA GTCCTCAGTA AACTGCTTCG

TGACTCCCAT

GTCCTTCACA

120

CTGCCTGCTG

180

CAGGACATTC

240

CTGGGACCCA

300

CTTGGGGCCC

360

CACAAGGATC

420

TTCCTGATGC

480

TCTCCCGCTC

540

GCAGACTGAG

TGGACTTTAG

TGGGAGCAGT

CTTGCCTCTC

TGCAGAGCCT

CCAATGCCAT

TTGTAGGAGG

CGCCTGCTTG

CCAGTGCCCA

CTTGGGAGAA

GACCCTTCTG

ATCCCTCCTG

CCTTGGAACC

CTTCCTGAGC

GTCCACCCTC

TGACCTCCGA

GAGGTTCACC

TGGAAAACCC

CTGGAGGGAG

GGGCAGCTTT

CAGCTTCCTC

TTCCAACACC

TGCGTCAGGG

GTCCTCAGTA

CTTTGCCTAC

AGATGGAGGA

TGATGGCAGC

CTGGACAGGT

CACAGGGCAG

TGCTCCGAGG

AATTCGGCGG

AACTGCTTCG

ACCTGTCCTG

GACCAAGGCA

ACGGGGACAA

CCGTCTCCTC

GACCACAGCT

AAAGGTGCGT

CAACATGGCG

TGACTCCCAT

WO 97/12985 PCTIUS96/1 5774 GTCCTTCACA GCAGACTGAG CCAGTGCCCA GAGGTTCACC

CTTTGCCTAC

600 CTGCCTGCTG TGGACTTTAG CTTGGGAGAA TGGAAAACCC

AGATGGAGGA

660 CAGGACATTC TGGGAGCAGT GACCCTTCTG CTGGAGGGAG

TGATGGCAGC

720 CTGGGACCCA CTTGCCTCTC ATCCCTCCTG GGGCAGCTTT

CTGGACAGGT

780 CTTGGGGCCC TGCAGAGCCT CCTTGGAACC CAGGGCAGGA

CCACAGCTCA

840 AATGCCATCT TCCTGAGCTT CCAACACCTG CTCCGAGGAA

AGGTGCGTTT

900 GTAGGAGGGT CCACCCTCTG

CGTCAGG

927 INFORMATION FOR SEQ ID NO: 81: SEQUENCE

CHARACTERISTICS:

LENGTH: 936 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)"

ACCTGTCCTG

GACCAAGGCA

ACGGGGACAA

CCGTCTCCTC

CAAGGATCCC

CCTGATGCTT

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 81: TCCCCAGCTC CACCTGCTTG TGACCTCCGA GTCCTCAGTA

AACTGCTTCG

GTCCTTCACA GCAGACTGAG CCAGTGCCCA GAGGTTCACC

CTTTGCCTAC

120 CTGCCTGCTG TGGACTTTAG CTTGGGAGAA TGGAAAACCC

AGATGGAGGA

180 CAGGACATTC TGGGAGCAGT GACCCTTCTG CTGGAGGGAG

TGATGGCAGC

240 CTGGGACCCA CTTGCCTCTC ATCCCTCCTG GGGCAGCTTT

CTGGACAGGT

300 CTTGGGGCCC TGCAGAGCCT CCTTGGAACC CAGCTTCCTC

CACAGGGCAG

360

TGACTCCCAT

ACCTGTCCTG

GACCAAGGCA

ACGGGGACAA

CCGTCTCCTC

GACCACAGCT

WO 97/1 2985 PCT/US96'1 5774 289 CACAAGGATC CCAATGCCAT CTTCCTGAGC TTCCAACACC TGCTCCGAGG

AAAGGTGCGT

420

TTCCTGATGC

480

CCCGCTCCGC

540

CTTCACAGCA

600

CCTGCTGTGG

660

GACATTCTGG

720

GGACCCACTT

780

GGGGCCCTGC

840

AAGGATCCCA

900

CTGATGCTTG

936

TTGTAGGAGG

CTGCTTGTGA

GACTGAGCCA

ACTTTAGCTT

GAGCAGTGAC

GCCTCTCATC

AGAGCCTCCT

ATGCCATCTT

TAGGAGGGTC

GTCCACCCTC

CCTCCGAGTC

GTGCCCAGAG

GGGAGAATGG

CCTTCTGCTG

CCTCCTGGGG

TGGAACCCAG

CCTGAGCTTC

TGCGTCAGGG

CTCAGTAAAC

GTTCACCCTT

AAAACCCAGA.

GAGGGAGTGA

CAGCTTTCTG

CTTCCTCCAC

CAACACCTGC

AATTCGGCAA~

TGCTTCGTGA

TGCCTACACC

TGGAGGAGAC

TGGCAGCACG

GACAGGTCCG

AGGGCAGGAC

TCCGAGGAAA

CATGGCGTCT

CTCCCATGTC

TGTCCTGCTG

CAAGGCACAG

GGGACAACTG

TCTCCTCCTT

CACAGCTCAC

GGTGCGTTTC

CACCCTCTGC GTCAGG INFORMATION FOR SEQ ID NO: 82: SEQUENCE

CHARACTERISTICS:

LENGTH: 939 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 82: TCCCCAGCTC CACCTGCTTG TGACCTCCGA GTCCTCAGTA AACTGCTTCG

TOACTOCCAT

GTCCTTCACA GCAGACTGAG CCAGTGCCCA GAGGTTCACC CTTTGCCTAC

ACCTGTCCTG

120 WO 97/12985 PCTIUS96/1577 4

CTGCCTGCTG

180 TGGACTTTAG CTTGGGAGAA~ TGGAAAACC AGATGGAGGA

GACCAAGGCA

CAGGACATTC

240

CTGGGACCCA

300

CTTGGGGCCC

360

CACAAGGATC

420

TTCCTGATGC

480

TCTCCCGCTC

540

GTCCTTCACA

600

CTGCCTGCTG

660

CAGGACATTC

720

CTGGGACCCA

780

CTTGGGGCCC

840

CACAAGGATC

900

TGGGAGCAGT

CTTGCCTCTC

TGCAGAGCCT

CCAATGCCAT

TTGTAGGAGG

CGCCTGCTTG

GCAGACTGAG

TGGACTTTAG

TGGGAGCAGT

CTTGCCTCTC

TGCAGAGCCT

CCAATGCCAT

GACCCTTCTG

ATCCCTCCTG

CCTTGGAACC

CTTCCTGAGC

GTCCACCCTC

TGACCTCCGA

CCAGTGCCCA

CTTGGGAGAA

GACCCTTCTG

ATCCCTCCTG

CCTTGGAACC

CTTCCTGAGC

CTGGAGGGAG

GGGCAGCTTT

CAGCTTCCTC

TTCCAACACC

TGCGTCAGGG

GTCCTCAGTA

GAGGTTCACC

TGGAAAACCC

CTGGAGGGAG

GGGCAGCTTT

CAGCTTCCTC

ETCCAACACC

TGATGGCAGC

CTGGACAGGT

CACAGGGCAG

TGCTCCGAGG

AATTCGGCGG

AACTGCTTCG

CTTTGCCTAC

AGATGGAGGA

TGATGGCAGC

CTGGACAGGT

CACAGGGCAG

rGCTCCGAGG

ACGGGGACAA

CCGTCTCCTC

GACCACAGCT

AAAGGTGCGT

CAACATGGCG

TGACTCCCAT

ACCTGTCCTG

GACCAAGGCA

ACGGGGACAA

CCGTCTCCTC

GACCACAGCT

kAAGGTGCGT TTCCTGATGC TTGTAGGAGG GTCCACCCTC

TGCGTCAGG

939 INFORMATION FOR SEQ ID NO: 83: Wi SEQUENCE

CHARACTERISTICS:

LENGTH: 948 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY:. linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)" WO 97/12985 PCTIUS96/1 5774 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 83: TCCCCAGCGC CGCCTGCTTG TGACCTCCGA GTCCTCAGTA AACTGCTTCG

TGACTCCCAT

GTCCTTCACI

120

CTGCCTGCTC

180

CAGGACATTC

240

CTGGGACCCA

300

CTTGGGGCCC

360

CACAAGGATC

420

TTCCTGATGC

480

AACATGGCGT

540

GACTCCCATG

600

CCTGTCCTC

660

ACCAAGGCAC

720

CGGGGACAAC

780

CGTCTCCTCC

840

ACCACAGCTC

900

~GCAGACTGAC

TGGACTTTAG

TGGGAGCAGT

CTTGCCTCTC

TGCAGAGCCT

CCAATGCCAT

TTGTAGGAGG

CCCCAGCGCC

TCCTTCACAG

TGCCTGCTGT

AGGACATTCT

TGGGACCCAC

TTGGGGCCCT

CCAGTGCCCA GAGGTTCAC(

CTTGGGAGAI

GACCCTTCTC

ATCCCTCCTG

CCTTGGAACC

CTTCCTGAGC

GTCCACCCTC

GCCTGCTTGT

CAGACTGAGC

GGACTTTAGC

GGGAGCAGTG

TTGCCTCTCA

GCAGAGCCTC

TGGAAAACCc

CTGGAGGGAC

GGGCAGCTT'I

CAGCTTCCTC

TTCCAACACC

TGCGTCAGGG

GACCTCCGAG

CAGTGCCCAG

TTGGGAGAAT

ACCCTTCTGC

TCCCTCCTGG

CTTGGAAcC

TTCCTGAGCT

CTTTGCCTAC

AGATGGAGG;

TGATGGCAGC

CTGGACAGGT

CACAGGGCAG

TGCTCCGAOG

AATTCGGCGG

TCCTCAGTA

AGGTTCACCC

GGAAAACCCA

TGGAGGGAGT

GGCAGCTTTC

AGCTTCCTCC

TCCAACACCT

-ACCTGTCCTG

GACCAAGGCA

ACGGGGACAA

CCGTCTCCTC

GACCACAGCT

AAAGGTGCGT

CAACGGCGGC

ACTGCTTCGT

TTTGCCTACA

GATGGAGGAG

GATGGCAGCA

TGGACAGGTC

ACAGGGCAGG

GCTCCGAGGA

ACAAGGATCC

CAATGCCATC

AAGGTGCGTT TCCTGATGCT TGTAGGAGGG TCCACCCTCT

GCGTCAGG

948 INFORMATION FOR SEQ ID NO: 84: WO 97/12985 PCTJUS96/15774 292 Mi SEQUENCE CHARACTERISTICS: LENGTH: 688 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc ="DNA (synthetic)" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 84: CATGGCTAAC TGCTCTATAA. TGATCGATGA AATTATACAT CACTTAAAGA

GACCACCTGC

ACCTTTGCTG

120

CCTTCGACTT

180

AGGTATTGAG

240

CTCTCGACAT

300

GTTCTATCTG,

360

TATAATGATC

420

GAACAACCTC

480

CCTGGAGAGC

540

TCTTCGTAAT

600

CATCATCAAG

660

CCTTGAGCAA

688

GACCCGAACA

CCAAACCTGG

GCAATTCTTC

CCAATCATCA

GTTACCCTTG

GATGAAATTA

AATGACGAAG

TTCGTAAGGG

CTCCAACCAT

GCAGGTGACT

GCGCAGGAAC

ACCTCAATGA

AGAGCTTCGT

GTAATCTCCA

TCAAGGCAGG

AGCAAGCGCA

TACATCACTT

ACGTCTCTAT

CTGTCAAGAA

GTCTGCCCTC

GGCAAGAATT

AACAGTAC

CGAAGACGTC

AAGGGCTGTC

ACCATGTCTG

TGACTGGCAA

GGAACAACAG

AAAGAGACCA

CCTGATGGAC

CTTAGAAAAT

TGCCACGGCC

CCGGGAAAAA

TCTATCCTGA

AAGAACTTAG

CCCTCTGCCA

GAATTCCGGG

GGTGGTGGCT

CCTGCACCTT

CGAAACCTTC

GCATCAGGTA

GCACCCTCTC

CTGACGTTCT

TGGACCGAAA

AAAATGCATC

CGGCCGCACC

AAAAACTGAC

CTAACTGCTC

TGCTGGACCC

GACTTCCAAA

TTGAGGCAAT

GACATCCAAT

ATCTGGTTAC

INFORMATION FOR SEQ ID NO: Wi SEQUENCE CHARACTERISTICS: LENGTH: 712 base pairs WO 97/12985 PCT/US96/1577 4 293 TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: CATGGCTAAC TGCTCTATA TGATCGATGA AATTATACAT

CACTTAAAGA

GACCACCTGC

ACCTTTGCTG GACCCGAACA ACCTCAATGA CGAAGACGTC TCTATCCTGA

TGGACCGAAA

120

CCTTCGACTT

180

AGGTATTGAG

240

CTCTCGACAT

300

GTTCTATCTG

360

CAGCGGCGGC

420

ACCACCTGCA

480

GGACCGAAAC

540

AAATGCATCA

600

GGCCGCACCC

660

AAAACTGACG

712

CCAAACCTGG

GCAATTCTTC

CCAATCATCA

GTTACCCTTG

GGTTCTAACT

CCTTTGCTGG

CTTCGACTTC

GGTATTGAGG

TCTCGACATC

TTCTATCTGG

AGAGCTTCGT

GTAATCTCCA

TCAAGGCAGG

AGCAAGCGCA

GCTCTATAAT

ACCCGAACAA

CAAACCTGGA

CAATTCTTCG,

CAATCATCAT

AAGGGCTGTC

ACCATGTCTG

TGACTGGCAA

GGAACAACAG

OATCGATGAA

CCTCAATGAC

GAGCTTCGTA

TAATCTCCAA

CAAGGCAGGT

AAGAACTTA

CCCTCTGCCA

GAATTCCGGG

GGTGGTGGCT

ATTATACATC

GAAGACGTCT

AGGGCTGTCA

CCATGTCTGC

GACTGGCAAG

AAAATGCATC

CGGCCGCACC

AAAAACTGAC

CTGGCGGTGG

ACTTAAAGAG

CTATCCTGAT

AGAACTTAGA.

CCTCTGCCAC

AATTCCGGGA.

TTACCCTTGA GCA.AGCGCAG, GAACAACAGT

AC

INFORMATION FOR SEQ ID NO: 86: Wi SEQUENCE

CHARACTERISTICS:

LENGTH: 975 base pairs TYPE: nucleic acid STRANDEDNESS: single WO 97/12985 PCT/US96/1 5774 TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 86: ATGGCTCTGG ACCCGAACAA CCTCAATGAC GAAGACGTCT

CTATCCTGAT

CTTCGACTTC CAAACCTGGA GAGCTTCGTA AGCGCTGTCA

AGAACTTAGA

120 GGTATTGACG CAATTCTTC!G TAATCTCCAA CCATGTCTGC

CCTCTGCCAC

180

GGACCGAAAC

AAATGCATCA

GGCCGCACCC

TCTCGACATC

240

TTCTATCTGG

300

ATAATGATCG

360

GGCGGTGGAG

420

CCGTCTAAAG

480

GCCTCTGCTT

540

CTGGAGGTGT

600

TCTCAGAGCT

660

GCGCTCCAGG

720

CTCGGACACT

780

CAGCTGGCAG

840

CAGGCCCTGG

900 CAATCATCAT CAAGGCAGG1

TTACCCTTGA

ATGAAATTAT

GCTCCCCGGG

AATCTCATAA

TCCAGCGCCG

CGTACCGCGT

TCCTGCTCAA

AGAAGCTGTG

CTCTGGGCAT

GCTGCTTGAG

GCAAGCGCAC

ACATCACTTA

TGAACCGTCT

ATCTCCAAAC

GGCAGGAGGG

TCTACGCCAC

GTCTTTAGAG

TGCCACCTAC

CCCCTGGGCT

CCAACTCCAT

GACTGGCAAc

GAACAACAGC

AAGAGACCAC

GGTCCAATCT

ATGGCTACCC

GTCCTGGTTG,

CTTGCGCAGC

CAAGTGAGAA

AAGCTGTGCC

CCCCTGAGCT

AGCGGCCTTT

AATTCCGGGP

GTGGTGGCTC

CTGCACCTTT

CTACTATCA

AGGGTGCCAT

CTAGCCATCT

CCTCTGGCGG

AGATCCAGGG

ACCCCGAGGA

CCTGCCCCAG

TCCTCTACCA

LAAAACTGACG

TAACTGCTCT

GTACGTAGAG

CCCGTCTCCT

GCCGGCCTTC

GCAGAGCTTC

CTCTGGCGGC

CGATGGCGCA

GCTGGTGCTG

CCAGGCCCTG

GGGGCTCCTG

AAGGGATATC CCCCGAGTTG GGTCCCACCT TGGACACACT

GCAGCTGGAC

WO 97/12985 PCTIUS96/15774 295 GTCGCCGACT TTGCCACCAC CATCTGGCAG CAGATGGAAG AACTGGGAAT

GGCCCCTGCC

960 CTGCAGCCCT

AATAA

975 INFORMATION FOR SEQ ID NO: 87: WI SEQUENCE

CHARACTERISTICS:

LENGTH: 975 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 87:

ATGGCTCTGG

CTTCGACTTC

120

GGTATTGAGG

180

TCTCGACATC

240

TTCTATCTGG

300

ATAATGATCG

360

GGCGGTGGAG

420

CCGTCTAAAG

480

GCCTCTGCTT

540

CTGGAGGTGT

600 ACCCGAACAA CCTCAATGAC GAAGACGTCT CTATCCTGAT GGACCGAAA3C

CAAACCTGGA

CAATTCTTCG

CAATCATCAT

TTACCCTTGA

ATGAAATTAT

GCTCCCCGGG

AATCTCATAA

TCCAGCGCCG

CGTACCGCGT

GAGCTTCGTA

TAATCTCCAA~

CAAGGCAGGT

GCAAGCGCAG

ACATCACTTA

TGAACCGTCT

ATCTCCAAAC

GGCAGGAGGG

TCTACGCCAC

AGGGCTGTCA AGAACTTAGA

AAATGCATCA

CCATGTCTGC CCTCTGCCAC

GGCCGCACCC

GACTGGCAAG AATTCCGGGA

AAAACTGACG

GAACAACAGG GTGGTGGCTC

TAACTGCTCT

AAGAGACCAC CTGCACCTTT

GTACGTAGAG

GGTCCAATCT CTACTATCAA

CCCGTCTCCT

ATGGCTACCC AGGGTGCCAT

GCCGGCCTTC

GTCCTGGTTG CTAGCCATCT

GCAGAGCTTC

CTTGCGCAGC CCTCTGGCGG CTCTGGCGGC WO 97/12985 PCTIUS96/15774 TCTCAGAGCT TCCTGCTCpjA GTCTTTAGAG CAAGTGAGAA

AGATCCAGGG

660 GCGCTCCAGG AGAAGCTGTG TGCCACCTAC AAGCTGTGCC

ACCCCGAGGA

720 CTCGGACACT CTCTGGGCAT CCCCTGGGCT CCCCTGAGCT

CCTGCCCCAG

780 CAGCTGGCAG GCTGCTTGAG CCAACTCCAT AGCGGCCTTT

TCCTCTACCA

840 CAGGCCCTGG AAGGGATATC CCCCGAGTTG GGTCCCACCT

TGGACACACT

900 GTCGCCGACT TTGCCACCAC CATCTGGCAG CAGATGGA.AG

AACTGGGAAT

960 CTGCAGCCCT

AATAA

975 INFORMATION FOR SEQ ID NO: 88: Wi SEQUENCE

CHARACTERISTICS:

LENGTH: 975 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)"

CGATGGCGCA

GCTGGTGCTG

CCAGGCCCTG

GGGGCTCCTG

GCAGCTGGAC

GGCCCCTGCC

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 88: ATGGCTGCAC CCTCTCGACA. TCCAATCATC ATCAAGGCAG

GTGACTGGCA

GAAAAACTGA CGTTCTATCT GGTTACCCTT GAGCAAGCGC

AGGAACAACA

120 TCTAACTGCT CTATAATGAT CGATGAAATT ATACATCACT

TAAAGAGACC

180 TTGCTGGACC CGAACAACCT CAATGACGAA GACGTCTCTA

TCCTGATGGA

240 CGACTTCCAA ACCTGGAGAG CTTCGTAA.GG GCTGTCAAGA

ACTTAGAAAA

300 ATTGAGGCAA TTCTTCGTAA. TCTCCAACCA TGTCTGCCCT

CTGCCACGGC

360

AGAATTCCGG,

GGGTGGTGGC

ACCTGCACCT

CCGAAACCTT

TGCATCAGGT

CTACGTAGAG

WO 97/12985 PCT/US96/1577 4 GGCGGTGGAG

GCTCCCCGGG

420 TGAACCGTCT GGTCCAATCT CTACTATCAA

CCCGTCTCCT

CCGTCTAAAG

480

GCCTCTGCTT

540

CTGGAGGTGT

600

TCTCAGAGCT

660

GCGCTCCAGG

720

CTCGGACACT

780

CAGCTGGCAG

840

CAGGCCCTGG

900

AATCTCATAA

TCCAGCGCCG

CGTACCGCGT

TCCTGCTCAA

AGAAGCTGTG

CTCTGGGCAT

GCTGCTTGAG

AAGGGATATC

ATCTCCAAJ~c

GGCAGGAGGG

TCTACGCCAC

GTCTTTAGAG

TGCCACCTAC

CCCCTGGGCT

CCAACTCCAT

CCCCGAGTTG

ATGGCTACCC

GTCCTGGTTG

CTTGCGCAGC

CAAGTGAGAA

AAGCTGTGCC

CCCCTGAGCT

AGCGGCCTTT

GGTCCCACCT

AGGGTGCCAT

CTAGCCATCT

CCTCTGGCGG

AGATCCAGGG

ACCCCGAGGA

CCTGCCCCAG

TCCTCTACCA

TGGACACACT

GCCGGCCTTC

GCAGAGCTTC

CTCTGGCGGC

CGATGGCGCA

GCTGGTGCTG

CCAGGCCCTG

GGGGCTCCTG

GCAGCTGGAC

GTCGCCGACT TTGCCACCAC CATCTGGCAG CAGATGGAAG AACTGGGAAT

GGCCCCTGCC

960 CTGCAGCCCT

AATAA

975 INFORMATION FOR SEQ ID NO: 89: Wi SEQUENCE

CHARACTERISTICS:

LENGTH: 975 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 89: ATGGCTGCAG GTGACTGGCA AGAATTCCGG GAAAAACTGA CGTTCTATCT

GGTTACCCTT

WO 97/12985 PCTIUS96/1 5774

GAGCAAGCGC

120

ATACATCACT

180 AGGA-ACAACA GGGTGGTGGC TCTAACTGCT CTATAATGAT

CGATGAAATT

TAAAGAGACC ACCTGCACCT

TTGCTGGACC

GACGTCTCTA TCCTGATGGA CCGAAACCTT

CGACTTCCAP

240 GCTGTCAAGA ACTTAGAAAA TGCATCAGGT

ATTGAGGCAA

300 TGTCTGCCCT CTGCCACGGC CGCACCCTCT

CGACATCCAA

360 GGCGGTGGAG GCTCCCCGGG TGAACCGTCT

GGTCCAATCT

420 CCGTCTAAAG AATCTCATAA ATCTCCAAAC

ATGGCTACCC

480 GCCTCTGCTT TCCAGCGCCG GGCAGGAGGG

GTCCTGGTTG

540 CTGGAGGTGT CGTACCGCGT TCTACGCCAC

CTTGCGCAGC

600 TCTCAGAGCT TCCTGCTCAA GTCTTTAGAG

CAAGTGAGA

660 GCGCTCCAGG AGAAGCTGTG TGCCACCTAC

AAGCTGTGCC

720 CTCGGACACT CTCTGGGCAT CCCCTGGGCT

CCCCTGAGCT

780 CAGCTGGCAG GCTGCTTGAG CCAACTCCAT

AGCGGCCTTT

840 CAGGCCCTGG AAGGGATATC CCCCGAGTTG

GGTCCCACCT

900 GTCGCCGACT TTGCCACCAC CATCTGGCAG CAGATGGAjiG 960 CTGCAGCCCT

AATAA

975 INFORMATION FOR SEQ'ID NO: SEQUENCE

CHARACTERISTICS:

LENGTH: 999 base pairs TYPE: nucleic acid STRANDEDNESS: single CGAACA3ACCT CAATGACGAAj LACCTGGAGAG

CTTCGTAAGG

TTCTTCGTAA

TCTCCAACCA

TCATCATCAA

GTACGTAGAG

CTACTATCAA

CCCGTCTCCT

AGGGTGCCA'T'GCCGGCCTTC

CTAGCCATCT

GCAGAGCTTC

CCTCTGGCGG

CTCTGGCGGC

AGATCCAGGG

CGATGGCGCA

ACCCCGAGGA

GCTGGTGCTG

CCTGCCCCAG CCAGGCCCTG

TCCTCTACCA

TGGACACACT

AACTGGGAAT

GGGGCTCCTG

GCAGCTGGAC

GGCCCCTGCC

WO 97/12985 PCTIUS96/15774 299 TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: ATGGCTCTGG ACCCGAACAA CCTCAATGAC GAAGACGTCT CTATCCTGAT

GGACCGAAAC

CTTCGACTTC

120

GGTATTGAGG

180

TCTCGACATC

240

TTCTATCTGG

300

AGCGGCGGCG

360

CCACCTGCAC

420

ATCTCTACTA

480

ACCCAGGGTG

540

GTTGCTAGCC

600

CAGCCCTCTG

660

AGAAAGATCC

720

TGCCACCCCG

780

AGCTCCTGCC

840

CTTTTCCTCT

900

CAAACCTGGA

CAATTCTTCG

CAATCATCAT

TTACCCTTGA

GTTCTAACTG

CTTTGTACGT

TCAACCCGTC

CCATGCCGGC

ATCTGCAGAG

GCGGCTCTGG

AGGGCGATGG

AGGAGCTGGT

CCAGCCAGGC

ACCAGGGGCT

GAGCTTCGTA

TAATCTCCA-A

CAAGGCAGGT

GCAAGCGCAG

CTCTATAATG

AGAGGGCGGT

TCCTCCGTCT

CTTCGCCTCT

CTTCCTGGAG

CGGCTCTCAG

CGCAGCGCTC

GCTGCTCGGA

CCTGCAGCTG

CCTGCAGGCC

AGGGCTGTCA

CCATGTCTGC

GACTGGCAAG

GAACAACAGG

ATCGATGAAA

GGAGGCTCCC

AAAGAATCTC

GCTTTCCAGC

GTGTCGTACC

AGCTTC!CTGC

CAGGAGAAGC

CACTCTCTGG

GCAGGCTGCT

CTCGAAGGGA

AGAACTTAGA

CCTCTGCCAC

AATTCCGGGA

GTGGTGGCTC

TTATACATCA

CGGGTGAACC

ATAAATCTCC

GCCGGGCAGG

GCGTTCTACG

TCAAGTCTTT

TGTGTGCCAC

GCATCCCCTG

TGAGCCAACT

TATCCCCCGA

AAATGCATCA

GGCCGCACCC

AAAACTGACG

TGGCGGTGGC

CTTAAAGAGA

GTCTGGTCCA

AAACATGGCT

AGGGGTCCTG

CCACCTTGCG

AGAGCAAGTG

CTACAAGCTG

GGCTCCCCTG

CCATAGCGGC

GTTGGGTCCC

WO 97/12985 PCT/US96/15774 ACCTTGGACA CACTGCAGCT GGACGTCGCC GACTTTGCCA CCACCATCTG

GCAGCAGATG

960 GAAGAACTGG GAATGGCCCC TGCCCTGCAG

CCCTAATAA

999 C2) INFORMATION FOR SEQ ID NO: 91: SEQUENCE CHARACTERISTICS: LENGTH: 999 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic),, (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 91: ATGGCTA.ATG CATCAGGTAT TGAGGCAATT CTTCGTAATC TCCAACCATG

TCTGCCCTCT

GCCACGGCCG

120

CGGGAAAAAC

180

GGCTCTGGCG

240

CATCACTTAA

300

GTCTCTATCC

360 GTCAAGkA.CT 420

ATCTCTACTA

480

ACCCAGGGTG

540

GTTGCTAGCC

600

CACCCTCTCG

TGACGTTCTA

GTGGCAGCGG

AGAGACCACC

TGATGGACCG

TAGAATACGT

TCAACCCGTC

CCATGCCGGC

ATCTGCAGAG

ACATCCAATC

TCTGGTTACC

CGGCGGTTCT

TGCACCTTTG

AAACCTTCGA

AGAGGGCGGT

TCCTCCGTCT

CTTCGCCTCT

CTTCCTGGAG

ATCATCAAGG

CTTGAGCAAG

AACTGCTCTA

CTGGACCCGA

CTTCCAAACC

GGAGGCTCCC

AAAGAATCTC

GCTTTCCAGC

GTGTCGTACC

CAGGTGACTG

CGCAGGAACA

TAATGATCGA

ACAACCTCPJA

TGGAGAGCTT

CGGGTGAACC

ATAAATCTCC

GCCGGGCAGG

GCGTTCTACG

GCAAGAATTC

ACAGGGTGGT

TGAAATTATA

TGACGAAGAC

CGTAAGGGCT

GTCTGGTCCA

AAACATGGCT

AGGGGTCCTG

CCACCTTGCG

WO 97/12985 PCTIUS96/1 5774 CAGCCCTCTG GCGGCTCTGG CGGCTCTCAG AGCTTCCTGC

TCAAGTCTTT

660 AGAAAGATCC AGGGCGATGG CGCAGCGCTC CAGGAGAAGC

TGTGTGCCAC

720 TGCCACCCCG AGGAGCTGGT GCTGCTCGGA CACTCTCTGG

GCATCCCCTG

780 AGCTCCTGCC CCAGCCAGGC CCTGCAGCTG GCAGGCTGCT

TGAGCCAACT

840 CTTTTCCTCT ACCAGGGGCT CCTGCAGGCC CTGGAAGGGA

TATCCCCCGA

900 ACCTTGGACA CACTGCAGCT GGACGTCGCC GACTTTGCCA

CCACCATCTG

960 GAAGAACTGG GAATGGCCCC TGCCCTGCAG

CCCTAATAA

999 INFORMATION FOR SEQ ID NO: 92: Wi SEQUENCE

CHARACTERISTICS:

LENGTH: 999 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid CA) DESCRIPTION: /desc "DNA (synthetic)"

AGAGCAAGTG

CTACAAGCTG

GGCTCCCCTG

CCATAGCGGC

GTTGGGTCCC

GCAGCAGATG

(Xi) SEQUENCE DESCRIPTION: SEQ ID NO: 92: ATGGCTGCAC CCTCTCGACA TCCAATCATC ATCAAGGCAG

GTGACTGGCA

GAAAAACTGA CGTTCTATCT GGTTACCCTT GAGCAAGCGC

AGGAACAACA

120 TCTGGCGGTG GCAGCGGCGG CGGTTCTAAC TGCTCTATA\

TGATCGATGA

180 CACTTAAAGA GACCACCTGC ACCTTTGCTG GACCCGAACA

ACCTCAATGA

240 TCTATCCTGA TGGACCGAAA CCTTCGACTT CCAAACCTGG

AGAGCTTCGT

300 AAGAACTTAG AAAATGCATC AGGTATTGAG GCAATTCTTC

GTAATCTCCA

360

AGAATTCCGG

GGGTGGTGGC

AATTATACAT

CGAAGACGTC

AAGGGCTGTC

ACCATGTCTG

WO 97/12985 PCT/US96/1577 4 CCCTCTGCCA CGGCCTACGT AGAGGGCGGT GGAGGCTCCC CGGGTGAACC

GTCTGGTCC.A

420

ATCTCTACTA

480

ACCCAGGGTG

540 GTTGCTAGCc 600

CAGCCCTCTG

660

AGAA-AGATCC

720

TGCCACCCCG

780

AGCTCCTGCC

840

CTTTTCCTCT

900

ACCTTGGACA

960

GAAGAACTGG

999

TCAACCCGTC

CCATGCCGGC

ATCTGCAGAG

GCGGCTCTGG

AGGGCGATGG

AGGAGCTGGT

CCAGCCAGGC

ACCAGGGGCT

CACTGCAGCT

GA.ATGGCCCC

TCCTCCGTCT

CTTCGCCTCT

CTTCCTGGAG

CGGCTCTCAG

CGCAGCGCTC

GCTGCTCGGA

CCTGCAGCTG

CCTGCAGGCC

GGACGTCGCC

AAAGAATCTC

GCTTTCCAGC

GTGTCGTACC

AGCTTCCTGC

CAGGAGAAGC

CACTCTCTGG

GCAGGCTGCT

CTGGAAGGGA

GACTTTGCCA

ATAAATCTCC

GCCGGGCAGG

GCGTTCTACG

TCAAGTCTTT

rGTGTGCCAC

GCATCCCCTG

TGAGCCAACT

TATCCCCCGA

CCACCATCTG

AAACATGGCT

AGGGGTCCTG

CCACCTTGCG

AGAGCAAGTG

CTACAAGCTG

GGCTCCCCTG

CCATAGCGGC

GTTGGGTcCCC

GCAGCAGATG

TGCCCTGCAG CCCTAATAA INFORMATION FOR SEQ ID NO: 93: Ci) SEQUENCE

CHARACTERISTICS:

LENGTH: 999 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)'l (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 93: ATGGCTGCAG GTGACTGGCA AGAATTCCGG GAAAAACTGA CGTTCTATCT

GGTTACCCTT

WO 97/12985 PCT/US96,'15774

GAGCAAGCGC

120

TGCTCTATA

180

GACCCGAACA

240

CCAAACCTGG

300

GCAATTCTTC

360

CCAATCATCA

420

ATCTCTACTA

480

ACCCAGGGTG

540

GTTGCTAGCC

600

CAGCCCTCTG

660

AGAAAGATCC

720

TGCCACCCCG

780

AGCTCCTGCC

840

CTTTTCCTCT

900

ACCTTGGACA

960

GAAGAACTGG

999

AGGAACAACA

TGATCGATGA

ACCTCAATGA

AGAGCTTCGT

GTAATCTCCA

TCAAGTACGT

TCAACCCGTC

CCATGCCGGC!

ATCTGCAGAG

GCGGCTCTGG

AGGGCGATGG

AGGAGCTGGT

CCAGCCAGGC

ACCAGGGGCT

CACTGCAGCT

GAATGGCCCC

GGGTGGTGGC

AATTATACAT

CGAAGACGTC

AAGGGCTGTC

ACCATGTCTG

AGAGGGCGGT

TCCTCCGTCT

CTTCGCCTCT

CTTCCTGGAG

CGGCTCTCAG

CGCAGCGCTC

GCTGCTCGGA

CCTGCAGCTG

CCTGCAGGCC

GACGTCGCC

rGCCCTGCAG

TCTGGCGGTG

CACTTAAAGA

TCTATCCTGA

AAGAACTTAG

CCCTCTGCCA

GGAGGCTCcC

AAAGAATCTC

GCTTTCCAGC

GTGTCGTACC

AGCTTCCTGC

CAGGAGAAGC

CACTCTCTGG

GCAGGCTGCT

CTGGAAGGGA

3ACTTTGCCA 2CCTAATAA

GCAGCGGCGG

GACCACCTGC

TGGACCGpAJA

AAAATGCATC

CGGccGCAcc

CGGGTGAACC

ATAAATCTC'C

GCCGGGCAGG

GCGTTCTACG

TCAAGTCTTT

TGTGTGCCAC

GCATCCCCTG

TGAGCCAACT

TATCCCCCGA

CCACCATCTG

CGGT'rCTA.AC

ACCTTTGCTG

CCTTCGACTT

AGGTATTGAG

CTCTCGACAT

GTCTGGTCCA

AAACATGGCT

AGGGGTCCTG

CCACCTTGCG

AGAGCAAGTG

CTACAAGCTG

GGCTCCCCTG

CCATAGCGGC

'TTGGGTCCC

'CAGCAGATG

INFORMATION FOR SEQ ID NO: 94: SEQUENCE CHARACTERISTICS: LENGTH: 918 base-pairs TYPE: nucleic acid STRANDEDNESS: single WO 97/12985 WO 9712985PCTIUS96/1 5774 304 TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: Idesc "DNA (synthetic),, (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 94: ATGGCTAACT GCTCTATAAT GATCGATGAA ATTATACATC ACTTAAAGAG

ACCACCTGCA

CCTTTGCTGG

120

CTTCGACTTC

180

GGTATTGAGG

240

TCTCGACATC

300

TTCTATCTGG

360

TCCCCGGGTG

420

GAGCTGGTGC

480

AGCCAGGCCC

540

CAGGGGCTCC

600

CTGCAGCTGG

660

ATGGCCCCTG

720

CGCCGGGCAG

780

CGCGTTCTAC

840

CTCAAGTCTT

900

ACCCGAACAA

CAAACCTGGA

CAATTCTTCG

CAATCATCAT

TTACCCTTGA

GTGGTTCTGG

TGCTCGGACA

TGCAGCTGGC

TGCAGGCCCT

ACGTCGCCGA

CCCTGCAGCC

GAGGGGTCCT

GCCACCTTGC

TACAGCAAGT

CCTCAATGAC

GAGCTTCGTA

TAATCTCCAA

CAAGGCAGGT

GCAAGCGCAG

CGGCGGCTCC

CTCTCTGGGC

AGGCTGCTTG

GGAAGGGATA

CTTTGCCACC

CACCCAGGGT

GGTTGCTAGC

GCAGCCCTCT

GAGAAAGATC

GAAGACGTCT

AGGGCTGTCA

CCATGTCTGC

GACTGGCAAG

GAACAACAGT

AACATGGCTT

ATCCCCTGGG

AGCCAACTCC

TCCCCCGAGT

ACCATCTGGC

GCCATGCCGG

CATCTGCAGA

GGCGGCTCTG

CAGGGCGATG

CTATCCTGAT

AGAACTTAGA

CCTCTGCCAC

AATTCCGGGA

ACGTAGAGGG

ACAAGCTGTG

CTCCCCTGAG

ATAGCGGCCT

TGGGTCCCAC

AGCAGATGGA

CCTTCGCCTC

GCTTCCTGGA

GCGGCTCTCA

GCGCAGCGCT

GGACCGAAAC

AAATGCATCA

GGCCGCACCC

AAAACTGACG

CGGTGGAGGC

CCACCCCGAG

CTCCTGCCCC

TTTCCTCTAC

CTTGGACACA

AGAACTGGGA

TGCTTTCCAG

GGTGTCGTAC

GAGCTTCCTG

CCAGGAGAAG

WO 97/12985 PCT/US96/15774 305 CTGTGTGCCA

CCTAATAA

918 INFORMATION FOR SEQ ID NO: SEQUENCE CHARACTERISTICS: LENGTH: 963 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: ATGGCTAACT GCTCTATAAT GATCGATGAA ATTATACATC ACTTAAAGAG

ACCACCTGCA

CCTTTGCTGG

120

CTTCGACTTC

180

GGTATTGAGG

240

TCTCGACATC

300

TTCTATCTGG

360

TCCCCGGGTG

420

TCTCATAAAT

480

GGACACTCTC

540

CTGGCAGGCT

600

GCCCTGGAAG

660

ACCCGAACAA

CAAACCTGGA

CAATTCTTCG

CAATCATCAT

TTACCCTTGA

AACCGTCTGG

CTCCAA.ACAT

TGGGCATCCC

GCTTGAGCCA

GGATATCCCC

CCTCAATGAC

GAGCTTCGTA

TAATCTCCAA

CAAGGCAGGT

GCAAGCGCAG

TCCAATCTCT

GGCTTACAAG

CTGGGCTCCC

ACTCCATAGC

CGAGTTGGGT

GAAGACGTCT

AGGGCTGTCA

CCATGTCTGC

GACTGGCAAG

GAACAACAGT

ACTATCAACC

CTGTGCCACC

CTGAGCTCCT

GGCCTTTTCC

CCCACCTTGG

CTATCCTGAT

AGAACTTAGA

CCTCTGCCAC

AATTCCGGGA

ACGTAGAGGG

CGTCTCCTCC

CCGAGGAGCT

GCCCCAGCCA

TCTACCAGGG

ACACACTGCA

GGACCGAAAC

AAATGCATCA

GGCCGCACCC

AAAACTGACG

CGGTGGAGGC

GTCTAAAGAA

GGTGCTGCTC

GGCCCTGCAG

GCTCCTGCAG

GCTGGACGTC

WO 97/12985 PCT/US96/1 5774 GCCGACTTTG CCACCACCAT CTGGCAGCAG ATGGAAGAAC

TGGGAATGGC

720 CAGCCCACCC AGGGTGCCAT GCCGGCCTTC GCCTCTGCTT

TCCAGCGCCG

780 GTCCTGGTTG CTAGCCATCT GCAGAGCTTC CTGGAGGTGT

CGTACCGCGT

840 CTTGCGCAGC CCTCTGGCGG CTCTGGCGGC TCTCAGAGCT

TCCTGCTCAA

900 CAAGTGAcp.A AGATCCAGGG CGATGGCGCA GCGCTCCAGG

AGAAGCTGTG

960

TAA

963 INFORMATION FOR SEQ ID NO: 96: Wi SEQUENCE

CHARACTERISTICS:

LENGTH: 918 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic),,

CCCTGCCCTG

GGCAGGAGGG

TCTACGCCAC

GTCTTTAGAG

TGCCACCTAA

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 96: ATGGCTAACT GCTCTATAT GATCGATGAA ATTATACATC

ACTTAAAGAG

CCTTTGCTGG ACCCGAACAA CCTCAATGAC GAAGACGTCT

CTATCCTGAT

120 CTTCGACTTC CAAACCTGGA GAGCTTCGTA AGGGCTGTCA

AGAACTTAGA

180 GGTATTGAGG CAATTCTTCG TAATCTCCAA CCATGTCTGC

CCTCTGCCAC

240 TCTCGACATC CAATCATCAT CAAGGCAGGT GACTGGCAAG

AATTCCGGGA

300 TTCTATCTGG TTACCCTTGA GCAAGCGCAG GAACAACAGT

ACGTAGAGGG

360 TCCCCGGGTG GTGGTTCTGG CGGCGGCTCC AACATGGCTC

CCGAGTTGGG

420

ACCACCTGCA

GGACCGAA~Jc

AAATGCATCA

GGCCGCACCC

AAAACTGACG

CGGTGGAGGC

TCCCACCTTG

WO 97/12985 WO 9712985PCTIUS96/1 5774 GACACACTGC AGCTGGACGT CGCCGACTTT GCCACCACCA

TCTGGCAGCA

480 CTGGGAATGG CCCCTGCCCT GCAGCCCACC CAGGGTGCCA

TGCCGGCCTT

540 TTCCAGCGCC GGGCAGGAGG GGTCCTGGTT GCTAGCCATC

TGCAGAGCTT

600 TCGTACCGCG TTCTACGCCA CCTTGCGCAG CCCTCTGGCG

GCTCTGGCGG

660 TTCCTGCTCA AGTCTTTAGA GCAAGTGAGA AAGATCCAGG GCGATGGCGC 720 GAGAAGCTGT GTGCCACCTA CAAGCTGTGC CACCCCGAGG

AGCTGGTGCT

780 TCTCTGGGCA TCCCCTGGGC TCCCCTGAGC TCCTGCCCCA

GCCAGGCCCT

840 GGCTGCTTGA GCCAACTCCA TAGCGGCCTT TTCCTCTACC

AGGGGCTCCT

900 GAAGGGATAT

CCTAATAA

918 INFORMAATION FOR SEQ ID NO: 97: SEQUENCE CHARACTERISTICS: LENGTH: 963 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)"

GATGGAJAG

CGCCTCTGCT

CCTGGAGGTG

CTCTCAGAGC

AGCGCTCCAG

GCTCGGACAC

GCAGCTGGCA

GCAGGCCCTG

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 97: ATGGCTAACT GCTCTATAAT GATCGATGAA ATTATACATC ACTTAAAGAG

ACCACCTGCA

CCTTTGCTGG ACCCGAACAA CCTCAATGAC GAAGACGTCT CTATCCTGAT

GGACCGAAAC

120 CTTCGACTTC CAAACCTGGA GAGCTTCGTA AGGGCTGTCA AGAACTTAGA

AAATGCATCA

180 WO 97/12985 PCT/US96/15774 308 GGTATTGAGG CAATTCTTCG TAATCTCCAA CCATGTCTGC CCTCTGCCAC

GGCCGCACCC

240

TCTCGACATC

300

TTCTATCTGG

360

TCCCCGGGTG

420

TCTCATAAAT

480

GACGTCGCCG

540

GCCCTGCAGC

600

GGAGGGGTCC

660

CGCCACCTTG

720

TTAGAGCAAG

780

ACCTACAAGC

840

TGGGCTCCCC

900

CAATCATCAT

TTACCCTTGA

AACCGTCTGG

CTCCAAACAT

ACTTTGCCAC

CCACCCAGGG

TGGTTGCTAG

CGCAGCCCTC

TGAGAAAGAT

TGTGCCACCC

TGAGCTCCTG

CAAGGCAGGT

GCAAGCGCAG

TCCAATCTCT

GGCTCCCGAG

CACCATCTGG

TGCCATGCCG

CCATCTGCAG

TGGCGGCTCT

CCAGGGCGAT

CGAGGAGCTG

CCCCAGCCAG

GACTGGCAAG AATTCCGGGA

AAAACTGACG

GAACAACAGT

ACTATCAACC

TTGGGTCCCA

CAGCAGATGG

GCCTTCGCCT

AGCTTCCTGG

GGCGGCTCTC

GGCGCAGCGC

GTGCTGCTCG

GCCCTGCAGC

ACGTAGAGGG

CGTCTCCTCC

CCTTGGACAC

AAGAACTGGG

CTGCTTTCCA

AGGTGTCGTA

AGAGCTTCCT

TCCAGGAGAA

GACACTCTCT

TGGCAGGCTG

CGGTGGAGGC

GTCTAAAGAA

ACTGCAGCTG

AATGGCCCCT

-GCGCCGGGCA

CCGCGTTCTA

GCTCAAGTCT

GCTGTGTGCC

GGGCATCCCC

CTTGAGCCAA

CTCCATAGCG GCCTTTTCCT CTACCAGGGG CTCCTGCAGG CCCTGGAAGG

GATATCCTAA

960

TAA

963 INFORMATION FOR SEQ ID NO: 98: SEQUENCE

CHARACTERISTICS:

LENGTH: 918 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic),, WO 97/12985 PCTIUS96/1 5774 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 98: ATGGCTAACT GCTCTATAAT GATCGATGA ATTATACATO

ACTTAAAGAG

CCTTTGCTGG ACCCGAACAA CCTCAATGAC GAAGACGTCT

CTATCCTGAT

120 CTTCGACTTC CAAACCTGGA GAGCTTCGTA AGGGCTGTCA

AGAACTTAGA

180

ACCACCTGCA

GGACCGAAC

AAATGCATCA

GGTATTGAGC

240

TCTCGACATC

300

TTCTATCTGC

360

TCCCCGGGTG

420

ACCCAGGGTG

480

GTTGCTAGCC

540

CAGCCCTCTG

600

AGAAAGATCC

660

TGCCACCCCG

720

AGCTCCTGCC

780

CTTTTCCTCT

840 3CAATTCTTCC

CAATCATCAI

TTACCCTTGA

GTGGTTCTGG

CCATGCCGGC

ATCTGCAGAG

GCGGCTCTGG

AGGGCGATGG

AGGAGCTGGT

CCAGCCAGGC

ACCAGGGGCT

TAATCTCCAP,

CAAGGCAGGTJ

GCAAGCGCAG

CGGCGGCTCC

CTTCGCCTCT

CTTCCTGGAG

CGGCTCTCAG

CGCAGCGCTC

GCTGCTCGGA

CCTGCAGCTG

CCTGCAGGCC

CCATGTCTGC

GACTGGCAAG

CCTCTGCCAC

AATTCCGGGA

GGCCGCACCC

AAAACTGACG

GAACAACAGT ACGTAGAGGG

CGGTGGAGGC

AACATGGCTA

GCTTTCCAGC

GTGTCGTACC

AGCTTCCTGC

CAGGAGAAGC

CACTCTCTGG

GCAGGCTGCT

CTGGAAGGGA

TGGCCCCTGC

GCCGGGCAOG

GCGTTCTACG

TCAAGTCTTT

TGTGTGCCAC

GCATCCCCTG

TGAGCCAACT

TATCCCCCGA

CCTGCAGCCC

AGGGGTCCTG

CCACCTTGCG

AGAGCAAGTG

CTACAAGCTG

GGCTCCCCTG

CCATAGCGGC

ACCTTGGACA CACTGCAGCT GGACGTCGCC GACTTTGCCA CCACCATCTG

GCAGCAGATG

900 GAAGAACTGG

GATAATAA

918 INFORMATION FOR SEQ ID NO: 99: WO 97/12985 PCTIUS96/15774 310 SEQUENCE

CHARACTERISTICS:

LENGTH: 963 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic), (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 99: ATGGCTAACT GCTCTATAAT GATCGATGAA ATTATACATC ACTTAAAGAG

ACCACCTGCA

CCTTTGCTGG

120

CTTCGACTTC

180

GGTATTGAGG

240

TCTCGACATC

300

TTCTATCTGG

360

TCCCCGGGTG

420

TCTCATAAAT.

480

CCGGCCTTCG

540

CAGAGCTTCC

600

TCTGGCGGCT

660

GATGGCGCAG

720

ACCCGAACAA

CAAACCTGGA

CAATTCTTCG

CAATCATCAT

TTACCCTTGA

AACCGTCTGG

CTCCAAACAT

CCTCTGCTTT

TGGAGGTGTC

CTCAGAGCTT

CGCTCCAGGA

CCTCA.ATGAC

GAGCTTCGTA

TAATCTCCA

CAAGGCAGGT

GCAAGCGCAG

TCCAATCTCT

GGCTATGGCC

CCAGCGCCGG

GTACCGCGTT

CCTGCTCAAG

GAAGCTGTGT

GAAGACGTCT CTATCCTGAT

GGACCGAAAC

AGGGCTGTCA AGAACTTAGA

AAATGCATCA

CCATGTCTGC CCTCTGCCAC GGCCGCAcC GACTGGCAAG AATTCCGGGA

AAAACTGACG

GAACA.ACAGT ACGTAGAGGG

CGGTGGAGGC

ACTATCAACC CGTCTCCTCC GTCTAzAAGA CCTGCCCTGC AGCCCACCCA

GGGTGCCATG

GCAGGAGGGG TCCTGGTTGC

TAGCCATCTG

CTACGCCACC TTGCGCAGCC

CTCTGGCGGC

TCTTTAGAGC AAGTGAGAAA

GATCCAGGGC

GCCACCTACA AGCTGTGCCA

CCCCGAGGAG

CTGGTGCTGC

780 TCGGACACTC TCTGGGCATC CCCTGGGCTC CCCTGAGCTC

CTGCCCCAGC

WO 97/12985 PCTIUS96/15774 311 CAGGCCCTGC AGCTGGCAGG CTGCTTGAGC CAACTCCATA GCGGCCTTTT

CCTCTACCAG

840 GGGCTCCTGC AGGCCCTGGA AGGGATATCC CCCGAGTTGG GTCCCACCTT

GGACACACTG

900 CAGCTGGACG TCGCCGACTT TGCCACCACC ATCTGGCAGC AGATGGAAGA

ACTGGGATAA

960

TAA

963 INFORMATION FOR SEQ ID NO: 100: Wi SEQUENCE CHARACTERISTICS: LENGTH: 918 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 100: ATGGCTAACT GCTCTATAAT GATCGATGAA ATTATACATC ACTTAAAGAG

ACCACCTGCA

CCTTTGCTGG

120

CTTCGACTTC

180

GGTATTGAGG

240

TCTCGACATC

300

TTCTATCTGG

360

TCCCCGGGTG

420

TTCGCCTCTG

480

TTCCTGGAGG

540

ACCCGAACAA

CAAACCTGGA

CAATTCTTCG

CAATCATCAT

TTACCCTTGA

GTGGTTCTGG

CTTTCCAGCG

TGTCGTACCG

CCTCAATGAC

GAGCTTCGTA

TAATCTCCAA.

CAAGGCAGGT

GCAAGCGCAG

CGGCGGCTCC

CCGGGCAGGA

CGTTCTACGC

GAAGACGTCT

AGGGCTGTCA

CCATGTCTGC

GACTGGCAAG

GAACAACAGT

AACATGGCTA

GGGGTCCTGG

CACCTTGCGC

CTATCCTGAT

AGAACTTAGA

CCTCTGCCAC

AATTCCGGGA

ACGTAGAGGG

CCCAGGGTGC

TTGCTAGCCA

AGCCCTCTGG

GGACCGAAA.C

AAATGCATCA

GGCCGCACCC

AAAACTGACG

CGGTGGAGGC

CATGCCGGCC

TCTGCAGAGC

CGGCTCTGGC

WO 97/12985 PCTJUS96/I 5774 GGCTCTCAGA GCTTCCTGCT CAAGTCTTTA GAGCAAGTGA GAAAGATCCA

GGGGTG

600 GGTC GCAGCGCTCC AGGAGAAGCT GTGTGCCACC TACAAGCTGT GCCACCCCGA

GGAGCTGGTG

660 CTGCTCGGAC ACTCTCTGGG CATCCCCTGG GCTCCCCTGA GCTCCTGCCC

CAGCCAGGCC

720 CTGCAGCTGG CAGGCTGCTT GAGCCAACTC CATAGCGGCC TTTTCCTCTA

CCAGGGGCTC

780 CTGCAGGCCC TGGAAGGGAT ATCCCCCGAG TTGGGTCCCA CCTTGGACAC

ACTGCAGCTG

840 GACGTCGCCG ACTTTGCCAC CACCATCTGG CAGCAGATGG AAGAACTGGG

AATGGCCCCT

900 GCCCTGCAGC

CCTAATAA

918 INFORMATION FOR SEQ ID NO: 101: Wi SEQUENCE

CHARACTERISTICS:

LENGTH: 963 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)" (Xi) SEQUENCE DESCRIPTION: SEQ ID NO: 101: ATGGCTAACT GCTCTATAAT GATCGATGAA ATTATACATC ACTTAAAGAG

ACCACCTGCA

CCTTTGCTGG ACCCGAACAA~ CCTCAATGAC GAAGACGTCT CTATCCTGAT

GGACCGAAAC

120 CTTCGACTTC CAAACCTGGA GAGCTTCGTA AGGGCTGTCA AGAACTTAGA

AAATGCATCA

180 GGTATTGAGG CAATTCTTCG TAATCTCCAA CCATGTCTGC CCTCTGCCAC

GGCCGCACCC

240 TCTCGACATC CAATCATCAT CAAGGCAGGT GACTGGCAAG AATTCCGGGA

AAAACTGACG

300 WO 97/12985 PCTIUS96/15774 313 TTCTATCTGG TTACCCTTGA GCAAGCGCAG GAACAACAGT ACGTAGAGGG

CGGTGGAGGC

360 TCCCCGGGTG AACCGTCTGG TCCAATCTCT ACTATCAACC

CGTCTCCTCC

420 TCTCATAAAT CTCCAAACAT GGCTACCCAG GGTGCCATGC

CGGCCTTCGC

480 CAGCGCCGGG CAGGAGGGGT CCTGGTTGCT AGCCATCTGC

AGAGCTTCCT

540 TACCGCGTTC TACGCCACCT TGCGCAGCCC TCTGGCGGCT

CTGGCGGCTC

600 CTGCTCAAGT CTTTAGAGCA AGTGAGAAAG ATCCAGGGCG

ATGGCGCAGC

660 AAGCTGTGTG CCACCTACAA~ GCTGTGCCAC CCCGAGGAGC

TGGTGCTGCT

720 CTGGGCATCC CCTGGGCTCC CCTGAGCTCC TGCCCCAGCC

AGGCCCTGCA

780 TGCTTGAGCC AACTCCATAG CGGCCTTTTC CTCTACCAGG

GGCTCCTGCA

840 GGGATATCCC CCGAGTTGGG TCCCACCTTG GACACACTGC

AGCTGGACGT

900 GCCACCACCA TCTGGCAGCA GATGGAAGAA CTGGGAATGG

CCCCTGCCCT

960

TAA

963 INFORMATION FOR SEQ ID NO: 102: SEQUENCE CHARACTERISTICS: LENGTH: 918 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: Idesc "DNA (synthetic)"

GTCTAAAGAA

CTCTGCTTTC

GGAGGTGTCG

TCAGAGCTTC

GCTCCAGGAG

CGGACACTCT

GCTGGCAGGC

GGCCCTGGAA

CGCCGACTTT

GCAGCCCTAA

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 102: ATGGCTA3-.CT GCTCTATAAT GATCGATGAA ATTATACATC ACTTAAAGAG

ACCACCTGCA

WO 97/12985 PCT/US96/15774

CCTTTGCTGG

120

CTTCGACTTC

180

GGTATTGAGG

240

TCTCGACATC

300

TTCTATCTGG

360

TCCCCGGGTG

420

GGAGGGGTCC

480

CGCCACCTTG

540

TTAGAGCAAG

600

ACCTACAAGC

660

TGGGCTCCCC

720

CTCCATAGCG

780

GAGTTGGGTC

840

TGGCAGCAGA

900

CCGGCCTTCG

918

ACCCGAACAAJ

CAAACCTGGA

CAATTCTTCG

CAATCATCAT

TTACCCTTGA

GTGGTTCTGG

TGGTTGCTAG

CGCAGCCCTC

TGAGAIAAGAT

TGTGCCACCC

TGAGCTCCTG

GCCTTTTCCT

CCACCTTGGA

TGGAAGAACT

CCTAATAA

CCTCAATGAC

GAGCTTCGTA

TAATCTCCAA

CAAGGCAGGT

GCAAGCGCAG

CGGCGGCTCC

CCATCTGCAG

TGGCGGCTCT

CCAGGGCGAT

CGAGGAGCTG

CCCCAGCCAG

CTACCAGGGG

CACACTGCAG

GA.AGACGTCT CTATCCTGAT

GGACCGAAAC

AGGGCTGTCA AGAACTTAGA

AAATGCATCA

CCATGTCTGC CCTCTGCCAC

GGCCGCACCC

GACTGGCAAG AATTCCGGGA

AAAACTGACG

GAACAACAGT ACGTAGAGGG

CGGTGGAGGC

AACATGGCTT CTGCTTTCCA

GCGCCGGGCA

AGCTTCCTGG AGGTGTCGTA

CCGCGTTCTA

GGCGGCTCTC AGAGCTTCCT

GCTCAAGTCT

GGCGCAGCGC TCCAGGAGAA

GCTGTGTGCC

GTGCTGCTCG GACACTCTCT

GGGCATCCCC

GCCCTGCAGC TGGCAGGCTG

CTTGAGCCAA

CTCCTGCAGG CCCTGGAAGG

GATATCCCCC

CTGGACGTCG CCGAC!TTTGC CACCACCATC GGGAATGGCC CCTGCCCTGC AGCCCACCCA

GGGTGCCATG

INFORMATION FOR SEQ ID NO: 103: SEQUENCE

CHARACTERISTICS:

LENGTH: 963 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear WO 97/12985 PCTIUS96/15774 315 (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)' (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 103: ATGGCTA.ACT GCTCTATAAT GATCGATGAA ATTATACATC ACTTAAAGAG ACC ACCTGCA

CCTTTGCTGG

120

CTTCGACTTC

180

GGTATTGAGG

240

TCTCGACATC

300

TTCTATCTGG

360

TCCCCGGGTG

420

TCTCATAAAT

480

GCTAGCCATC

540

CCCTCTGGCG

600

AAGATCCAGG

660

CACCCCGAGG

720

TCCTGCCCCA

780

TTCCTCTACC

840

TTGGACACAC

900

ACCCGAACAA

CAAACCTGGA

CAATTCTTCG

CAATCATCAT

TTACCCTTGA

AACCGTCTGG

CTCCAAACAT

TGCAGAGCTT

GCTCTGGCGG

GCGATGGCGC

AGCTGGTGCT

GCCAGGCCCT

AGGGGCTCCT

TGCAGCTGGA

CCTCAATGAC

GAGCTTCGTA

TAATCTCCAA

CAAGGCAGGT

GCAAGCGCAG

TCCAATCTCT

GGCTTCTGCT

CCTGGAGGTG

CTCTCAGAGC

AGCGCTCCAG

GCTCGGACAC

GCAGCTGGCA

GCAGGCCCTG

CGTCGCCGAC

GAAGACGTCT

AGGGCTGTCA

CCATGTCTGC

GACTGGCAAG

GAACAACAGT

ACTATCAACC

TTCCAGCGCC

TCGTACCGCG

TTCCTGCTCA

GAGAAGCTGT

TCTCTGGGCA

GGCTGCTTGA

GAAGGGATAT

TTTGCCACCA

CTATCCTGAT

GGACCGAAAC

AGAACTTAGA

AAATGCATCA

CCTCTGCCAC.,GGCCGCACCC

AATTCCGGGA AAAACTGACG ACGTAGAGGG

CGGTGGAGGC

CGTCTCCTCC

GTCTAAAGAA

GGGCAGGAGG

GGTCCTGGTT

TTCTACGCCA CCTTGCGCAG AGTCTTTAGA GCAAGTGAGA GTOCCACCTA

CAAGCTGTGC

TCCCCTGGGC TCCCCTGAGC GCCAACTCCA TAGCGGCCTT CCCCCGAGTT

GGGTCCCACC

CCATCTGGCA GCAGATGGAA WO 97/12985 PCTIUS96/15774 316 GAACTGGGAA TGGCCCCTGC CCTGCAGCCC ACCCAGGGTG CCATGCCGGC

CTTCGCCTAA

960

TAA

963 INFORMATION FOR SEQ ID NO: 104: SEQUENCE CHARACTERISTICS: LENGTH: 927 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 104: ATGGCTAACT GCTCTATAAT GATCGATGAA ATTATACATC ACTTAAAGAG

ACCACCTGCA

CCTTTGCTGG

120

CTTCGACTTC

180

GGTATTGAGG

240

TCTCGACATC

300

TTCTATCTGG

360.

TCCCCGGGTG

420

GAGCTGGTGC

480

AGCCAGGCCC

540

CAGGGGCTCC

600

CTGCAGCTGG

660

ACCCGAACAA

CAAACCTGGA

CAATTCTTCG

CAATCATCAT

TTACCCTTGA

GTGGTTCTGG

TGCTCGGACA

TGCAGCTGGC

TGCAGGCCCT

CCTCAATGAC

GAGCTTCGTA

TAATCTCCA

CAAGGCAGGT

GCAAGCGCAG

CGGCGGCTCC

CTCTCTGGGC

AGGCTGCTTG

GGAAGGGATA

GAAGACGTCT

AGGGCTGTCA

CCATGTCTGC

GACTGGCAAG

GAACAACAGT

AACATGGCTT

ATCCCCTGGG

AGCCAACTCC

TCCCCCGAGT

CTATCCTGAT

AGAACTTAGA

CCTCTGCCAC

AATTCCGGGA

ACGTAGAGGG

ACAAGCTGTG

CTCCCCTGAG

ATAGCGGCCT

TGGGTCCCAC

GGACCGAAAC

AA.ATGCATCA

GGCCGCACCC

AAAACTGACG

CGGTGGAGGC

CCACCCCGAG

CTCCTGCCCC

TTTCCTCTAC

CTTGGACACA

ACGTCGCCGA CTTTGCCACC ACCATCTGGC AGCAGATGGA AGAACTGGGA WO 97/12985 PCTIUS96/'15774 317 ATGGCCCCTG CCCTGCAGCC CACCCAGGGT GCCATGCCGG CCTTCGCCTC

TGCTTTCCAG

720 CGCCGGGCAG GAGGGGTCCT GGTTGCTAGC CATCTGCAGA GCTTCCTGGA

GGTGTCGTAC

780 CGCGTTCTAC GCCACCTTGC GCAGCCCACA CCATTGGGCC CTGCCAGCTC

CCTGCCCCAG

840 AGCTTCCTGC TCAAGTCTTT AGAGCAAGTG AGAAAGATCC AGGGCGATGG

CGCAGCGCTC

900 CAGGAGAAGC TGTGTGCCAC CTAATAA 927 INFOMTION FOR SEQ ID NO: 105: Wi SEQUENCE CHARACTERISTICS: LENGTH: 972 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: Idesc "DNA (synthetic),, (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 105: ATGGCTAACT GCTCTATAAT GATCGATGAA ATTATACATC

ACTTAAAGAG

CCTTTGCTGG ACCCGAACAA CCTCAATGAC GAAGACGTCT

CTATCCTGAT

120 CTTCGACTTC CAAACCTGGA GAGCTTCGTA AGGGCTGTCA

AGAACTTAGA

180 GGTATTGAGG CAATTCTTCG TAATCTCCAA CCATGTCTGC

CCTCTGCCAC

240 TCTCGACATC CAATCATCAT CAAGGCAGGT GACTGGCAAG

AATTCCGGGA

300 TTCTATCTGG TTACCCTTGA GCAAGCGCAG GAACAACAGT

ACGTAGAGGG

360 TCCCCGGGTG AACCGTCTGG TCCAATCTCT ACTATCAACC

CGTCTCCTCC

420

ACCACCTGCA

GGACCGAAAC

AAATGCATCA

GGCCGCACCC

AAAACTGACG

CGGTGGAGGC

GTCTAAAGAA

WO 97/12985 PCT/UJS96,I 5774 TCTCATAAAT CTCCAAACAT GGCTTACAAG CTGTGCCACC

CCGAGGAGCT

480 GGACACTCTC TGGGCATCCC CTGGGCTCCC CTGAGCTCCT

GCCCCAGCCA

540 CTGGCAGGCT GCTTGAGCCA ACTCCATAGC GGCCTTTTCC

TCTACCAGGG

600 GCCCTGGAAG GGATATCCCC CGAGTTGGGT CCCACCTTGG

ACACACTGCA

660 GCCGACTTTG CCACCACCAT CTGGCAGCAG ATGGAAGAAC

TGGGAATGGC

720 CAGCCCACCC AGGGTGCCAT GCCGGCCTTC GCCTCTGCTT

TCCAGCGCCG

780 GTCCTGGTTG CTAGCCATCT GCAGAGCTTC CTGGAGGTGT

CGTACCGCGT

840 CTTGCGCAGC CCACACCATT GGGCCCTGCC AGCTCCCTGC

CCCAGAGCTT

900 TCTTTAGAGC AAGTGAGAAA GATCCAGGGC GATGGCGCAG

CGCTCCAGGA

960 GCCACCTAAT

AA

972 INFORMATION FOR SEQ ID NO: 106: i)SEQUENCE

CHARACTERISTICS:

LENGTH: 927 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc DNA (synthetic)'

GGTGCTGCTC

GGCCCTGCAG

GCTCCTGCAG

GCTGGACGTC

CCCTGCCCTG

GGCAGGAGGG

TCTACGCCAC

CCTGCTCAAG

GAAGCTGTGT

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 106: ATGGCTAACT GCTCTATAAT GATCGATGAA ATTATACATC ACTTAAAGAG

ACCACCTGCA

CCTTTGCTGG ACCCGAACAA CCTCAATGAC GAAGACGTCT CTATCCTGAT

GGACCGAAAC

120 CTTCGACTTC CAAACCTGGA GAGCTTCGTA AGGGCTGTCA AGAACTTAGA

AAATGCATCA

180 WO 97/12985 PCTIUS96/1 5774

GGTATTGAGG

240

TCTCGACATC

300

TTCTATCTGG

360

TCCCCGGGTG

420

GACACACTGC

480

CTGGGAATGG

540

TTCCAGCGCC

600

TCGTACCGCG

660

CCCCAGAGCT

720

GCGCTCCAGG

780

CTCGGACACT

840

CAGCTGGCAG

900

CAGGCCCTGG

927

CAATTCTTCG

CAATCATCAT

TTACCCTTGA

GTGGTTCTGG

AGCTGGACGT

CCCCTGCCCT

GGGCAGGAGG

TTCTACGCCA

TCCTGCTCAA.

AGAAGCTGTG

CTCTGGGCAT

GCTGCTTGAG

AAGGGATATC

TAATCTCCAA

CAAGGCAGGT

GCAAGCGCAG

CGGCGGCTCC

CGCCGACTTT

GCAGCCCACC

GGTCCTGGTT

CCTTGCGCAG

GTCTTTAGAG

TGCCACCTAC

CCCCTGGGCT

CCAACTCCAT

CTAATAA

CCATGTCTGC

GACTGGCAAG

GAACAACAGT

AACATGGCTC

GCCACCACCA

CAGGGTGCCA

GCTAGCCATC

CCCACACCAT

CAAGTGAGAA

AAGCTGTGCC

CCCCTGAGCT

AGCGGCCTTT

CCTCTGCCAC

GGCCGCACCC

AATTCCGGGA

AAAACTGACG

ACGTAGAGGG

CGGTGGAGGC

CCGAGTTGGG

TCCCACCTTG

TCTGGCAGCA

GATGGAAGAA

TGCCGGCCTT

CGCCTCTGCT

TGCAGAGCTT

CCTGGAGGTG

TGGGCCCTGC

CAGCTCCCTG

AGATCCAGGG

CGATGGCGCA

ACCCCGAGGA

GCTGGTGCTG

CCTGCCCCAG

CCAGGCCCTG

TCCTCTACCA GGGGCTCCTG INFORMATION FOR SEQ ID NO: 107: Wi SEQUENCE CHARACTERISTICS: LENGTH: 972 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic),' WO 97/12985 PCTIUS96/'15774 320 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 107: ATGGCTAACT GCTCTATAAT GATCGATGAA ATTATACATC ACTTAAAGAG

ACCACCTGCA

CCTTTGCTGG ACCCCAACAA CCTCAATGAC

G.

120 CTTCGACTTC CAAACCTGGA GAGCTTCGTA

A(

180 GGTATTGAGG CAATTCTTCG TAATCTCCAA.

C(

240 TCTCGACATC CAATCATCAT CAAGGCAGGT

G~

300 TTCTATCTGG TTACCCTTGA GCAAGCGCAG

GI

360 TCCCCGGGTG AACCGTCTGG TCCAATCTCT

AC

420 TCTCATAAAT CTCCAAACAT GGCTCCCGAG T9) 480 GACGTCGCCG ACTTTGCCAC CACCATCTGG C.l 540 GCCCTGCAGC CCACCCAGGG TGCCATGCCG

GC

600 GGAGGGGTCC TGGTTGCTAG CCATCTGCAG

AG

660 CGCCACCTTG CGCAGCCCAC ACCATTGGGC

CC

720 CTCAAGTCTT TAGAGCAAGT GAGAAAGATC

CA

780 CTGTGTGCCA CCTACAAGCT GTGCCACCCC

GA

840 GGCATCCCCT GGGCTCCCCT GAGCTCCTGC

CC

900 TTGAGCCAAC TCCATAGCGG CCTTTTCCTC

TA

960 ATATCCTAAT

AA

972 INFORMATION FOR SEQ ID NO: 108:

AAGACGTCT

GGGCTGTCA

CATGTCTGC

kCTGGCAAG

ACAACAGT

~TATCAACC

EGGGTCCCA

~GCAGATGG

~CTTCGCCT

~CTTCCTGG

TGCCAGCT

~GGGCGATG

GGAGCTGG

CAGCCAGG

.CCAGGGGC

CTATCCTGAT

GGACCGAAAC

AGAACTTAGA

AAATGCATCA

CCTCTGCCAC

GGCCGCACCC

AATTCCGGGA

AAAACTGACG

ACGTAGAGGG-CGGTGGAGGC

CGTCTCCTCC

GTCTAAAGAA

CCTTGGACAC

ACTGCAGCTG

AAGAACTGGG

AATGGCCCCT

CTGCTTTCCA

GCGCCGGGCA

AGGTGTCGTA

CCGCGTTCTA

CCCTGCCCCA

GAGCTTCCTG

GCGCAGCGCT

CCAGGAGAAG

TGCTGCTCGG

ACACTCTCTG

CCCTGCAGCT

GGCAGGCTGC

TCCTGCAGGC CCTGGAAGGG WO 97/12985 PCT/US96/15774 321 SEQUENCE CHARACTERISTICS: LENGTH: 927 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic),- (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 108: ATGGCTAACT GCTCTATAAT GATCGATGAA ATTATACATC ACTTAAAGAG ACCACCTGCA

CCTTTGCTGG

120

CTTCGACTTC

180

GGTATTGAGG

240

TCTCGACATC

300

TTCTATCTGG

360

TCCCCGGGTG

420

ACCCAGGGTG

480

GTTGCTAGCC

540

CAGCCCACAC

600

GAGCAAGTGA

660

TACAAGCTGT

720

GCTCCCCTGA

780

ACCCGAACAA

CAAACCTGGA

CAATTCTTCG

CAATCATCAT

TTACCCTTGA

GTGGTTCTGG

CCATGCCGGC

ATCTGCAGAG

CATTGGGCCC

GAAAGATCCA

GCCACCCCGA

GCTCCTGCCC

CCTCAATGAC

GAGCTTCGTA

TAATCTCCAA

CAAGGCAGGT

GCAAGCGCAG

CGGCGGCTCC

CTTCGCCTCT

CTTCCTGGAG

TGCCAGCTCC

GGGCGATGGC

GGAGCTGGTG

CAGCCAGGCC

GAAGACGTCT

AGGGCTGTCA

CCATGTCTGC

GACTGGCAAG

GAACAACAGT

AACATGGCTA

GCTTTCCAGC

GTGTCGTACC

CTGCCCCAGA

GCAGCGCTCC

CTGCTCGGAC

CTGCAGCTGG

CTATCCTGAT GGACCGAAAC AGAACTTAGA AAATGCATCA CCTCTGCCAC GGCCGCACCC AATTCCGGGA AAAACTGACG ACGTAGAGGG CGGTGGAGGC TGGCCCCTGC CCTGCAGCCC GCCGGGCAGG AGGGGTCCTG GCGTTCTACG CCACCTTGCG GCTTCCTGCT CAAGTCTTTA AGGAGAAGCT GTGTGCCACC ACTCTCTGGG CATCCCCTGG CAGGCTGCTT GAGCCAACTC WO 97/12985 PCT/UJS96/1 5774 322 CATAGCGGCC TTTTCCTCTA CCAGGGGCTC CTGCAGGCCC TGGAAGGGAT

ATCCCCCGAG

840 TTGGGTCCCA CCTTGGACAC ACTGCAGCTG GACGTCGCCG ACTTTGCCAC

CACCATCTGG

900 CAGCAGATGG AAGAACTGGG

ATAATAA

927 INFORMATION FOR SEQ ID NO: 109: WI SEQUENCE CHARACTERISTICS: LENGTH: 972 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic),, (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 109: ATGGCTAACT GCTCTATAAT GATCGATGAA ATTATACATC ACTTAAAGAG

ACCACCTGCA

CCTTTGCTGG

120

CTTCGACTTC

180

GGTATTGAGG

240

TCTCGACATC

300

TTCTATCTGG

360

TCCCCGGGTG

420

TCTCATAAAT

480

CCGGCCTTCG

540

CAGAGCTTCC

600

ACCCGAACAA

CAAACCTGGA

CAATTCTTCG

CAATCATCAT

TTACCCTTGA

AACCGTCTGG

CTCCAAACAT

CCTCTGCTTT

TGGAGGTGTC

CCTCAATGAC

GAGCTTCGTA

TAATCTCCAA

CAAGGCAGGT

GCAAGCGCAG

TCCAATCTCT

GGCTATGGCC

CCAGCGCCGG

GTACCGCGTT

GAAGACGTCT

AGGGCTGTCA

CCATGTCTGC

GACTGGCAAG

GAACAACAGT

ACTATCAACC

CCTGCCCTGC

GCAGGAGGGG

CTACGCCACC

CTATCCTGAT

AGAACTTAGA

CCTCTGCCAC

AATTCCGGGA

ACGTAGAGGG

CGTCTCCTCC

AGCCCACCCA

TCCTGGTTGC

TTGCGCAGCC

GGACCGAAAC

AAATGCATCA

GGCCGCACCC

AAAACTGACG

CGGTGGAGGC

GTCTAAAGAA

GGGTGCCATG

TAGCCATCTG

CACACCATTG

WO 97/12985 PCTIUS96/1 5774 GGCCCTGCCA GCTCCCTGCC CCAGAGCTTC CTGCTCAAGT

CTTTAGAGCA

660 ATCCAGGGCG ATGGCGCAGC GCTCCAGGAG AAGCTGTGTG

CCACCTACAA

720 CCCGAGGAGC TGGTGCTGCT CGGACACTCT CTGGGCATCC

CCTGGGCTCC

780 TGCCCCAGCC AGGCCCTGCA GCTGGCAGGC TGCTTGAGCC

AACTCCATAG

840 CTCTACCAGG GGCTCCTGCA GGCCCTGGAA GGGATATCcc

CCGAGTTGGG

900 GACACACTGC AGCTGGACGT CGCCGACTTT GCCACCACCA

TCTGGCAGCA

960 CTGGGATAAT

AA

972 INFORMATION FOR SEQ ID NO: 110: SEQUENCE CHARACTERISTICS: LENGTH: 927 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc ="DNA (synthetic)"

AGTGAGAAAG

GCTGTGCCAC

CCTGAGCTCC

CGGCCTTTTC

TCCCACCTTG

GATGGAAGAJA

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 110: ATGGCTAACT GCTCTATAAT GATCGATGAA ATTATACATC

ACTTAAAGAG

CCTTTGCTGG ACCCGAACAA CCTCAATGAC GAAGACGTCT

CTATCCTGAT

120 CTTCGACTTC CAAACCTGGA GAGCTTCGTA AGGGCTGTCA

AGAACTTAGA

180 GGTATTGAGG CAATTCTTCG TAATCTCCAA CCATGTCTGC

CCTCTGCCAC

240 TCTCGACATC CAATCATCAT CAAGGCAGGT GACTGGCA-AG

AATTCCGGGA

300

ACCACCTGCA

GGACCGAAAC

AA.ATGCATCA

GGCCGCACCC

AAAACTGACG

WO 97/12985 PCTIUS96/1 5774 324 TTCTATCTGG TTAccCTTGA GCAAGCGCAG GAACAACAGT ACGTACAGGG

CGGTGGAGGC

360

TCCCCGGGTG

420

TTCGCCTCTG

480

TTCCTGGAGG

540

GCCAGCTCCC

600

GGCGATGGCG

660

GAGCTGGTGC

720

AGCCAGGCCC

780

CAGGGGCTCC

840

CTGCAGCTGG

900

ATGGCCCCTG

927

GTGGTTCTGG

CTTTCCAGCG

TGTCGTACCG

TGCCCCAGAG

CAGCGCTCCA

TGCTCGGACA

TGCAGCTGGC

TGCAGGCCCT

ACGTCGCCGA

CCCTGCAGCC

CGGCGGCTCC

CCGGGCAGGA

CGTTCTACGC

CTTCCTGCTC

GGAGAAGCTG

CTCTCTGGGC

AGGCTGCTTG

GGAAGGGATA

CTTTGCCACC

CTAATAA

AACATGGCTA

GGGGTCCTGG

CACCTTGCGC

AAGTCTTTAG

TGTGCCACCT

ATCCCCTGGG

AGCCAACTCC

TCCCCCGAGT

CCCAGGGTGC

TTGCTAGCCA

AGCCCACACC

AGCAAGTGAG

ACAAGCTGTG

CTCCCCTGAG-

ATAGCGGCCT

TGGGTCCCAC

CATGCCGGCC

TCTGCAGAGC

ATTGGGCCCT

AA.AGATCCAG

CCACCCCGAG

CTCCTGCCCC

TTTCCTCTAC

CTTGGACACA

ACCATCTGGC AGCAGATGGA AGAACTGGGA INFORMATION FOR SEQ ID NO: 111: SEQUENCE

CHARACTERISTICS:

LENGTH: 972 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 111: ATGGCTAACT GCTCTATAJAT GATCGATGA ATTATACATC ACTTAAAGAG

ACCACCTGCA

CCTTTGCTGG ACCCGAACAA CCTCAATGAC GAAGACGTCT CTATCCTGAT

GGACCGAAAC

120 WO 97/12985PCIS6157 PCT/US96/15774 CTTCGACTTC CAAACCTGGA 180 GGTATTGAGG CAATTCTTCG 240 TCTCGACATC CAATCATCAT 300 TTCTATCTGG TTACCCTTGA 360 TCCCCGGGTG AACCGTCTGG 420 TCTCATAAAT

CTCCAAACAT

480 CAGCGCCGGG CAGGAGGGGT 540 TACCGCGTTC TACGCCACCT 600 CAGAGCTTCC TGCTCAAGTC 660 CTCCAGGAGA

AGCTGTGTGC

720 GGACACTCTC TGGGCATCCC 780 CTGGCAGGCT GCTTGAGCCA 840 GCCCTGGAAG GGATATCCCC 900 GCCGACTTTG CCACCACCAT 960 CAGCCCTAAT AA 972

GAGCTTCGTA

TAATCTCCAA

CAAGGCAGGT

GCAAGCGCAG

TCCAATCTCT

GGCTACCCAG

CCTGGTTGCT

TGCGCAGCCC

TTTAGAGCAA

CACCTACAAG

CTGGGCTCCC

ACTCCATAGC

CGAGTTGGGT

CTGGCAGCAG

AGGGCTGTCA AGA.ACTTAGA

AAATGCATCA

CCATGTCTGC CCTCTGCCAC

GGCCGCACCC

GACTGGCAAG A.ATTCCGGGA

AAAACTGACG

GAACAACAGT ACGTAGAGGG

CGGTGGAGGC

ACTATCAACC CGTCTCCTCC

GTCTAAAGAA

GGTGCCATGC CGGCCTTCGC

CTCTGCTTTC

AGCCATCTGC AGAGCTTCCT

GGAGGTGTCG

ACACCATTGG GCCCTGCCAG

CTCCCTGCCC

GTGAGAAAGA TCCAGGGCGA

TGGCGCAGCG

CTGTGCCACC CCGAGGAGCT

GGTGCTGCTC

CTGAGCTCCT GCCCCAGCCA GGCCCTGCAG GGCCTTTTCC TCTACCAGGG GCTCCTGCAG CCCACCTTGG ACACACTGCA

GCTGGACGTC

ATGGAAGA-AC TGGGAATGGC CCCTGCCCTG INFORMATION FOR SEQ ID NO: 112: SEQUENCE CHARACTERISTICS: LENGTH: 927 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear WO 97112985 PCT/US96/1 5774 326 (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)" (xd) SEQUENCE DESCRIPTION: SEQ ID NO: 112: ATGGCTAACT GCTCTATAAT GATCGATGAA ATTATACATC ACTTAAAGAG

ACCACCTGCA

CCTTTGCTGG

120

CTTCGACTTC

180 GGTATTcJAGG 240

TCTCGACATC

300 TTCU2ATCTGG 360

TCCCCGGGTG

420

GGAGGGTCC

480 CGCCAC CTTG 540 CTCAAG T'CTT 600

CTGTGGCCA

660

GGCA'PCCCCT

720 TTGAkGCCAAC 780

ATATCCCCCG

840 ACCAkCCkTCT 900

ACCCGAACAA

CAAACCTGGA

CAATTCTTCG

CAATCATCAT

TTACCCTTGA

GTGGTTCTGG

TGGTTGCTAG

CGCAGCCCAC

TAGAGCAAGT

CCTACAAGCT

GGGCTCCCCT

TCCATAGCGG

AGTTGGGTCC

GGCAGCAGAT

CCTCAATGAC

GAGCTTCGTA

TAATCTCCAA

CAAGGCAGGT

GCAAGCGCAG

CGGCGGCTCC

CCATCTGCAG

ACCATTGGGC

GAGAAAGATC

GTGCCACCCC

GAGCTCCTGC

CCTTTTCCTC

CACCTTGGAC

GGAAGAACTG

GAAGACGTCT

AGGGCTGTCA

CCATGTCTGC

GACTGGCAAG

GA-ACAACAGT

AACATGGCTT

AGCTTCCTGG

CCTGCCAGCT

CAGGGCGATG

GAGGAGCTGG

CCCAGCCAGG

TACCAGGGGC

ACACTGCAGC

GGAATGGCCC

CTATCCTGAT

AGAACTTAGA

CCTCTGCCAC

AATTCCGGGA

ACGTAGAGGG

CTGCTTTCCA

AGGTGTCGTA

CCCTGCCCCA

GCGCAGCGCT

TGCTGCTCGG

CCCTGCAGCT

TCCTGCAGGC

TGGACGTCGC

CTGCCCTGCA

GGACCGAAAC

AA.ATGCATCA

GGCCGCACCC

AAAACTGACG

CGGTGGAGGC

GCGCCGGGCA

CCGCGTTCTA

GAGCTTCCTG

CCAGGAGAAG

ACACTCTCTG

GGCAGGCTGC

CCTGGAAGGG

CGACTTTGCC

GCCCACCCAG

WO 97/12985 PCTIUS96/15774 327 GGTGCCATGC CGGCCTTCGC

CTAATAA

927 INFORMATION FOR SEQ ID NO: 113: Wi SEQUENCE CHARACTERISTICS: LENGTH: 972 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic),, (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 113: ATGGCTAACT GCTCTATAAT GATCGATGAA ATTATACATC ACTTAAAGAG

ACCACCTGCA

CCTTTGCTGG

120

CTTCGACTTC

180

GGTATTGAGG

240

TCTCGACATC

300

TTCTATCTGG

360

TCCCCGGGTG

420

TCTCATAAAT

480

GCTAGCCATC

540

CCCACACCAT

600

CAAGTGAGAA

660

AAGCTGTGCC

720

ACCCGAACAA

CAAACCTGGA

CA.ATTCTTCG

CAATCATCAT

TTACCCTTGA

AACCGTCTGG

CTCCAAACAT

TGCAGAGCTT

TGGGCCCTGC

AGATCCAGGG

ACCCCGAGGA

CCTCAATGAC

GAGCTTCGTA

TAATCTCCAA

CAAGGCAGGT

GCAAGCGCAG

TCCAATCTCT

GGCTTCTGC!T

CCTGGAGGTG

CAGCTCCCTG

CGATGGCGCA

GCTGGTGCTG

GAAGACGTCT

AGGGCTGTCA

CCATGTCTGC

GACTGGCAAG

GAACAACAGT

ACTATCAACC

TTCCAGCGCC

TCGTACCGCG

CCCCAGAGCT

GCGCTCCAGG

CTCGGACACT

CTATCCTGAT

AGAACTTAGA

CCTCTGCCAC

AATTCCGGGA

ACGTAGAGGG

CGTCTCCTCC

GGGCAGGAGG

TTCTACGCCA

TCCTGCTCAA

AGAAGCTGTG

CTCTGGGCAT

GGACCGAAAC

AAATGCATCA

GGCCGCACCC

AAAACTGACG

CGGTGGAGGC

GTCTAAAGAA

GGTCCTGGTT

CCTTGCGCAG

GTCTTTAGAG

TGCCACCTAC

CCCCTGGGCT

WO 97/12985 PCTIUS96/15774 328 CCCCTGAGCT CCTGCCCCAG CCAGGCCCTG CAGCTGGCAG GCTGCTTGAG

CCAACTCCAP

AGCGGCCTTT TCCTCTACCA GGGGCTCCTG CAGGCCCTGG AAGGGATATC

CCCCGAGTTG

840 GGTCCCACCT TGGACACACT GCAGCTGGAC GTCGCCGACT TTGCCACCAC

CATC'PGGCAG

900 CAGATGGAAG AACTGGGAAT GGCCCCTGCc CTGCAGCCCA CCCAGGGTGC

CATGCCGGC!C

960 TTCGCCTAAT

AA

972 INFORMATION FOR SEQ ID NO: 114: Wi SEQUENCE CHARACTERISTICS: LENGTH: 963 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: Idesc "DNA (synthetic)" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 114: ATGGCTAACT GCTCTAACAT GATCGATGAA ATCATCACCC

ACCTGAAGCA

CCGCTGCTGG ACTTCAACAA CCTCAATGGT GAAGACCAAG

ATATCCTAJAT

120 CTTCGTCGTC CAAACCTCGA GGCATTCAAC CGTGCTGTCA

AGTCTCTGCA

180 GCAATTGAGA GCATTCTTA AAATCTCCTG CCATGTCTGC

CGCTAGCCAC

240 ACGCGACATC CAATCCATAT CAAGGACGGT GACTGGAATG

AATTCCGTCG

300 TTCTATCTGA AAACCTTGGA GAACGCGCAG GCTCAACAGT

ACGTAGAGGG

360 TCCCCGGGTG AA CCGTCTGG TCCAATCTCT ACTATCAACC

CGTCTCCTCC

420

GCCACCGCTG

GGACAATAAC

GAATGCATCA

GGCCGCA.CCC

TAAACTGACC

CGGTGGAGGC

GTCTAAAGAA

WO 97/12985 WO 97/ 2985PCT/US96/15774 TCTCATAAAT CTCCAAACAT GGCTACCCAG GGTGCCATGC CGGCCTTCGC 480 CAGCGCCGGG CAGGAGGGGT CCTGGTTGCT AGCCATCTGC

AGAGCTTCCT

540 TACCGCGTTC TACGCCACCT TGCGCAGCCC TCTGGCGGCT CTGGCGGCTC 600 CTGCTCAAGT CTTTAGAGCA AGTGAGAAAG ATCCAGGGCG ATGGCGCAGC 660 AAGCTGTGTG CCACCTACAA GCTGTGCCAC CCCGAGGAGC

TGGTGCTGCT

720 CTGGGCATCC CCTGGGCTCC CCTGAGCTCC TGCCCCAGCC

AGGCCCTGCA

780 TGCTTGAGCC ALACTCCATAG CGGCCTTTTC CTCTACCAGG

GGCTCCTGCA

840 GGGATATCCC CCGAGTTGGG TCCCACCTTG GACACACTGC

AGCTGGACGT

900 GCCACCACCA TCTGGCAGCA GATGGAAGAA CTGGGAATGG

CCCCTGCCCT

960

TAA

963 INFORMATION FOR SEQ ID NO: 115: Wi SEQUENCE CHARACTERISTICS: LENGTH: 972 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic),,

CTCTGCTTTC

GGAGGTGTCG

TCAGAGCTTC

GCTCCAGGAG

CGGACACTCT

GCTGGCAGGC

GGCCCTGGAA

CGCCGACTTT

GCAGCCCTAX

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 115: ATGGCTAACT GCTCTAACAT GATCGATGAA ATCATCACCC ACCTGAAGCA

GCCACCGCTG

CCGCTGCTGG ACTTCAACAA CCTCAATGGT GAAGACCAAG ATATCCTGAT

GGAAAATAAC

120 CTTCGTCGTC CAAACCTCGA GGCATTCAAC CGTGCTGTCA AGTCTCTGCA

GAATGCATCA

180 WO 97/12985 PCT/US9'6/1 5774 GCAATTGAGA GCATTCTTAA AAATCTCCTG CCATGTCTGC CCCTGGCCAC

GGCCGCACCC

240

ACGCGACATC

300

TTCTATCTGA

360

TCCCCGGGTG

420

TCTCATAAAT

480

CAGCGCCGGG

540

TACCGCGTTC

600

CAGAGCTTCC

660

CTCCAGGAGA

720

GGACACTCTC

780

CAATCATCAT

AAACCTTGGA

AACCGTCTGG

CTCCAAACAT

CAGGAGGGGT

TACGCCACCT

TGCTCAAGTC

AGCTGTGTGC

TGGGCATCCC

CCGTGACGGT

GAACGCGCAG

TCCAATCTCT

GGCTACCCAG

CCTGGTTGCT

TGCGCAGCCC

TTTAGAGC)JA

CACCTACAAG

CTGGGCTC CC

GACTGGAATG

GCTCAACAGT

ACTATCAACC

GGTGCCATGC

AGCCATCTGC

ACACCATTGG

GTGAGAAAGA

CTGTGCCACC

CTGAGCTCCT

AATTCCGTCG

TAAACTGACC

ACOTAGAGGO

CGGTGGAGGC

CGTCTCCTCC

GTCTAAAGA

CGGCCTTCGC

CTCTGCTTTC

AGAGCTTCCT

GGAGGTGTCG

GCCCTGCCAG

CTCCCTGCCC

TCCAGGGCGA

TGGCGCAGCG

CCGAGGAGCT

GGTGCTGCTC

GCCCCAGCCA

GGCCCTGCAG

CTGGCAGGCT GCTTGAGCCA ACTCCATAGC GGCCTTTTCC

'CTACCAGGG

840 GCCCTGGAJAG GGATATCCCC CGAGTTGGGT CCCACCTTGG

ACACACTGCA

900 GCCGACTTTG CCACCACCAT CTGGCAGCAG ATGGAAGAAC

TGGGAATGGC

960 CAGCCCTAAT

AA

972 INFORMATION FOR SEQ ID NO: 116: SEQUENCE

CHARACTERISTICS:

LENGTH: 963 base pairs TYPE: nucleic acid STRANTJEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc ="DNA (synthetic),-

GCTCCTGCAG

GCTGGACGTC

CCCTGCCCTPG

WO 97/12985 PCT/US96/15774 331 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 116: ATGGCTAACT GCTCTAACAT GATCGATGAA ATCATCACCC ACCTGAAGCA

GCCACCGCTG

CCGCTCCTGG

120

CTTCGTCGTC

180

GCAATTGAGA

240

ACGCGACATC

300

TTCTATCTGA

360

TCCCCGGGTG

420

TCTCATAAAT

480

CAGCGCCGGG

540

TACCGCGTTC

600

CTGCTCAAGT

660

AAGCTGTGTG

720

CTGGGCATCC

780

TGCTTGAGCC

840

GGGATATCCC

900

GCCACCACCA

960

ACTTCAACAA

CAAACCTCGA

GCATTCTTAA

CAATCATCAT

AAACCTTGGA

AACCGTCTGG

CTCCAAACAT

CAGGAGGGGT

TACGCCACCT

CTTTAGAGCA

CCACCTACAA

CCTGGGCTCC

AACTCCATAG

CCGAGTTGGG

TCTGGCAGCA

CCTCAATGGT

GGCATTCAAC

AAATCTCCTG

CCGTGACGGT

GAACGCGCAG

TCCAATCTCT

GGCTACCCAG

CCTGGTTGCT

TGCGCAGCCC

AGTGAGAAAG

GCTGTGCCAC

CCTGAGCTCC

CGGCCTTTTC

TCCCACCTTG

GATGGAAGAA

GAAGACCAAG

CGTGCTGTCA

CCATGTCTGC

GACTGGAATG

GCTCAACAGT

ACTATCAACC

GGTGCCATGC

AGCCATCTGC

TCTGGCGGCT

ATCCAGGGCG

CCCGAGGAGC

TGCCCCAGCC

CTCTACCAGG

GACACACTGC

CTGGGAATGG

ATATCCTGAT

AGTCTCTGCA

CCCTGGCCAC

AATTCCGTp

ACGTAGAGGG

CGTCTCCTCC

CGGCCTTCGC

AGAGCTTCCT

CTGGCGGCTC

ATGGCGCAGC

TGGTGCTGCT

AGGCCCTGCA

GGCTCCTGCA

AGCTGGACGT

CCCCTGCCCT

GGA7AATAAC

GAATGCATCA

GGCCGCACCC

TAAACTGACC

CGGTGGAGGC

GTCTAAAGAA

CTCTGCTTTC

GGAGGTGTC!G

TCAGAGCTTC

GCTCCAGGAG

CGGACACTCT

GCTGGCAGGC

GGCCCTGGAA

CGCCGACTTT

GCAGCCCTAA

WO 97/12985 PCTIUS96/15774 332

TAA

963 INFORMATION FOR SEQ ID NO: 117: ()SEQUENCE

CHARACTERISTICS:

LENGTH: 972 base pairs TYPE: nucleic acid STRANDEDNESS; single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic),- (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 117: ATGGCTAACT GCTCTAACAT GATCGATGAA ATCATCACCC ACCTGAAGCA

GCCACCGCTG

CCGCTGCTGG ACTTCAACAA CCTCAATGGT.GAAGACCAG ATATCCTAAT

GGACAATAAC

120

CTTCGTCGTC

180

GCAATTGAGA

240

ACGCGACATC

300

TTCTATCTGA

360

TCCCCGGGTG

420.

TCTCATAAAT

480

CAGCGCCGGG

540

TACCGCGTTC

600

CAGAGCTTCC

660

CTCCAGGAGA

720

CAAACCTCGA

GCATTCTTAA

CAATCCATAT

AAACCTTGGA

AACCGTCTGG

CTCCAAACAT

CAGGAGGGGT

TACGCCACCT

TGCTCAAGTC

AGCTGTGTGC

GGCATTCAAC CGTGCTGTCA AGTCTCTGCA

GAATGCATCA

AAATCTCCTG

CAAGGACGGT

GAACGCGCAG

TCCAATCTCT

GGCTACCCAG

CCTGGTTGCT

TGCGCAGCCC

TTTAGAGCA

CACCTACAAG

CCATGTCTGC

GACTGGAATG

GCTCAACAGT

ACTATCAACC

GGTGCCATGC

AGCCATCTGC

ACACCATTGG

GTGAGAAAGA

CTGTGCCACC

CGCTAGCCAC

GGCCGCACCC

AATTCCGTCG

TAAACTGACC

ACGTAGAGGG

CGGTGGAGGC

CGTCTCCTCC GTCTAAAGAAj CGGCCTTCGC

CTCTGCTTTC

AGAGCTTCCT

GGAGGTGTCG

GCCCTGCCAG

CTCCCTGCCC

TCCAGGGCGA

TGGCGCAGCG

CCGAGGAGCT GGTGCTGCTC WO 97/12985 PCTJUS96/1 S774 333 GGACACTCTC TGGGCATCCC CTGGGCTCCC CTGAGCTCCT GCCCCAGCCA

GGCCCTGCAG

780 CTGGCAGGCT GCTTGAGCCA ACTCCATAGC GGCCTTTTCC TCTACCAGGG

GCTCCTGCAG

840 GCCCTGGAAG GGATATCCCC CGAGTTGGGT CCCACCTTGG ACACACTGCA

GCTGGACGTC

900 GCCGACTTTG CCACCACCAT CTGGCAGCAG ATGGAAGAAC TGGGAATGGC

CCCTGCCCTG

960 CAGCCCTAAT

AA

972 INFORMATION FOR SEQ ID NO: 118: SEQUENCE CHARACTERISTICS: LENGTH: 918 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 118: GCTAACTGCT CTATAATGAT CGATGAAATT ATACATCACT TAAAGAGACC

ACCTGCACCT

TTGCTGGACC CGAACAACCT CAATGACGAA GACGTCTCTA TCCTGATGGA

CCGAAACCTT

120 CGACTTCCAA ACCTGGAGAG CTTCGTAAGG GCTGTCAA.GA ACTTAGAAAA

TGCATCAGGP

180 ATTGAGGCAA TTCTTCGTAA TCTCCAACCA TGTCTGCCCT CTGCCACGGC

CGCACCCTCP

240 CGACATCCAA TCATCATCAA GGCAGGTGAC TGGCAAGAAT TCCGGGAAAA~

ACTGACGTTC

300 TATCTGGTTA CCCTTGAGCA AGCGCAGGA CAACAGTACG TAGAGGGCGG TGGAGGCTcC 360 CCGGGTGAAC CGTCTGGTCC AATCTCTACT ATCAACCCGT CTCCTCCGTC

TAAAGAATCT

420 WO 97/12985 PCTIUS9615774 CATAAATCTC CPNJUCATGGA GGTTCACCCT TTGCCTACAC CTGTCCTGCT

GCCTGCTGTG

480 GACTTTAGC? IXGGAGAATG GAAAACCCAG ATGGAGGAGA CCAAGGCACA

GGACATTCTG

540 GGAGCAGTG-k CCTTCTGCT GGAGGGAGTG ATGGCAGCAC GGGGACAACT

GGGACCCACT

600 TGCCTC-TCAT CCF!CCTGGG GCAGCTTTCT GGACAGGTCC GI'CTCCTCCT

TGGGGCCCTG

660 CAGAGCCTCC TVIGGAACCCA GCTTCCTCCA CAGGGCAGGA CCACAGCTCA

CAAGGATCCC

720 AATGCCATC? 'r!CrGAGCTT CCAACACCTG CTCCGAGGAA AGGTGCGTTT

CCTGATGCTT

780 GTAGGAGGGT CC~kCCCTCTG CGTCAGGGAA TTCGGCGGCA ACATGGCGTC

TCCCGCTCCG

840 CCTGCTTGM .AZC 'CCGAGT CCTCAGTAAA CTGCTTCGTG ACTCCCATGT

CCTTCACAGC

900 AGACTGAGCT AC VGCCCA 918 INFOR{ATZ09~ FOR SEQ ID NO: 119: Wi SEQCJB1CE

CHARACTERISTICS:

-(AD LENGTH: 918 base pairs 1VYPE: nucleic acid STRANDEDNESS: single VOPOLOGy: linear (ii) I{OEECIJLE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)" (xi) grQUJETCE DESCRIPTION: SEQ ID NO: 119: GCI'AACTGLT C'TA'AATGAT CGATGAAATT ATACATCACT TAAAGAGACC

ACCTGCACCT

TTGCTGGACC CQACAACCT CAATGACGAA~ GACGTCTCTA TCCTGATGGA

CCGAAACCTT

120 CGACTTCCk AICCTGGAGAG CTTCGTAAGG GCTGTCAAGA ACTTAGAJA

TGCATCAGGT

180 ATTGAGGCPA PICTCGTAA TCTCCAACCA TGTCTGCCCT CTGCCACGGC

CGCACCCTCT

240 WO 97/1 2985 PCT/US96/15774

CGACATCCAA

300

TATCTGGTTA

360

CCGGGTGAAC

420

CATAAATCTC

480

GGAGAATGGA

540

CTTCTGCTGG

600

CTCCTGGGGC

660

GGAACCCAGC

720

CTGAGCTTCC

780

ACCCTCTGCG

840

CTCCGAGTCC

900

TGCCCAGAGG

918

TCATCATCAA

CCCTTGAGCA

CGTCTGGTCC

CAAACATGTT

AAACCCAGAT

AGGGAGTGAT

AGCTTTC!TGG

TTCCTCCAC!A

AACACCTGCT

TCAGGGAATT

TCAGTAAACT

TTCACCCT

GGCAGG'TGAC

AGCGCAGGAP.

AATCTCTACT

GCCTACAC-CP

GGAGGAGA\CC

GGCAGCACGG

ACAGGTCC

GGGCAGGACC

CCGAGGAAAC

CGGCGGCAAC:

7GGCAAGAAT

CAACAGTACG

A.TCAACCCGT

GTCCTGCTGC

AAGGCACAGG

GGACAACTGG

CTCCTCCTTG

k-CAGCTCACA

GTGCGTTTCC

ATGGCGTCTC

TCCGGGAAAA

TAGAGGGCGG

CTCCTCCGTC

CTGCTGTGGA

ACATTCTGGG

GACCCACTTG

GGGCCCTGCA

AGGATCCCAA

TGATGCTTGT

CCGCTCCGCC

ACTGACGTTC

TGGAGGCTCC

TAAAGAATCT

CTTTAGCTTG

AGCAGTGACC

CCTCTCATCC

GAGCCTCCTT

TGCCATCTTC

AGGAGGGTCC

TGCTTGTGAC

GCTTCGTGAC! VCCCATGTCC TTCACAGCAG ACTGAGCCAG INFORMATION FOR SEQ ID NO: 120: Mi SEQUENCE CHARACTERISTZCS: LENGTH: 918 base pairs TYPE: nucleic aocia STRANDEDNESS: s-ingle TOPOLOGY: linea= (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /dasc "DNA (synthetic),, (xi) SEQUENCE DESCRIPTIO9 S8Q ID NO: 120: WO 97/12985 PCT/US96/I 5774 GCTAACTGCT CTATAATGAr CGATGAAATT ATACATCACT TAAAGAGACC

ACCTGCACCT

TTGCTGGACC

120

CGACTTCCAJ

180

ATTGAGGCAP

240

CGACATCCAZ,

300

TATCTGGTTA

360

CCGGGTGAAC

420

CATAAATCTC

480

ACCCAGATGG

540

GGAGTGATGG

600

CTTTCTGGAC

660

CCTCCACAGG

720

CGACAACC~

ACCTGG-krGAcG -TTCTTCGrAA rCATCkT!2A CCCTTGA&

C

CGTCTG ~'C

CAAACMTG

AGGAG&CCA

CAGCACMG~3 AGGTCC7GTICT GCAG3GXCC3AC CAATGACGAA GACGTCTCTA TCCTGATGGA

CCGAAACCTT

CTTCGTAAGG GCTGTCAAGA TCTCCAACCz GGCAGGTGAc

AGCGCAGGAA

AATCTCTACT

CCTGCTGCCT

GGCACAGGAC

ACAACTGGGA

CCTCCTTGGG

AGCTCACAAG

TGTCTGCCCT

TGGCAAGAAT

CAACAGTACG

ATCAACCCGT

GCTGTGGACT

ATTCTGGGAG

CCCACTTGCC

GCCCTGCAGA

GATCCCAATG

ACTTAGAAA

CTGCCACGGC

TCCGGGAAAA

TAGAGGGCGG

CTCCTCCGTC

TTAGCTTGGG

CAGTGACCCT

TCTCATCCCT

GCCTCCTTGG

CCATCTTCCT

3AGGGTCCAC

C

=TGTGACCT

C

PGAGCCAGTG

C

TGCATCAGGT

CGCACCCTCT

ACTGACGTTC

TGGAGGCTCC

TAAAGAATCT

AGAATGGWA

TCTGCTGGAG

CCTGGGGCAG

ACCCAGCTT

'AGCTTCCAA

~CTCTGCGTC

-CGAGTCCTC

.CCAGAGGTT

CACCTGCTCC GAGGAAGCT GCGTTTCCTG

ATG

780 AGGGAATTCG GCGGCAC-AT GGCGTCTCCC

GCC

840 AGTAAACTGC TTCG'rGAC TC CCATGTCCTT

CAC

900 CACCCTTTGC

CTACACCT

918 INFORMATION Fo0r. SEQ ID NO: 121: Wi SEQUENc

CC-PARACTERISTICS.

LENG?1P: 918 base pairs TYPE: nucleic acid STRAAfEDNESS: single

CTTGTAG

CCGCCTG

AGCAGAC

WO 97/12985 PCTIUS96/1 5774 337 TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic),, (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 121: GCTAACTGCT CTATAATGAT CGATGAAATT ATACATOACT TAAAGAGACC

ACCTGCACCT

TTGCTGGACC CGAACAACCT CAATGACGAA GACGTCTCTA TCCTGATGGA

CCGAAACCTT

120 CGACTTCCAA ACCTGGAGAG CTTCGTAAGG GCTGTCAAGA ACTTAGAAAA

TGCATCAGGT

180 ATTGAGGCAA TTCTTCGTA TCTCCAACCA TGTCTGCCCT CTGCCACGGC

CGCACCCTCT

240 CGACATCCAA TCATCATCAA GGCAGGTGAC TGGCAAGAAT TCCGGGAAAA

ACTGACGTTC

300 TATCTGGTTA CCCTTGAGCA AGCGCAGGAA~ CAACAGTACG TAGAGGGCGG

TGGAGGCTCC

360 CCGGGTGAA~C CGTCTGGTCC AATCTCTACT ATCAACCCGT CTCCTCCGTC

TAAAGAATCT

420 CATAAATCTC CAAACATGGC TGTGGACTTT AGCTTGGGAG AATGGAAAAC

CCAGATGGAG

480 GAGACCAAGG CACAGGACAT TCTGGGAGCA GTGACCCTTC TGCTGGAGGG

AGTGATGGCA

540 GCACGGGGAC AACTGGGACC CACTTGCCTC TCATCCCTCC TGGGGCAGCT

TTCTGGACAG

600 GTCCGTCTCC TCCTTGGGGC CCTGCAGAGC CTCCTTGGAA CCCAGCTTCC

TCCACAGGGC

660 AGGACCACAG CTCACAAGGA TCCCAATGCC ATCTTCCTGA GCTTCCAACA

CCTGCTCCGA

720 GGAAAGGTGC GTTTCCTGAT GCTTGTAGGA GGGTCCACCC TCTGCGTCAG

GGAATTCGGC

780 GGCAACATGG CGTCTCCCGC TCCGCCTGCT TGTGACCTCC GAGTCCTCAG

TAAACTGCTT

840 CGTGACTCCC ATGTCCTTCA CAGCAGACTG AGCCAGTGCC CAGAGGTTCA

CCCTTTGCCT

900 WO 97/12985 PCT/US96/157 7 4 338 ACACCTGTCC

TGCTGCCT

918 INFORMATION FOR SEQ ID NO: 122: Mi SEQUENCE

CHARACTERISTICS:

LENGTH: 918 base pairs TYPE: nucleic acid STRANDEDNESs: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 122:- GCTAACTGCT CTATAATGAT CGATGAAATT ATACATCACT TAAAGAGACC

ACCTGCACCT

TTGCTGGACC CGAACAACCT CAATGACGAA GACGTCTCTA TCCTGATGGA

CCGAAACCTT

120 CGACTTCCAA ACCTGGAGAG CTTCGTAAGG GCTGTCAAGA ACTTAGAA

TGCATCAGGT

180 ATTGAGGCAA TTCTTCGTAA TCTCCAACCA TGTCTGCCCT CTGCCACGGC

CGCACCCTCT

240 CGACATCCAA TCATCATCA GGCAGGTGAC TGGCAAGAAT TCCGGGAAAAJ

ACTGACGTTC

300 TATCTGGTTA CCCTTGAGCA AGCGCAGGAA CAACAGTACG TAGAGGGCGG

TGGAGGCTCC

360 CCGGGTGAAC CGTCTGGTCC AATCTCTACT ATCAACCCGT CTCCTCCGTC

TAAAGATCT

420 CATAAATCTC CAAACATGGA CTTTAGCTTG GGAGAATGGA AAACCCAGAT

GGAGGAGACC

480 AAGGCACAGG ACATTCTGGG AGCAGTGACC CTTCTGCTGG AGGGAGTGAT

GGCAGCACGG

540 GGACAACTGG GACCCACTTG CCTCTCATCC CTCCTGGGGC AGCTTTCTGG

ACAGGTCCGT

600 CTCCTCCTTG GGGCCCTGCA GAGCCTCCTT GGAACCCAGC TTCCTCCACA

GGGCAGGACC

660 WO 97/1 2985 PCT/US96,1 5774 339 ACAGCTCACA AGGATCCCAA TGCCATCTTC CTGAGCTTCC AACACCTGCT

CCGAGGAAAG

720 GTGCGTTTCC TGATGCTTGT AGGAGGGTCC ACCCTCTGCG TCAGGGAATT

CGGCGGCAAC

780 ATGGCGTCTC CCGCTCCGCC TGCTTGTGAC CTCCGAGTCC TCAGTAAACT

GCTTCGTGAC

840 TCCCATGTCC TTCACAGCAG ACTGAGCCAG TGCCCAGAGG TTCACCCTTT

GCCTACACOT

900 GTCCTGCTGC

CTGCTGTG

918 INFORMATION FOR SEQ ID NO: 123: SEQUENCE

CHARACTERISTICS:

LENGTH: 907 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc DNA (synthetic)" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 123: GCTAACTGCT CTATAATGAT CGATGAAATT ATACATCACT TAAAGAGACC

ACCTGCACCT

TTGCTGGACC CGAACAACCT CAATGACGAA GACGTCTCTA TCCTGATGGA

CCGAAACCTT

120 CGACTTCCAA ACCTGGAGAG CTTCGTAAGG GCTGTCAAGA ACTTAGAAAA

TGCATCAGGT

180 ATTGAGGC. TTCTTCGTAA TCTCCAACCA TGTCTGCCCT CTGCCACGGC

CGCACCCTCT

240 CGACATCCAA TCATCATCAA GGCAGGTGAC TGGCAAGAAT TCCGGGAAAA

ACTGACGTTC

300 TATCGGTTAC CCTTGAGCAAk GCGCAGGAAC AACAGTACGT AGAGGGCGGT

GGAGGCTCCC

360 CGGGGAACCG TCTGGTCCAA TCTCTACTAT CAACCCGTCT CCTCCGTCTA

AAGAATCTCA

420 TAAACTCCAA ACATGGGAGA ATGGAAAACC CAGATGGAGG AGACCAAGGC

ACAGGACATT

480 WO 97/12985 PCTIUS96/'15774 CTGGAGCAGT GACCCTTCTG CTGGAGGGAG TGATGGCAGC ACGGGGACAA

CTGGGACCCA

540 CTTGCTCTCA TCCCTCCTGG GGCAGCTTTC TGGACAGGTC CGTCTCCTCC

TTGGGGCCCT

600 GCAGGCCTCC TTGGAACCCA GCTTCCTCCA CAGGGCAGGA CCACAGCTCA

CAAGGATCCC

660 AATGCATCTT CCTGAGCTTC CAACACCTGC TCCGAGGAAA GGTGCGTTTC

CTGATGCTTG

720 TAGGGGGTCC ACCCTCTGCG TCAGGGAATT CGGCGGCAAC ATGGCGTCTC

CCGCTCCGCC

780 TGCTGTGACC TCCGAGTCCT CAGTAAACTG CTTCGTGACT CCCATGTCCT

TCACAGCAGA

840 CTGACCAGTG CCCAGAGGTT CACCCTTTGC CTACACCTGT CCTGCTGCCT

GCTGTGGACT

900

TTAGTTG

907 INFORMATION FOR SEQ ID NO: 124: SEQUENCE

CHARACTERISTICS:

LENGTH: 918 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 124: GCTAACTGCT CTATAATGAT CGATGAAATT ATACATCACT TAAAGAGACC

ACCTGCACCT

TTGCTGGACC CGAACAACCT CAATGACGAA GACGTCTCTA TCCTGATGGA

CCGAAACCTT

120 CGACTTCCAA ACCTGGAGAG CTTCGTAAGG GCTGTCAAGA ACTTAGAAAA

TGCATCAGGT

180 ATTGAGGCAA TTCTTCGTA. TCTCCAACCA TGTCTGCCCT CTGCCACGGC

CGCACCCTCT

240 WO 97/12985 PCT/JS96I15774 341 CGACATCCAA TCATCATCAA GGCAGGTGAC TGGCAAGAT TCCGGGAAJAJ

ACTGACGTTC

300

TATCTGGTTA

360

CCGGGTGAAC

420

CATAAATCTC

480

CAGGTCCGTC

540

GGCAGGACCA

600

CGAGGAAAGG

660

GGCGGCAACA

720

CTTCGTGACT

780

CCTACACCTG

840

GAGGAGACCA

900

GCAGCACGGG

918

CCCTTGAGCA

CGTCTGGTCC

CAAACATGGG

TCCTCCTTGG

CAGCTCACAA

TGCGTTTCCT

TGGCGTCTCC

CCCATGTCCT

TCCTGCTGCC

AGGCACAGGA

GACAACTG

AGCGCAGGAA

AATCTCTACT

ACCCACTTGC

GGCCCTGCAG

GGATCCCAAT

GATGCTTGTA

CGCTCCGCCT

TCACAGCAGA

TGCTGTGGAC

CATTCTGGGA

CAACAGTACG

ATCAACCCGT

CTCTCATCCC

AGCCTCCTTG

GCCATCTTCc

GGAGGGTCCA

GCTTGTGACC

CTGAGCCAGT

TTTAGCTTGG

GCAGTGACCC

TAGAGGGCGG

CTCCTCCGTC

TCCTGGGGCA

GAACCCAGCT

TGAGCTTCCA

CCCTCTGCG'

TCCGAGTCCT

GCCCAGAGGT

GAGAATGGA

TTCTGCTGGA

TGGAGGCTCC

TAAAGAATCT

GCTTTCTGGA

TCCTCCACAG

ACACCTGCTC

CAGGGAATTC

CAGTAAACTG

TCACCCTTTG

AACCCAGATG

GGGAGTGATG

INFORMATION FOR SEQ ID NO: 125: Wi SEQUENCE

CHARACTERISTICS:

LENGTH: 848 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 125: GCTAACTGCT CTATAATGAT CGATGAA.ATT ATACATCACT TAAAGAGACC

ACCTGCACCT

WO 97/12985 PCTIUS96/'15774

TTGCTGGACC

120 CGAACAACCT CAATGACGL GACGTCTCTA TCCTGATGGA

CCCAAACCTT

CGACTTCCAA ACCTGGAGAG CTTCGTAAGG GCTGTCAAGA

ACTTAGAAA]

180 ATTGAGGCAA TTCTTCGTA TCTCCAACCA TGTCTGCCCT

CTGCCACGGC

240 CGACATCCA TCATCATCAA GGCAGGTGAC TGGCAAGAAT TCCGGGAAj 300 TATCTGGTTA CCCTTGAGCA AGCGCAGGAA CAACAGTACG

TAGAGGGCGG

360 CCGGGTGAAC CGTCTGGTCC AATCTCTACT ATCAACCCGT

CTCCTCCGTC

420 CATAAATCTC CAAACATGGG AACCCAGCTT CCTCCACAGG

GCAGGACCAC

480 GATCCCAATG CCATCTTCCT GAGCTTCCAjA CACCTGCTCC

GAGGAAAGGT

540 ATGCTTGTAG GAGGGTCCAC CCTCTGCGTC AGGGAATTCG

GCGGCAACAT

600 GCTCCGCCTG CTTGTGACCT CCGAGTCCTC AGTAAACTGC

TTCGTGACTC

660 CACAGCAGAC TGAGCCAGTG CCCAGAGGTT CACCCTTTGC

CTACACCTGT

720 GCTGTGGACT TTAGCTTGGG AGAATGGAAA ACCCAGATGG

AGGAGACCAA

780 ATTCTGGGAG CAGTGACCCT TCTGCTGGAG GGAGTGATGG

CAGCACGGGG

840

CCCACTTG

848 INFORMATION FOR SEQ ID NO: 126: Wi SEQUENCE

CHARACTERISTICS:

LENGTH: 918 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc ="DNA (synthetic)"

TGCATCAGGT

CGCACCCTCT

ACTGACGTTC

TGGAGGCTCC

TAAAGAATCT

AGCTCACAAG

GCGTTTCCTG

GGCGTCTCCC

CCATGTCCTT

CCTGCTGCCT

GGCACAGGAC

ACAACTGGGA

WO 97/12985 PCT/US96/15774 343 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 126:

GCTAACTGCT

CTATAATGAT CGATGAAATT ATACATCACT TAAAGAGACC

ACCTGCACCT

TTGCTGGACC

120 CGACTTCCzA 180 ATTGAGGCAjA 240

CGACATCC,

300

TATCTGGTTA

360

CCGGGTGAAC

420

CATAAATCTC

480 AGCTTCCA~c 540

CTCTGCGTCA

600

CGAGTCCTCA

660

CCAGAGGTTC

720

GAATGGAAAA

CGAACAACCT

ACCTGGAGAG

TTCTTCGTAA

TCATCATCAA

CCCTTGAGCA

CGTCTGGTCC

CAAACATGGG

ACCTGCTCCG

GGGAATTCGG

GTAAACTGCT

ACCCTTTGCC

CCCAGATGGA

CAATGACGAA

CTTCGTAAGG

TCTCCAACCA

GGCAGGTGAC

AGCGCAGGpjA

AATCTCTACT

CAGGACCACA

AGGAAAGGTG

CGGCAACATG

TCGTGACTCC

rACACCTGTC

GGAGACCAAGC

GACGTCTCTA

GCTGTCAAGA

TGTCTGCCCT

TGGCAAkGAAT

CAACAGTACG

ATCAACCCGT

GCTCACAAGG

CGTTTCCTGA

GCGTCTCCCG

CATGTCCTTC

TGCTGCCTG

'CACAGGACA

~AACTGGGAC

C

TCCTTGGGG

C

TCCTGATGGA

ACTTAGAAAA

CTGCCACGGC

TCCGGGAAA

TAGAGGGCGG

CTCCTCCGTC

ATCCCAATGC

TGCTTGTAGG

C2TCCGCCTGC

ACAGCAGACT

TGTGGACTT ['TCTGGGAGC

P

~CACTTGCCT

C

~CCTGCAGAG

C

CCGAAACCTT

TGCATCAGGT

CGCACCCTCT

ACTGACGTTC

TGGAGGCTCC

TAAAGAATCT

CATCTTCCTG

kGGGTCCACC

L'TGTGACCTC

.AGCCAGTGC

'AGCTTGGGA

LGTGACCCTT

.TCATCCCTC

CTCCTTGGA

CTGCTGGAGG GAGTGATGGC AGCACGGGGA

C

840 CTGGGGCAGC TTTCTGGACA GGTCCGTCTC

C

900 ACCCAGCTTC

CTCCACAG

918 INFORMA4TION FOR SEQ ID NO: 127 WO 97/12985 PCTIUS96/'1577 4 344 Wi SEQUENCE

CHARACTERISTICS:

LENGTH: 918 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 127: GCTAACTGCT CTATAATGAT CGATGA.JATT ATACATCACT TAAAGAGACC

ACCTGCACCT

TTGCTGGACC CGAACAACCT

CAATGACGA

120

CGACTTCCAA

180

ATTGAGGCAA.

240

CGACATCCAA

300

TATCTGGTTA

360

CCGGGTGAAC

420

CATAAATCTC

480

CTGCTCCGAG

540

GAATTCGGCG

600

AAACTGCTTC

660

CCTTTGCCTA

720

ACCTGGAGAG

TTCTTCGTAA

TCATCATCAA

CCCTTGAGCA

CGTCTGGTCC

CAAACATGGC

GAAAGGTGCG

GCAACATGGC

GTGACTCCCA

CTTCGTAAGG

TCTCCAACCA

GGCAGGTGAC

AGCGCAGGJA

AATCTCTACT

TCACAAGGAT

TTTCCTGATG

GTCTCCCGCT

TGTCCTTCAC

GACGTCTCTA TCCTGATGGV

CCGAAACCTT

GCTGTCAAGA ACTTAGAAAA

TGCATCAGGT

TGTCTGCCCT CTGCCACGGC

CGCACCCTCT

TGGCAAGAAT TCCGGGAAAA

ACTGACGTTC

CAACAGTACG TAGAGGGCGG

TGGAGGCTCC

ATCAACCCGT CTCCTCCGTC

TAAAGAATCT

CCCAATGCCA TCTTCCTGAG

CTTCCAACAC

CTTGTAGGAG GGTCCACCCT

CTGCGTCAGG

CCGCCTGCTT GTGACCTCCG

AGTCCTCAGT

AGCAGACTGA GCCAGTGCCC

AGAGGTTCAC

GTGGACTTTA GCTTGGGAGA ATGGAXAAACC CACCTGTCCT

GCTGCCTGCT

CAGATGGAGG

780 AGACCAAGGC ACAGGACATT CTGGGAGCAG TGACCCTTCT

GCTGGAGGGA

WO 97112985 PCTIUS96/1 5774 345 GTGATGGCAG CACGGGGACA ACTGGGACCC ACTTGCCTCT CATCCCTCCT

GGGGCAGCTT

840 TCTGGACAGG TCCGTCTCCT CCTTGGGGCC CTGCAGAGCC TCCTTGG.AAC

CCAGCTTCCT

900 CCACAGGGCA

GGACCACA

918 INFORMATION FOR SEQ ID NO: 128: SEQUENCE

CHARACTERISTICS:

LENGTH: 918 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)", (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 128: GCTAACTGCT CTATAATGAT CGATGAAATT ATACATCACT TAAAGAGACC

ACCTGCACCT

TTGCTGGACC

120

CGACTTCCAA

180

ATTGAGGCAIA

240

CGACATCCAA

300

TATCTGGTTA

360

CCGGGTGAAC

420

CATAAATCTC

480

GGAAAGGTGC

540

GGCAACATGG

600

CGAACAACCT

ACCTGGAGAG

TTCTTCGTAA

TCATCATCAA

CCCTTGAGCA

CGTCTGGTCC

CAAACATGGA

GTTTCCTGAT

CGTCTCCCGC

CAATGACGAA

CTTCGTAAGG

TCTCCAACCA

GGCAGGTGAC

AGCGCAGGAA

AATCTCTACT

TC!CCAATGCC

GCTTGTAGGA

TCCGCCTGCT

GACGTCTCTA

GCTGTCAAGA

TGTCTGCCCT

TGGCAAGAAT

CAACAGTACG

ATCAACCCGT

ATCTTCCTGA

GGGTCCACCC

TGTGACCTCC

TCCTGATGGA

CCGAAACCTT

ACTTAGAAAA

TGCATCAGGT

CTGCCACGGC

CGCACCCTCT

TCCGGGAAAA

ACTGACGTTC

TAGAGGGCGG

TGGAGGCTCC

CTCCTCCGTC

TAAAGAATCT

GCTTCCAACA

CCTGCTCCGA

TCTGCGTCAG

GGAATTCGGC

GAGTCCTCAG TAAACTGCTT WO 97/12985 PCTIUS96/157 7 4 CGTGACTCCc ATGTCCTTCA CAGCAGACTG AGCCAGTGCC

CAGAGGTTCA

660 ACACCTGTCC TGCTGCCTGC TGTGGACTTT AGCTTGGGAG

AATGGAAAAC

720 GAGACCAAGG CACAGGACAT TCTGGGAGCA GTGACCCTTC

TGCTGGAGGG

780 GCACGGGGAC AACTGGGACC CACTTGCCTC TCATCCCTCC

TGGGGCAGCT

840 GTCCGTCTCC TCCTTGGGGC CCTGCAGAGC CTCCTTGGAA

CCCAGCTTCC

900 AGGACCACAG

CTCACAAG

918 INFORMATION FOR SEQ ID NO: 129: SEQUENCE

CHARACTERISTICS:

LENGTH: 918 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)"

CCCTTTGCCT

CCAGATGGAG

AGTGATGGCA

TTCTGGACAG

TCCACAGGGC

(Xi) SEQUENCE DESCRIPTION: SEQ ID NO: 129: GCTAACTGCT CTATAATGAT CGATGAAATT ATACATCACT

TAAAGAGACC

TTGCTGGACC CGAACAACCT CAATGACGA GACGTCTCTA

TCCTGATGGA

120 CGACTTCCA ACCTGGAGAG CTTCGTAAGG GCTGTCAAGA

ACTTAGAA

180 ATTGAGGC.ZA TTCTTCGTAA TCTCCAACCA TGTCTGCCCT

CTGCCACGGC

240 CGACATCCA TCATCATCAA GGCAGGTGAC TGGCAAGAAT

TCCGGGAAAA

300 TATCTGGTTA CCCTTGAGCA AGCGCAGOAA CAACAGTACG

TAGAGGGCGG

360

ACCTGCACCT

CCGAAACCTT

TGCATCAGGT

CGCACCCTCT

ACTGACGTTC

TGGAGGCTCC

WO 97/12985 PCT/US96/15774 CCCGGTGAAC CGTCTGGTCC AATCTCTACT ATCAACCCGT

CTCCTCCGTC

420 CATAAATCTC CAAACATGGC CATCTTCCTG AGCTTCCAAC

ACCTGCTCCG

480 CGTTTCCTGA TGCTTGTAGG AGGGTCCACC CTCTGCGTCA

GGGAATTCGG

540 GCGTCTCCCG CTCCGCCTGC TTGTGACCTc CGAGTCCTCA

GTAAACTGCT

600 CATGTCCTTC ACAGCAGACT GAGCCAGTGC CCAGAGGTTC

ACCCTTTGCC

660 CTGCTGCCTG CTGTGGACTT TAGCTTGGA GAATGGAAAA

CCCAGATGGA

720 GCACAGGACA TTCTGGGAGC AGTGACCCTT CTGCTGGAGG

GAGTGATGG

780 CAACTGGGAC CCACTTGCCT CTCATCCCTC CTGGGGCAGC

TTTCTGGACA

840 CTCCTTGGGG CCCTGCAGAG CCTCCTTGGA ACCCAGCTTC

CTCCACAGGG

900 GCTCACAAoo

ATCCCAAT

918 INFORMATION FOR SEQ ID NO: 130: Wi SEQUENCE

CHARACTERISTICS:

LENGTH: 915 base pairs TYPE: nucleic acid STRAN~DEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)"

TAAAGAATCT

AGGAAAGGTG

CGGCA.ACATG

TCGTGACTCC

TACACCTGTC

GGAGACCAAG

AGCACGGGGA

GGTCCGTCTC

CAGGACCACA

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 130: GCTA.ACTGCT CTATAATGAT CGATGAAATT ATACATCACT TAAAGAGACC

ACCTGCACCT

TTGCTGGACC CGAACAACCT CAATGACGAA GACGTCTCTA TCCTGATGGA

CCGAAACCTT

120 CGACTTCCAA ACCTGGAGAG CTTCGTAAGG GCTGTCAAGA ACTTAGAAAA

TGCATCAGGT

180 WO 97/12985 PCT/US96'1 5774 ATTGAGGCAJA TTCTTCGTAA TCTCCAACCA TGTCTGCCCT

CTGCCACGGC

240 CGACATCCAA~ TCATCATCAA GGCAGGTGAC TGGCAAGAT TCCGGGAApJA 300 TATCTGGTTA CCCTTGAGCA AGCGCAGGAA CAACAGTACG

TAGAGGGCGG

360 CCGGGTGAAC CGTCTGGTCC AATCTCTACT ATCAACCCGT

CTCCTCCGTC

420 CATAAATCTC CAAACATGGA GGTTCACCCT TTGCCTACAC

CTGTCCTGCT

480 GACTTTAGCT TGGGAGAATG GAAAACCCAG ATGGAGGAGA

CCAAGGCACA

540 GGAGCAGTGA CCCTTCTGCT GGAGGGAGTG ATGGCAGCAC

GGGGACAACT

600 TGCCTCTCAT CCCTCCTGGG GCAGCTTTCT GGACAGGTCC

GTCTCCTCCT

660 CAGAGCCTCC TTGGAACCCA GCTTCCTCCA CAGGGCAGGA CCACAGCTCA

C

720 AATGCCATCT TCCTGAGCTT CCAACACCTG CTCCGAGGAA AGGTGCGTTT

C

780 GTAGGAGGGT CCACCCTCTG CGTCAGGGAA TTCGGCAACA TGGCGTCTCC

C

840 GCTTGTGACC TCCGAGTCCT CAGTAAACTG CTTCGTGACT CCCATGTCCT

T

900 CTGAGCCAGT

GCCCA

915 INFORMATION FOR SEQ ID NO: 131: Wi SEQUENCE

CHARACTERISTICS:

LENGTH: 915 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: 'other nucleic acid DESCRIPTION: /desc "DNA (synthetic)"

CGCACCCTCT

ACTGACGTTC

TGGAGGCTCC

TAAAGAATCT

GCCTGCTGTG

GGACATTCTG

GGGACCCACT

['GGGGCCCTG

.AAGGATCCC

CTGATGCTT

GCTCCGCCT

CACAGCAGA

WO 97/12985 PCT/US96115774 349 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 131: GCTAACTGCT CTATAATGAT CGATGA.AATT A'TACATCACT TAAAGAGACC

ACCTGCACCT

TTGCTGGACC

120

CGACTTCCAA

180

ATTGAGGCAA

240

CGACATCCAA

300

TATCTGGTTA

360

CCGGGTGAAC

420

CATAAATCTC

480

GGAGAATGGA

540

CTTCTGCTGG

600

CTCCTGGGGC

660

GGAACCCAGC

720

CTGAGCTTCC

780

ACCCTCTGCG

840

*CGAACAACCT

ACCTGGAGAG

TTCTTCGTAA

TCATCATCAA

CCCTTGAGCA

CGTCTGGTCC

CAAACATGTT

AAACCCAGAT

AGGGAGTGAT

AGCTTTCTGG

TTCCTCCACA

AACACCTGCT

TCAGGGAATT

CAATGACGAA

CTTCGTAAGG

TCTCCAACCA

GGCAGGTGAC

AGCGCAGGAA

AATCTCTACT

GCCTACACCT

GGAGGAGACC

GGCAGCACGG

ACAGGTCCGT

GGGCAGGACC

CCGAGGAAAG

CGGCAACATG

GACGTCTCTA

GCTGTCAAGA

TGTCTGCCCT

TGGCAAGAAT

CAACAGTACG

ATCAACCCGT

GTCCTGCTGC

AAGGCACAGG

GGACAACTGG

CTCCTCCTTG

ACAGCTCACA

GTGCGTTTCC

GCGTCTCCCG

*TCCTGATGGA

ACTTAGAAAA~

CTGCCACGGC

TCCGGGAJAJ\

TAGAGGGCGG

CTCCTCCGTC

CTGCTGTGGA

ACATTCTGGG

GACCCACTTG

GGGCCCTGCA

AGGATCCCAA

TGATGCTTGT

CTCCGCCTGC

CCGAAACCTT

TGCATCAGGT

CGCACCCTCT

ACTGACGTTC

TGGAGGCTCC

TAAAGAATCT

CTTTAGCTTG

AGCAGTGACC

CCTCTCATCC

GAGCCTCCTT

TGCCATCTTC

AGGAGGGTCC

TTGTGACCTC

CGAGTCCTCA GTAAACTGCT TCGTGACTCC CATGTCCTTC ACAGCAGACT

GAGCCAGTGC

900 CCAGAGGTTC

ACCCT

915 INFORMATION FOR SEQ ID NO: 132: SEQUENCE

CHARACTERISTICS:

LENGTH: 915 base pairs WO 97/12985 PCTIUS96/1 5774 350 TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 132: GCTAACTGCT CTATAATGAT CGATGAAATT ATACATCACT TAAAGAGACC

ACCTGCACCT

TTGCTGGACC

120

CGACTTCCA.

180

ATTGAGGCAA

240

CGACATCCAA

300

TATCTGGTTA

360

CCGGGTGAAC

420

CATAAATCTC

480

ACCCAGATGG

540

GGAGTGATGG

600

CTTTCTGGAC

660

CCTCCACAGG

720

CACCTGCTCC

780

AGGGAATTCG

840

CGAACAACCT

ACCTGGAGAG

TTCTTCGTAA

TCATCATCAA

CCCTTGAGCA

CGTCTGGTCC

CAAACATGGT

AGGAGACcAAz

CAGCACGGGG

AGGTCCGTCT

GOAGGACCAC

GAGGAAAGGT

GCAACATGGC

CAATGACGAA

CTTCGTAAGG

TCTCCAACCA

GGCAGGTGAC

AGCGCAGGAJA

AATCTCTACT

CCTGCTGCCT

GGCACAGGAC

ACAACTGGGA

CCTCCTTGGG

AGCTCACAAG

GCGTTTCCTG

GTCTCCCGCT

GACGTCTCTA

GCTGTCAAGA

TGTCTGCCCT

TGGCAAGAAT

CAACAGTACG

ATCAACCCGT

GCTGTGGACT

ATTCTGGGAG

CCCACTTGCC

GCCCTGCAGA

GATCCCAATG

ATGCTTGTAG

CCGCCTGCTT

*TCCTGATGGA

ACTTAGA~a5

CTGCCACGGC

TCCGGGAAAA

TAGAGGGCGG

CTCCTCCGTC

TTAGCTTGGG

CAGTGACCCT

TCTCATCCCT

GCCTCCTTGG

CCATCTTCCT

CCGAAACCTT

TGCATCAGGT

CGCACCCTCT

ACTGACGTTC

TGGAGGCTCC

TAAAGAATCT

AGAATGGAAA

TCTGCTGGAG

CCTGGGGCAG

AACCCAGCTT

GAGCTTCCAA

GAGGGTCCAC

CCTCTGCGTC

GTGACCTCCG

AGTCCTCAGT

WO 97/12985 PCT/US96/1 5774 351 AAACTGCTTC GTGACTCCCA TGTCCTTCAC AGCAGACTGA GCCAGTGCCC

AGAGGTTCAC

900 CCTTTGCCTA

CACCT

915 INFORMATION FOR SEQ ID NO: 133: SEQUENCE

CHARACTERISTICS:

LENGTH: 915 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 133: GCTAACTGCT CTATAATGAT CGATGAAATT ATACATCACT TAAAGAGACC

ACCTGCACCT

TTGCTGGACC

120

CGACTTCCAA

180

ATTGAGGCAA

240

CGACATCCAA

300

TATCTGGTTA

360

CCGGGTGAAC

420

CATAAATCTC

480

GAGACCAAGG

540

GCACGGGGAC

600

GTCCGTCTCC

660

CGAACAACCT

ACCTGGAGAG

TTCTTCGTpjA

TCATCATCA

CCCTTGAGCA

CGTCTGGTCC

CAAACATGGC

CACAGGACAT

AACTGGGACC

CAATGACGAJA

CTTCGTAAGG

TCTCCAACCA

GGCAGGTGAC

AGCGCAGGAA

AATCTCTACT

TGTGGACTTT

TCTGGGAGCA

CACTTGCCTC

GACGTCTCTA

GCTGTCAAGA

TGTCTGCCCT

TGGCAAGAAT

CAACAGTACG

ATCAACCCGT

AGCTTGGGAG

GTGACCCTTC

TCCTGATGGA

ACTTAGAA

CTGCCACGGC

TCCGGGA)AAA

TAGAGGGCGG

CTCCTCCGTC

AATGGAAAAC

TGCTGGAGGG

CCGAAACCTT

TGCATCAGGT

CGCACCCTCT

ACTGACGTTC

TGGAGGCTCC

TAAAGAATCT

CCAGATGGAG

AGTGATGGCA

TCATCCCTCC TGGGGCAGCT

TTCTGGACAG

TCCTTGGGGC CCTGCAGAGC CTCCTTGGAA

CCCAGCTTCC

TCCACAGGGC

WO 97/12985 PCTIUS96/1 5774 352 AGGACCACAG CTCACAAGGA TCCCAATGCC ATCTTCCTGA GCTTCCAACA

CCTGCTCCGA

720 GGAAAGGTGC GTTTCCTGAT GCTTGTAGGA GGGTCCACCC TCTGCGTCAG

GGAATTCGGC

780 AACATGGCGT CTCCCGCTCC GCCTGCTTGT GACCTCCGAG TCCTCAGTAA

ACTGCTTCGT

840 GACTCCCATG TCCTTCACAG CAGACTGAGC CAGTGCCCAG AGGTTCACCC

TTTGCCTACA

900 CCTGTCCTGC

TGCCT

915 INFORMATION FOR SEQ ID NO: 134: i) SEQUENCE

CHARACTERISTICS:

LENGTH: 915 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: ldesc "DNA (synthetic)" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 134: GCTAACTGCT CTATAATGAT CGATGAAATT ATACATCACT TAAAGAGACC

ACCTGCACCT

TTGCTGGACC CGAACAACCT CAATGACGAA GACGTCTCTA TCCTGATGGA

CCGAAACCTT

120 CGACTTCCAA ACCTGGAGAG CTTCGTAAGG GCTGTCAAGA ACTTAGAAAA

TGCATCAGGT

180 ATTGAGGCAA TTCTTCGTAA TCTCCAACCA TGTCTGCCCT CTGCCACGGC

CGCACCCTCT

240 CGACATCCAA TCATCATCAA GGCAGGTGAC TGGCAAGAAT TCCGGGAAAA

ACTGACGTTC

300 TATCTGGTTA CCCTTGAGCA AGCGCAGGAA CAACAGTACG TAGAGGGCGG

TGGAGGCTCC

360 CCGGGTGAAC CGTCTGGTCC AATCTCTACT ATCAACCCGT CTCCTCCGTC

TAAAGAATCT

420 WO 97/12985 PCT/US96,1 5774 CATAAATCTC CAAACATGGA CTTTAGCTTG GGAGAATGGA

AAACCCAGAT

480 AAGGCACAGG ACATTCTGGG AGCAGTGACC CTTCTGCTGG

AGGGAGTGAT

540 GGACAACTGG GACCCACTTG CCTCTCATCC CTCCTGGGGC

AGCTTTCTGG

600 CTCCTCCTTG GGGCCCTGCA GAGCCTCCTT GGAACCCAGC

TTCCTCCACA

660 ACAGCTCACA AGGATCCCA TGCCATCTTC CTGAGCTTCC

AACACCTGCT

720 GTGCGTTTCC TGATGCTTGT AGGAGGGTCC ACCCTCTGCG

TCAGGGAATT

780 GCGTCTCCCG CTCCGCCTGC TTGTGACCTC CGAGTCCTCA GTAAACTGCj 840 CATGTCCTTC ACAGCAGACT GAGCCAGTGC CCAGAGGTTC

ACCCTTTGCC

900 CTGCTGCCTG

CTGTG

915 INFORMATION FOR SEQ ID NO: 135: SEQUENCE

CHARACTERISTICS:

LENGTH: 915 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)"

GGAGGAGACC

GGCAGCACGG

ACAGGTCCGT

GGGCAGGACC

CCGAGGAAAG

CGGCAACATG

TCGTGACTCC

TACACCTGTC

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 135: GCTAACTGCT CTATAATGAT CGATGAAATT ATACATCACT TAAAGAGACC

ACCTGCACCT

TTGCTGGACC CGAACAACCT CA-ATGACGAA GACGTCTCTA TCCTGATGGA

CCGAAACCTT

120 CGACTTCC,.A ACCTGGAGAG CTTCGTAAGG GCTGTCAAGA ACTTAGAAAM

TGCATCAGGT

180 ATTGAGGCAA TTCTTCGTAS TCTCCAACCA TGTCTGCCCT CTGCCACGGC

CGCACCCTCT

240 WO 97/12985 PCTI[US96/1 5774 CGACATCCAJA TCATCATCA GGCAGGTGAC TGGCAAGAAT TCCGGGAApJA

ACTGACGTTC

300 TATCTGGTTA CCCTTGAGCA AGCGCAGGA CAACAGTACG TAGAGGGCGG

TGGAGGCTCC

360 CCGGGTGAAC CGTCTGGTCC AATCTCTACT ATCAACCCGT CTCCTCCGTC

TAAAGAATCT

420 CATAAATCTC CAAACATGGG AGAATGGAAA ACCCAGATGG AGGAGACCAJA

GGCACAGGAC

480 ATTCTGGGAG CAGTGACCCT TCTGCTGGAG GGAGTGATGG CAGCACGGGG

ACAACTGGGA

540 CCCACTTGCC TCTCATCCCT CCTGGGGCAG CTTTCTGGAC AGGTCCGTCT

CCTCCTTGGG

600 GCCCTGCAGA GCCTCCTTGG AACCCAGCTT CCTCCACAGG GCAGGACCAC

AGCTCACAAG

660 GATCCCAATG CCATCTTCCT GAGCTTCCAA CACCTGCTCC GAGGAAAGGT

GCGTTTCCTG

720 ATGCTTGTAG GAGGGTCCAC CCTCTGCGTC AGGGAATTCG GCAACATGGC

GTCTCCCGCT

780 CCGCCTGCTT GTGACCTCCG AGTCCTCAGT AAACTGCTTC GTGACTCCCA

TGTCCTTCAC

840 AGCAGACTGA GCCAGTGCCC AGAGGTTCAC CCTTTGCCTA CACCTGTCCT

GCTGCCTGCT

900 GTGGACTTTA

GCTTG

915 INFORMATION FOR SEQ ID NO: 136: WI SEQUENCE

CHARACTERISTICS:

LENGTH: 915 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 136: WO 97/12985 PCTIUS96/1 5774 355 GCTAACTGCT CTATAATGAT CGATGAATT ATACATCACT TAAAGAGACC

ACCTGCACCT

TTGCTGGACC CGAACAACCT CAATGACGJA

GA

120 CGACTTCCAA ACCTGGAGAG CTTCGTAAGG

GC

180 ATTGAGGCA TTCTTCGTAA TCTCCAACCA

TG

240 CGACATCCAJA TCATCATCAA GGCAGGTGAC

TG(

300 TATCTGGTTA CCCTTGAGCA AGCGCAGGAA

CA)

360 CCGGGTGAAC CGTCTGGTCC AATCTCTACT

AT(

420 CATAAATCTC CAAACATGGG ACCCACTTGC

CTC

480 CAGGTCCGTC TCCTCCTTGG GGCCCTGCAG

AGC

540 GGCAGGACCA CAGCTCACAA GGATCCCAAT

GCC

600 CGAGGAAAGG TGCGTTTCCT GATGCTTGTA

GGA

660 GGCAACATGG CGTCTCCCGc TCCGCCTGCT

TGT

720 CGTGACTCCC ATGTCCTTCA CAGCAGACTG

AGC

780 ACACCTGTCC TGCTGCCTGC TGTGGACTTT

AGC

840 GAGACCAAGG CACAGGACAT TCTGGGAGCA

GTG

900 GCACGGGGAC

AACTG

915 INFORMATION FOR SEQ ID NO: 137: Wi SEQUENCE

CHARACTERISTICS:

LENGTH: 915 base pairs TYPE: nucleic acid STRANDEDNESS: single

CGTCTCTI

TGTCAAGA

TCTGCCCT

GCAAGAAT

CAGTACG

~AACCCGT

~TCATCCC

~CTCCTTG

ATCTTCC

GGGTCCA

GACCTCC

CAGTGCC

TTGGGAG

ACCCTTC

TCCTGATGGP

ACTTAGAJA

CTGCCACGGC

TCCGGGAAAA

TAGAGGGCGG

CTCCTCCGTC

TCCTGGGGCA

GAACCCAGCT

TGAGCTTCCA

CCCTCTGCGT

GAGTCCTCAG

CAGAGGTTCA

AATGGAAA\C

TGCTGGAGGG

CCGAAACCTT

TGCATCAGGT

CGCACCCTCT

ACTGACGTTC

TGGAGGCTCC

TAAAGAATCT

GCTTTCTGGA

TCCTCCACAG

ACACCTGCTC

CAGGGAATTC

TAAACTGCTT

CCCTTTGCCT

CCAGATGGAG

AGTGATGGCA

WO 97/12985 PCTJS96/1 5774 356 TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 137: GCTAACTGCT CTATAATGAT CGATGAAATT ATACATCACT TAAAGAGACC

ACCTGCACCT

TTGCTGGACC

120

CGACTTCCAA

180

ATTGAGGCAA

240

CGACATCCAA

300

TATCTGGTTA

360

CCGGGTGAAC

420

CATAAATCTC

480

GATCCCAATG

540

ATGCTTGTAG

600

CCGCCTGCTT

660

AGCAGACTGA

720

GTGGACTTTA

780 CTGGGAGCA3 840

ACTTGCCTCT

900

CGAACAACCT

ACCTGGAGAG

TTCTTCGTAA

TCATCATCAA

CCCTTGAGCA

CGTCTGGTCC

CAAACATGGG

CCATCTTCCT

GAGGGTCCAC

GTGACCTCCG

GCCAGTGCCC

GCTTGGGAGA

TGACCCTTCT

CATCCCTCCT

CAATGACGAA

CTTCGTAAGG

TCTCCAACCA

GGCAGGTGAC

AGCGCAGGAA\

AATCTCTACT

AACCCAGCTT

GAGCTTCCA

CCTCTGCGTC

AGTCCTCAGT

AGAGGTTCAC

ATGGAAAACC

GCTGGAGGGA

GGGGCAGCTT

*GACGTCTCTA

GCTGTCAAGA

TGTCTGCCCT

TGGCAAGAAT

CAACAGTACG

ATCAACCCGT

CCTCCACAGG

CACCTGCTCC

AGGGAATTCG

AAACTGCTTC

CCTTTGCCTA

CAGATGGAGG

GTGATGGCAG

TCTGGACAGG

TCCTGATGGA

ACTTAGAAAA

CTGCCACGGC

TCCGGGAAAA

TAGAGGGCGG

CTCCTCCGTC

GCAGGACCAC

GAGGAAAGGT

GCAACATGGC

GTGACTCCCA

CACCTGTCCT

AGACCAAGGC

CACGGGGACA

TCCGTCTCCT

CGCACCCTCT

ACTGACGTTC

TGGAGGCTCC

TAAAGAATCT

AGCTCACAAG

GCGTTTCCTG

GTCTCCCGCT

TGTCCTTCAC

GCTGCCTGCT

ACAGGACATT

ACTGGGACCC

CCTTGGGGCC

WO 97/12985 PCT/US96/15774 357 CTGCAGAGCC

TCCTT

915 INFORMATION FOR SEQ ID NO: 138: SEQUENCE CHARACTERISTICS: LENGTH: 915 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc ='DNA (synthetic)-" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 138: GCTAACTGCT CTATAATGAT CGATGAAATT ATACATCACT TAAAGAGACC

ACCTGCACCT

TTGCTGGACC

120

CGACTTCCAA

180

ATTGAGGCA

240

CGACATCCAA

300

TATCTGGTTA

360

CCGGGTGAAC

420

CATAAATCTC

480

AGCTTCCAAC

540

CTCTGCGTCA

600

GTCCTCAGTA

660

CGAACAACCT

ACCTGGAGAG

TTCTTCGTAA

TCATCATCAA

CCCTTGAGCA

CGTCTGGTCC

CAAACATGGG

ACCTGCTCCG

GGGAATTCGG

AACTGCTTCG

CAATGACGPAk

CTTCGTAAGG

TCTCCAACCA

GGCAGGTGAC

AGCGCAGGAA

AATCTCTACT

CAGGACCACA

AGGAAAGGTG

CAACATGGCG

TGACTCCCAT

GACGTCTCTA

GCTGTCAAGA

TGTCTGCCCT

TGGCAAGAAT

CAACAGTACG

ATCAACCCGT

GCTCACAAGG

CGTTTCCTGA

TCTCCCGCTC

GTCCTTCACA

TCCTGATGGA

ACTTAGAAAA

CTGCCACGGC

TCCGGGAAAA

TAGAGGGCGG

CTCCTCCGTC

ATCCCAATGC

TGCTTGTAGG

CGCCTGCTTG

GCAGACTGAG

CCGAAACCTT

TGCATCAGGT

CGCACCCTCT

ACTGACGTTC

TGGAGGCTCC

TAAAGAATCT

CATCTTCCTG

AGGGTCCACC

TGACCTCCGA

CCAGTGCCCA

WO 97/12985 PCT/US96/15 7 74 358 GAGGTTCACC CTTTGCCTAC ACCTGTCCTG CTGCCTGCTG TGGACTTTAG

CTTGGGAGAA

720 TGGAAAACCC AGATGGAGGA GACCAAGGCA CAGGACATTC TGGGAGCAGT

GACCCTTCTG

780 CTGGAGGGAG TGATGGCAGC ACGGGGACAA CTGGGACCCA CTTGCCTCTC

ATCCCTCCTG

840 GGGCAGCTTT CTGGACAGGT CCGTCTCCTC CTTGGGGCCC TGCAGAGCCT

CCTTGGAACC

900 CAGCTTCCTC

CACAO

915 INFORMATION FOR SEQ ID NO: 139: SEQUENCE

CHARACTERISTICS:

LENGTH: 915 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 139: GCTAACTGCT CTATAATGAT CGATGAAATT ATACATCACT TAAAGAGACC

ACCTGCACCT

TTGCTGGACC CGAACAACCT CAATGACGAA GACGTCTCTA TCCTGATGGA

CCGAAACCTT

120 CGACTTCCAA ACCTGGAGAG CTTCGTAAGG GCTGTCAAGA ACTTAGAAAA

TGCATCAGGT

180 ATTGAGGCAA TTCTTCGTAA TCTCCAACCA TGTCTGCCCT CTGCCACGGC

CGCACCCTCT

240 CGACATCCAA TCATCATCAA GGCAGGTGAC TGGCAAGAAT TCCGGGAAAA

ACTGACGTTC

300 TATCTGGTTA CCCTTGAGCA AGCGCAGGAA CAACAGTACG TAGAGGGCGG

TGGAGGCTCC

360 CCGGGTGAAC CGTCTGGTCC AATCTCTACT ATCAACCCGT CTCCTCCGTC

TAAAGAATCT

420 CATAAA~TCTC CAAACATGGC TCACAAGGAT CCCAATGCCA TCTTCCTGAG

CTTCCAACAC

480 WO 97/12985 PCTIUS96/1 5774 CTGCTCCGAG GAAAGGTGCG TTTCCTGATG CTTGTAGGAG GGTCCACCCT

CTGCGTCAGG

540 GAATTCGGCA ACATGGCGTC TCCCGCTCCG CCTGCTTGTG ACCTCCGAGT

CCTCAGTAAA

600 CTGCTTCGTG ACTCCCATGT CCTTCACAGC AGACTGAGCC AGTGCCCAGA

GGTTCACCCT

660 TTGCCTACAC CTGTCCTGCT GCCTGCTGTG GACTTTAGCT TGGGAGAATG

GAAAACCCAG

720 ATGGAGGAGA CCAAGGCACA GGACATTCTG GGAGCAGTGA CCCTTCTGCT

GGAGGGAGTG

780 ATGGCAGCAC GGGGACAACT GGGACCCACT TGCCTCTCAT CCCTCCTGGG

GCAGCTTTCT

840 GGACAGGTCC GTCTCCTCCT TGGGGCCCTG CAGAGCCTCC TTGGAACCCA

GCTTCCTCCA

900 CAGGOCAGGA

CCACA

915 INFORMATION FOR SEQ ID NO: 140: Wi SEQUENCE

CHARACTERISTICS:

LENGTH: 915 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 140: GCTAACTGCT CTATAATGAT CGATGAAATT ATACATCACT TAAAGAGACC

ACCTGCACCT

TTGCTGGACC CGAACAACCT CAATGACGAA GACGTCTCTA TCCTGATGGA

CCGAAACCTT

120 CGACTTCCAA ACCTGGAGAG CTTCGTAAGG GCTGTCAAGA ACTTAGAAA

TGCATCAGGT

180 ATTGAGGCAA TTCTTCGTAA TCTCCAACCA TGTCTGCCCT CTGCCACGGC

CGCACCCTCT

240 WO 97/1 2985 PCT/US96/15 7 7 4 CGACATCCAA TCATCATCA.J GGCAGGTGAC TGGCAAGAAT

TCCGGGAA

300 TATCTGGTTA CCCTTGAGCA AGCGCAGGAA CAACAGTACG

TAGAGGGC(

360 CCGGGTGAAC CGTCTGGTCC AATCTCTACT ATCAACCCGT

CTCCTCCG'

420 CATAAATCTC CAAACATGGA TCCCAATGCC ATCTTCCTGA

GCTTCCAAC

480 GGAAAGGTGC GTTTCCTGAT GCTTGTAGGA GGGTCCACCC

TCTGCGTCA

540 AACATGGCGT CTCCCGCTCC GCCTGCTTGT GACCTCCGAG

TCCTCAGTA

600 GACTCCCATG TCCTTCACAG CAGACTGAGC CAGTGCCCAG

AGGTTCACC

660 CCTGTCCTGC TGCCTGCTGT GGACTTTAGC TTGGGAGAJAT

GGAAAACCC

720 ACCAAGGCAC AGGACATTCT GGGAGCAGTG ACCCTTCTGC

TGGAGGGAG'

780 CGGGGACAAC TGGGACCCAC TTGCCTCTCA TCCCTCCTGG

GGCAGCTTTC

840 CGTCTCCTCC TTGGGGCCCT GCAGAGCCTC CTTGGAACCC

AGCTTCCTCC

900 ACCACAGCTC

ACAAG

9:15 INFORJMATION FOR SEQ ID NO: 141: SEQUENCE

CHARACTERISTICS:

LENGTH: 915 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)"

GC

P'C

A

C

A

~ACTGACGTTC

TGGAGGCTCC

TAA-AGAATCT

CCTGCTCCGA

GGAATTCGGC

ACTGCTTCGT

TTTGCCTACA

GATOGAGGAG

GATGGCAGCA

TGGACAGGTC

ACAGGGCAGG

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 141: GCTAACTGCT CTATAATGAT CGATGAAATT ATACATCACT TAAAGAGACC

ACGAC

ACGAC

WO 97/12985 PCTIUS96/15774

TTGCTGGACC

120

CGACTTCCAA

180

ATTGAGGCAA

240 CGACATCCAjA 300

TATCTGGTTA

360

CCGGGTGAAC

420

CATAAATCTC

480

CGTTTCCTGA

540

TCTCCCGCTC

600

GTCCTTCACA

660

CTGCCTGCTG

720

CGAACAACCT

ACCTGGAGAG

TTCTTCGTAA

TCATCATCA\

CCCTTGAGCA

CGTCTGGTCC

CAAACATGGC

TGCTTGTAGG

CGCCTGCTTG

"CAGACTGAG PGGACTTTAG C

CAATGACGAA

CTTCGTAAGG

TCTCCAACCA

GGCAGGTGAC

AGCGCAGGAA~

AATCTCTACT

CATCTTCCTG

AGGGTCCACC

EGACCTCCGA

~CAGTGCCCAC

TTGGGAGAA 'I

GACGTCTCTA

GCTGTCAAGA

TGTCTGCCCT

TGGCAAGAAT

CAACAGTACG

ATCAACCCGT

AGCTTCCAAC

CTCTGCGTCA

3TCCTCAGTA2

AGGTTCACC

'GGAAAACCC

TCCTGATGGA

ACTTAGAAAAj

CTGCCACGGC

TCCGGGAAA

TAGAGGGCGG

CTCCTCCGTC

ACCTGCTCCG

GGGAATTCGG

%ACTGCTTCG9 ~TTTGCCTAC z ~GATGGAGGA

G

CCGAAACCTT

TGCATCAGGT

CGCACCCTCT

ACTGACGTTC

TGGAGGCTCC

TAAAGAATCT

AGGAAAGGTG

.AACATGGCG

rGACTCCCAT

~CCTGTCCTG

~ACCAAGGCA

CAGGACATTC TGGGAGCAGT GACCCTTCTG

CTGGAGGGAG

780 CTGGGACCCA CTTGCCTCTC ATCCCTCCTG

GGGCAGCTTT

840 CTTGGGGCCC TGCAGAGCCT CCTTGGAACC

CAGCTTCCTC

900 CACAAGGATC

CCAAT

915 INFORMATION FOR SEQ ID NO: 142: Wi SEQUENCE

CHARACTERISTICS:

LENGTH: 921 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear

TGATGGCAGC

CTGGACAGGT

CACAGGGCAG

ACGGGGACAA

CCGTCTCCTC

GACCACAGCT

WO 97/12985 PCTJS96/1 5774 362 (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc ="DNA (synthetic),, (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 142: GCTAACTGCT CTATAATGAT CGATGAAATT ATACATCACT TAAAGAGACC

ACCTGCACCT

TTGCTGGACC CGAACAACCT CAATGACGAA GACGTCTCTA TCCTGATGGA

CCGAAACCTT

120 GACTTCCAAA CCTGGAGACC TTCGTAAGGG CTGTCAAGAA CTTAGAAAAT

GCATCAGGTA

180 TGAGGCAATT CTTCOTAATC TCCAACCATG TCTGCCCTCT GCCACGGCCG

CACCCTCTCG

240 CATCCAATCA TCATCAAGGC AGGTGACTGG CAAGAATTCC GGGA-AAAACT

GACCTTCTAT

300 TGGTTACCCT TGAGCAAGCG CAGGAACAAC AGTACGTAGA GGGCGGTGGA

GGCTCCCCGG

360 TAACCGTCTG GTCCAATCTC TACTATCAAC CCGTCTCCTC CGTCTAAAGA

ATCTCATAAAJ

420 TCTCCAAACA TGGAGGTTCA CCCTTTGCCT ACACCTGTCC TGCTGCCTGC

TGTGGACTTT

480 AGCTTGGGAG AATGGAAAAC CCAGATGGAG GAGACCAAGG CACAGGACAT

TCTGGGAGCA

540 GTGACCCTTC TGCTGGAGGG AGTGATGGCA GCACGGGGAC AACTGGGACC

CACTTGCCTC

600 TCATCCCTCC TGGGGCAGCT TTCTGGACAG GTCCGTCTCC TCCTTGGGGC

CCTGCAGAGC

660 CTCCTTGGAi.J CCCAGCTTCC TCCACAGGGC AGGACCACAG CTCACAAGGA

TCCCAATGCC

720 ATCTTCCTGA GCTTCCAACA CCTGCTCCGA GGAAAGGTGC GTTTCCTGAT

GCTTGTAGGA

780 GGGTCCACCC TCTGCGTCAG GGAATTCGGC GGCAACGGCG GCAACATGGC

GTCCCCAGCG

840 CCGCCTGCTT GTGACCTCCG AGTCCTCAGT AAACTGCTTC GTGACTCCCA

TGTCCTTCAC

900 WO 97/12985 PCT/US96/15 7 74 363 AGCAGACTGA GCCAGTGCCC

A

921 INFORMATION FOR SEQ ID NO: 143: i) SEQUENCE

CHARACTERISTICS:

LENGTH: 927 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic).

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 143: GCTAACTGCT CTATAATGAT CGATGAAATT ATACATCACT TAAAGAGACC

ACCTGCACCT

TTGCTGGACC CGAACAACCT CAATGACGAA GACGTCTCTA TCCTGATGGA

CCGAAACCTT

120 CGACTTCCAA ACCTGGAGAG CTTCGTAAGG GCTGTCAAGA ACTTAGAAAA

TGCATCAGGT

180 ATTGAGGCAA TTCTTCGTJAA TCTCCAACCA TGTCTGCCCT CTGCCACGGC

CGCACCCTCT

240 CGACATCCAA TCATCATCAA GGCAGGTGAC TGGCAAGAAT TCCGGGAAAA

ACTGACGTTC

300 TATCTGGTTA CCCTTGAGCA AGCGCAGGAA CAACAGTACG TAGAGGGCGG

TGGAGGCTCC

360 CCGGGTGAAC CGTCTGGTCC AATCTCTACT ATCAACCCGT CTCCTCCGTC

TAAAGAATCT

420 CATAAATCTC CAAACATGTT GCCTACACCT GTCCTGCTGC CTGCTGTGGA

CTTTAGCTTG

480 GGAGAATGGA AAACCCAGAT GGAGGAGACC AAGGCACAGG ACATTCTGGG

AGCAGTGACC

540 CTTCTGCTGG AGGGAGTGAT GGCAGCACGG GGACAACTGG GACCCACTTG

CCTCTCATCC

600 CTCCTGGGGC AGCTTTCTGG ACAGGTCCGT CTCCTCCTTG GGGCCCTGCA

GAGCCTCCTT

660 GGAACCCAGC TTCCTCCACA GGGCAGGACC ACAGCTCACA AGGATCCCAA

TGCCATCTTC

720 WO 97/12985 PCTIUS96/1 5774 364 CTGAGCTTCC AACACCTGCT CCGAGGAG GTGCGTTTCC TGATGCTTGT

AGGAGGGTCC

780 ACCCTCTGCG TCAGGGAATT CGGCGGCAAC GGCGGCAACA TGGCGTCCCC

AGCGCCGCCT

840 GCTTGTGACC TCCGAGTCCT CAGTAAACTG CTTCGTGACT CCCATGTCCT

TCACAGCAGA

900 CTGAGCCAGT GCCCAGAGGT

TCACCCT

927 INFORMATION FOR SEQ ID NO: 144: SEQUENCE

CHARACTERISTICS:

LENGTH: 927 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 144: GCTAACTGCT CTATAATGAT CGATGAAATT ATACATCACT TAAAGAGACC

ACCTGCACCT

TTGCTGGACC CGAACAACCT CAATGACGAA GACGTCTCTA TCCTGATGGA

CCGAAACCTT

120 CGACTTCCAA ACCTGGAGAG CTTCGTAAGG GCTGTCAAGA ACTTAGAAAA

TGCATCAGGT

180 ATTGAGGCAA TTCTTCGTAA TCTCCAACCA TGTCTGCCCT CTGCCACGGC

CGCACCCTCT

240 CGACATCCAA TCATCATCAA GGCAGGTGAC TGGCAAGAAT TCCGGGAAAA

ACTGACGTTC

300 TATCTGGTTA CCCTTGAGCA AGCGCAGGAA CAACAGTACG TAGAGGGCGG

TGGAGGCTCC

360 CCGGGTGAJAC CGTCTGGTCC AATCTCTACT ATCAACCCGT CTCCTCCGTC

TAAAGAATCT

420 CATAAATCTC CAAACATGGT CCTGCTGCCT GCTGTGGACT TTAGCTTGGG

AGAATGGA

480 WO 97/12985 PCT/US96/15774 ACCCAGATGG AGGAGACCAA GGCACAGGAC ATTCTGGGAG CAGTGACCCT

TCTGCTGGAG

540 GGAGTGATGG CAGCACGGGG ACAACTGGGA CCCACTTGCC TCTCATCCCT

CCTGGGGCAG

600 CTTTCTGGAC AGGTCCGTCT CCTCCTTGGG GCCCTGCAGA GCCTCCTTGG

AACCCAGCTT

660 CCTCCACAGG GCAGGACCAC AGCTCACAAG GATCCCAATG CCATCTTCCT

GAGCTTCCA

720 CACCTGCTCC GAGGAAAGGT GCGTTTCCTG, ATGCTTGTAG GAGGGTCCAC

CCTCTGCGTC

780 AGGGAATTCG GCGGCAACGG CGGCAACATG GCGTCCCCAG CGCCGCCTGC

TTGTGACCTC

840 CGAGTCCTCA GTAAACTGCT TCGTGACTCC CATGTCCTTC

ACAGCAGACT'GAGCCAGTGC

900 CCAGAGGTTC ACCCTTTGCC

TACACCT

927 INFORM4ATION FOR SEQ ID NO: 145: Wi SEQUENCE

CHARACTERISTICS:

LENGTH: 927 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 145: GCTAACTGCT CTATAATGAT CGATGAAATT ATACATCACT

TAAAGAGACC

TTGCTGGACC CGAACA3ACCT CAATGACGAA GACGTCTCTA

TCCTGATGGA

120 CGACTTCCAA ACCTGGAGAG CTTCGTAAGG GCTGTCAAGA

ACTTAGAAAA

180 ATTGAGGCA TTCTTCGTA TCTCCAACCA TGTCTGCCCT

CTGCCACGGC

240 CGACATCCAA TCATCATCAA GGCAGGTGAC TGGCAAGAT

TCCGGGAAAA~

300

ACCTGCACCT

CCGAAACCTT

TGCATCAGGT

CGCACCCTCT

ACTGACGTTC

WO 97/1 2985 PCTIUS96/1 5774 366 TATCTGGTTA CCCTTGAGCA AGCGCAGGAA CAACAGTACG TAGAGGGCGG

TGGAGGCTCC

360 CCGGGTGAAC CGTCTGGTCC AATCTCTACT ATCAACCCGT CTCCTCCGTC

TAAAGAATCT

420 CATAAATCTC CAAACATGGC TGTGGACTTT AGCTTGGGAG AATGGAAAAC

CCAGATGGAG

480 GAGACCAAGG CACAGGACAT TCTGGGAGCA GTGACCCTTC TGCTGGAGGG

AGTGATGGCA

540 GCACGGGGAC AACTGGGACC CACTTGCCTC TCATCCCTCC TGGGGCAGCT

TTCTGGACAG

600 GTCCCTCTCC TCCTTGGGGC CCTGCAGAGC CTCCTTGGAA CCCAGCTTCC

TCCACAGGGC

660 AGGACCACAG CTCACAAGGA TCCCAATGCC ATCTTCCTGA GCTTCCALACA

CCTGCTCCGA

720 GGAAAGGTGC GTTTCCTGAT GCTTGTAGGA GGGTCCACCC TCTGCGTCAG

GGAATTCGGC

780 GGCAACGGCG GCAACATGGC GTCCCCAGCG CCGCCTGCTT GTGACCTCCG

AGTCCTCAGT

840 AAACTGCTTC GTGACTCCCA TGTCCTTCAC AGCAGACTGA GCCAGTGCCC

AGAGGTTCAC

900 CCTTTGCCTA CACCTGTCCT

GCTGCCT

927 INFORMATION FOR SEQ ID NO: 146: SEQUENCE

CHARACTERISTICS:

LENGTH: 927 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 146: GCTAACTGCT CTATAATGAT CGATGAAATT ATACATCACT TAAAGAGACC

ACCTGCACCT

WO 97/1 2985 PCTIUS96/15774

TTGCTGGACC

120

CGACTTCA

180 CGAACAACCT

CAATGACGA-A

ACCTGGAGAG

CTTCGTAAGG

GACGTCTCTA

GCTGTCAAGA

TCCTGATGGA

ACTTAGAAAAJ

CCGAAACCTT

TGCATCAGGT

ATTGAGGCA TTCTTCGTAA TCTCCAACCA TGTCTGCCCT CTGCCACGGC

CGCACCCTCT

240 CGACATCCp.A 300

TATCTGGTTA

360

CCGGGTGAAC

420

CATAAATCTC

480

AAGGCACAGG

540

GGACAACTGG

600

CTCCTCCTTG

660

ACAGCTCACA

720

TCATCATCA

CCCTTGAGCA

CGTCTGGTCC

CAAACATGGA

ACATTCTGGG

GACCCACTTG

GGGCCCTGCA

AGGATCCCAA

GGCAGGTGAC

AGCGCAGGA

AATCTCTACT

CTTTAGCTTG

AGCAGTGACC

CCTCTCATCC

GAGCCTCCTT

TGCCATCTTC

TGGCAAGAAT

CAACAGTACG

ATCA.ACCCGT

GGAGAATGGA

CTTCTGCTGG

CTCCTGGGGC

GGAACCCAGC

CTGAGCTTCC

TCCGGGAAAA

TAGAGGGCGG

CTCCTCCGTC

AAACCCAGAT;

AGGGAGTGAT

AGCTTTCTGG

TTCCTCCACA

ACTGACGTTC

TGGAGGCTCC

TAAAGAATCT

GGAGGAGACC

GGCAGCACGG

ACAGGTCCGT

GGGCAGGACC

AACACCTGCT CCGAGGAAAG GTGCGTTTCC TGATGCTTGT AGGAGGGTCC

ACCCTCTGCG

780 GGCGGCAACA TGGCGTCCCC AGCGCCGCCT

GCTTGTGACC

840 CTTCGTGACT CCCATGTCCT TCACAGCAGA

CTGAGCCAGT

900 CCTACACCTG TCCTGCTGCC

TGCTGTG

927 INFORMATION FOR SEQ ID NO: 147: SEQUENCE

CHARACTERISTICS:

LENGTH: 927 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid

TCAGGGAATT

TCCGAGTCCT

GCCCAGAGGT

CGGCGGCA\C

CAGTAAACTG

TCACCCTTTG

WO 97/12985 PCT/UJS96/15 7 7 4 368 DESCRIPTION: /desc "DNA (synthetic), (Xi) SEQUENCE DESCRIPTION: SEQ ID NO: 147: GCTAACTGCT CTATAATGAT CGATGAAATT ATACATCACT TAAAGAGACC

ACCTGCACCT

TTGCTGGACC CGAACAACCT CAATGACGA GACGTCTCTA TCCTGATGGA

CCGAAACCTT

120 CGACTTCCAA ACCTGGAGAG CTTCGTAAGG GCTGTCAAGA ACTTAGAAA

TGCATCAGGT

180 ATTGAGGCAJA TTCTTCGTAA TCTCCAACCA TGTCTGCCCT CTGCCACGGC

CGCACCCTCT

240 CGACATCCAA TCATCATCAA GGCAGGTGAC TGGCAAGAAT TCCGGGAAAA

ACTGACGTTC

300 TATCTGGTTA CCCTTGAGCA AGCGCAGGAA CAACAGTACG TAGAGGGCGG

TGGAGGCTCC

360 CCGGGTGAAC CGTCTGGTCC AATCTCTACT ATCAACCCGT CTCCTCCGTC

TAAAGAATCT

420 CATAAATCTC CAAACATGGG AGAATGGAAJA ACCCAGATGG AGGAGACCAA

GGCACAGGAC

480 ATTCTGGGAG CAGTGACCCT TCTGCTGGAG GGAGTGATGG CAGCACGGGG

ACAACTGGGA

540 CCCACTTGCC TCTCATCCCT CCTGGGGCAG CTTTCTGGAC AGGTCCGTCT

CCTCCTTGGG

600 GCCCTGCAGA GCCTCCTTGG AACCCAGCTT CCTCCACAGG GCAGGACCAC

AGCTCACAAG

660 GATCCCAATG CCATCTTCCT GAGCTTCCAA CACCTGCTCC GAGGAAAGGT

GCGTTTCCTG

720 ATGCTTGTAG GAGGGTCCAC CCTCTGCGTC AGGGAATTCG GCGGCAACGG

CGGCAACATG

780 GCGTCCCCAG CGCCGCCTGC TTGTGACCTC CGAGTCCTCA GTAAACTGCT

TCGTGACTCC

840 CATGTCCTTC ACAGCAGACT GAGCCAGTGC CCAGAGGTTC ACCCTTTGCC

TACACCTGTC

900 CTGCTGCCTG CTGTGGACTT

TAGCTTG

927 WO 97/12985 PCT/US96/1 5774 369 INFORMATION FOR SEQ ID NO: 148: SEQUENCE

CHARACTERISTICS:

LENGTH: 927 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc ="DNA (synthetic),, (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 148:

GCTAACTGCT

CTATAATGAT CGATGAAATT ATACATCACT TAAAGAGACC

ACCTGCACCT

TTGCTGGACC

120

CGACTTCCAA

180

ATTGAGGCAA

240

CGACATCCAA

300

TATCTGGTTA

360

CCGGGTGAAC

420

CATAAATCTC

480

CGAACAACCT

ACCTGGAGAG

TTCTTCGT.A

TCATCATCAA

CCCTTGAGCA

CGTCTGGTCC

CAAACATGGG

CAATGACGAA

CTTCGTAAGG

TCTCCAACCA

GGCAGGTGAC

AGCGCAGGAAJ

AATCTCTACT

ACCCACTTGC

GACGTCTCTA

GCTGTCAAGA

TGTCTGCCCT

TGGCAAGAAT

CAACAGTACG

ATCAACCCGT

CTCTCATCCC

TCCTGATGGA

ACTTAGAAAA

CTGCCACGGC

TCCGGGAAAA

TAGAGGGCGG

CTCCTCCGTC

rCCTGGGGCA

CCGAAACCTT

TGCATCAGGT

CGCACCCTCT

ACTGACGTTC

TGGAGGCTCC

TAAAGAATCT

GCTTTCTGGA

CAGGTCCGTC

540

GGCAGGACCA

600

CGAGGAAAGG

660

GGCGGCAACG

720

TCCTCCTTGG

CAGCTCACAA

TGCGTTTCCT

GCGGCAACAT

GGCCCTGCAG

GGATCCCAAT

GATGCTTGTA

GGCGTCCCCA

AGCCTCCTTG

GCCATCTTCC

GGAGGGTCCA

GCGCCGCCTG

GAACCCAGCT

TCCTCCACAG

TGAGCTTCCA

ACACCTGCTC

CCCTCTGCGT

CAGGGAATTC

CTTGTGACCT CCGAGTCCTC WO 97/12985 PCT[US96/15774 370 AGTAAACTGC TTCGTGACTC CCATGTCCTT CACAGCAGAC TGAGCCAGTG

CCCAGAGGTT

780 CACCCTTTGC CTACACCTGT CCTGCTGCCT GCTGTGGACT TTAGCTTGGG AGAATGGAAjA 840 ACCCAGATGG AGGAGACCAA GGCACAGGAC ATTCTGGGAG CAGTGACCCT

TCTGCTGGAG

900 GGAGTGATGG CAGCACGGGG

ACAACTG

927 INFORMATION FOR SEQ ID NO: 149: SEQUENCE

CHARACTERISTICS:

LENGTH: 927 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc ="DNA (synthetic)" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 149:

GCTAACTGCT

TTGCTGGACC

120

CGACTTCCAA

180

ATTGAGGCAA

240

CGACATCCAA

300

TATCTGGTTA

360

CCGGGTGAAC

420

CATAAATCTC

480 CTATAATGAT CGATGAAATT ATACATCACT TAAAGAGACC

ACCTGCACCT

CGAACAACCT

ACCTGGAGAG

TTCTTCGTAA.

TCATCATCAA

CCCTTGAGCA

CGTCTGGTCC

CAAACATGGG

CAATGACGAA

CTTCGTAAGG

TCTCCAACCA

GGCAGGTGAC

AGCGCAGGAA

AATCTCTACT

AACCCAGCTT

GACGTCTCTA

GCTGTCAAGA

TGTCTGCCCT

TGGCAAGAAT

CAACAGTACG

ATCAACCCGT

CCTCCACAGG

TCCTGATGGA

ACTTAGApA

CTGCCACGGC

TCCGGGAAAJA

TAGAGGGCGG

CTCCTCCGTC

GCAGGACCAC

CCGAAACCTT

TGCATCAGGT

CGCACCCTCT

ACTGACGTTC

TGGAGGCTCC

TAAAGAATCT

AGCTCACAAG

GCGTTTCCTG

GATCCCAATG

540 CCATCTTCCT GAGCTTCCAA CACCTGCTCC

GAGGAAAGGT

WO 97/12985 PCT/US96/1 5774 ATGCTTGTAG GAGGGTCCAC CCTCTGCGTC AGGGAATTCG

GCGGCAACGG

600 GCGTCCCCAG CGCCGCCTGC TTGTGACCTC CGAGTCCTCA

GTAAACTGCT

660 CATGTCCTTC ACACCAGACT GAGCCAGTGC CCAGAGGTTC

ACCCTTTGCC

720 CTGCTGCCTG CTGTGGAC'rT TAGCTTGGGA GAATGGAAAA

CCCAGATGGA

780 GCACAGGACA TTCTGGGAGC AGTGACCCTT CTGCTGGAGG

GAGTGATGGC

840 CAACTGGGAC CCACTTGCCT CTCATCCCTC CTGGGGCAGC

TTTC!TGGACA

900 CTCCTTGGGG CCCTGCAGAG

CCTCCTT

927 INFORMATION FOR SEQ ID NO: 150: Wi SEQUENCE

CHARACTERISTICS:

LENGTH: 927 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)"

CGGCAACATG

TCGTGACTCC

TACACCTGTC

GGAGACCAAG

AGCACGGGGA

GGTCCGTCTC

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 150: GCTAACTGCT CTATAATGAT CGATGAAATT ATACATCACT TAAAGAGACC

ACCTGCACCT

TTGCTGGACC CGAACAACCT CAATGACGAA GACGTCTCTA TCCTGATGGA

CCGAAACCTT

120 CGACTTCCAA ACCTGGAGAG CTTCGTAAGG GCTGTCAAGA ACTTAGAA

TGCATCAGGT

180 ATTGAGGCAA TTCTTCGTAA TCTCCA3ACCA TGTCTGCCCT CTGCCACGGC

CGCACCCTCT

240 CGACATCCA TCATCATCAA GGCAGGTGAC TGGCAAGAAT TCCGGGAAA

ACTGACCTTC

300 WO 97/12985 PCTIUS96,'1577 4 372 CCCTTGAGCA AGCGCAGGAA CAACAGTACG TAGAGGGCGG

TGGAGGCTCC

TATCTGGTTA

360

CCGGGTGAAC

420

CATAAATCTC

480

AGCTTCCAAC

540

CTCTGCGTCA

600

TGTGACCTCC

660

AGCCAGTGCC

720

AGCTTGGGAG

780

GTGACCCTTC

840

TCATCCCTCC

900

CGTCTGGTCC

CAAACATGGG

ACCTGCTCCG

GGGAATTCGG

GAGTCCTCAG

CAGAGGTTCA

AATGGAAAC

TGCTGGAGGG

TGGGGCAGCT

AATCTCTACT

CAGGACCACA

AGGAAAGGTG

CGGCAACGGC

TAAACTGCTT

CCCTTTGCCT

CCAGATGGAG

AGTGATGGCA

ATCAACCCGT

GCTCACAAGG

CGTTTCCTGA

GGCAACATGG

CGTGACTCCC

ACACCTGTCC

GAGACCAAGG

GCACGGGGAC

CTCCTCCGTC

ATCCCAATGC

TGCTTGTAGG

CGTCCCCAGC

ATGTCCTTCA

TGCTGCCT6C

CACAGGACAT

AACTGGGACC

TAAAGAATCT

CATCTTCCTG

AGGGTCCACC

GCCGCCTGCT

CAGCAGACTG

TGTGGACTTT

TCTGGGAGCA

CACTTGCCTC

TTCTGGACAG GTCCGTCTCC TCCTTGGGGC

CCTGCAGAGC

CTCCTTGGAA CCCAGCTTCC

TCCACAG

927 INFORMATION FOR SEQ ID NO: 151: Wi SEQUENCE

CHARACTERISTICS:

LENGTH: 927 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc ="DNA (synthetic)" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 151: GCTAACTGCT CTATAATGAT CGATGAAATT ATACATCACT TAAAGAGACC

ACCTGCACCT

TTGCTGGACC CGAACAACCT CAATGACGAA GACGTCTCTA TCCTGATGGA

CCGAAACCTT

120 WO 97/12985 PCT/1JS96/1 5774

CGACTTCCAA

180 ACCTGGAGAG CTTCGTAAGG GCTGTCAAGA ACTTAGAAJAjA

TGCATCAGGT

ATTGAGGCAA TTCTTCGTAA TCTCCAACCA

TGTCTGCCCT

240

CGACATCCAJA

300

TATCTGGTTA

360

CCGGGTGAAC

420

CATAAATCTC

480

CTGCTCCGAG

540

GAATTCGGCG

600

GTCCTCAGTA

660

GAGGTTCACC

720

TGGAAAACCC

780

CTGGAGGGAG

840

GGGCAGCTTT

900

CAGCTTCCTC

927

TCATCATCAA

CCCTTGAGCA

CGTCTGGTCC

CAAACATGGC

GAAAGGTGCG

GCAACGGCGG

AACTGCTTCG

CTTTGCCTAC

AGATGGAGGA

TGATGGCAGC

CTGGACAGGT

CACAGGGCAG

GGCAGGTGAC

AGCGCAGGAA

AATCTCTACT

TCACAAGGAT

TTTCCTGATG

CAACATGGCG

TGACTCCCAT

ACCTGTCCTG

GACCAAGGCA

ACGGGGACAA

CCGTCTCCTC

GACCACA

TGGCAAGAAT

CAACAGTACG

ATCAACCCGT

CCCAATGCCA

CTTGTAGGAG

TCCCCAGCGC

GTCCTTCACA

CTGCCTGCTG

CAGGACATTC

CTGGGACCCA

CTTGGGGCCC

CTGCCACGGC

TCCGGGAAJAJ

TAGAGGGCGG

CTCCTCCGTC

TCTTCCTGAG

GGTCCACCCT

CGCCTGCTTG

GCAGACTGAG

TGGACTTTAG

TGGGAGCAGT

CTTGCCTCTC

TGCAGAGCCT

CGCACCCTCT

ACTGACGTTC

TGGAGGCTCC

TAAAGAATCT

CTTCCAACAC

CTGCGTCAGG

TGACCTCCGA

CCAGTGCCCA

CTTGGGAGAA

GACCCTTCTG

ATCCCTCCTG

CCTTGGAACC

INFORMATION FOR SEQ ID NO: 152: Wi SEQUENCE CHARACTERISTICS: LENGTH: 927 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic),, WO 97/12985 PCTIUJS96/I 5774 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 152: GCTAACTGCT CTATAATGAT CGATGAJAATT ATACATCACT

TAAAGAGACC

TTGCTGGACC CGAACAACCT CAATGACGAA GACGTCTCTA

TCCTGATGGA

120 CGACTTCCAA ACCTGGAGAG CTTCGTAAGG GCTGTCAAGA

ACTTAGAAA

180 ATTGAGGCAA TTCTTCGTAA TCTCCAACCA TGTCTGCCCT

CTGCCACGGC

240

ACCTGCACCT

CCG-PAACCTT

TGCATCAGGT

CGCACCCTCT

CGACATCCAA

300

TATCTGGTTA

360

CCGGGTGAA~C

420

CATAAATCTC

480

GGAAAGGTGC

540

GGCAACGGCG

600

AAACTGCTTC

660

CCTTTGCCTA

720 TCATCATCAA

GGCAGGTGAC

CCCTTGAGCA

CGTCTGGTCC

CAAACATGGA

GTTTCCTGAT

GCAACATGGC

GTGACTCCCA

CACCTGTCCT

*AGCGCAGGAA

AATCTCTACT

TCCCAATGCC

GCTTGTAGGA

GTCCCCAGCG

TGTCCTTCAC

GCTGCCTGCT

TGGCAAGAAT

CAACAGTACG

ATCAACCCGT

ATCTTCCTGA

GGGTCCACCC

CCGCCTGCTT

AGCAGACTGA

GTGGACTTTA

TCCGGGAAAA

TAGAGGGCGG

CTCCTCCGTC

GCTTCCAACA

TCTGCGTCAG

GTGACCTCCG

GCCAGTGCCC

GCTTGGGAGA

'ACTGACGTTC

TGGAGGCTCC

TAAAGAATCT

CCTGCTCCGA

GGAATTCGGC

AGTCCTCAGT

AGAGGTTCAC

ATGGAAAACC

CAGATGGAGG AGACCAAGGC ACAGGACATT

CTGGGAGCAG

780 GTGATGGCAG CACGGGGACA ACTGGGACCC

ACTTGCCTCT

840 TCTGGACAGG TCCGTCTCCT CCTTGGGGCC

CTGCAGAGCC

900 CCACAGGGCA GGACCACAGC

TCACAAG

927 INFORMATION FOR SEQ ID NO: 153:

TGACCCTTCT

CATCCCTCCT

TcCTTGGAAC

GCTGGAGGGA

GGGGCAGCTT

CCAGCTTCCT

WO 97/12985 PCTIUS96/1 5774 375 SEQUENCE

CHARACTERISTICS:

LENGTH: 927 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic),- (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 153: GCTAACTGCT CTATAATGAT CGATGAAATT ATACATCACT TAAAGAGACC

ACCTGCACCT

TTGCTGGACC

120

CGACTTCCAA~

180

ATTGAGGCAA

240

CGACATCCAA

300

TATCTGGTTA

360

CCGGGTGAAC

420

CATAAATCTC

480

CGTTTCCTGA

540

GGCAACATGG

600

CGTGACTCCC

660

ACACCTGTCC

720

GAGACCAAGG

780

CGAACAACCT

ACCTGGAGAG

TTCTTCGTAA

TCATCATCAA

CCCTTGAGCA

CGTCTGGTCC

CAAACATGGC

TGCTTGTAGG

CGTCCCCAGC

ATGTCCTTCA

TGCTGCCTGC

CACAGGACAT

CA.ATGACGAJA GACGTCTCTA TCCTGATGGA

C'CGAAACCTT

CTTCGTAAGG

TCTCCAACCA

GGCAGGTGAC

AGCGCAGGA

AATCTCTACT

CATCTTCCTG

AGGGTCCACC

GCCGCCTGCT

CAGCAGACTG

TGTGGACTTT

TCTGGGAGCA

GCTGTCAAGA ACTTAGAAAA

TGCATCAGGT

TGTCTGCCCT CTGCCACGGC

CGCACCCTCT

TGGCAAGAAT TCCGGGAAAJA

ACTGACGTTC

CAACAGTACG TAGAGGGCGG

TGGAGGCTCC

ATCAACCCGT CTCCTCCGTC

TAAAGAATCT

AGCTTCCAAC ACCTGCTCCG

AGGAAAGGTG

CTCTGCGTCA GGGAATTCGG

CGGCAACGGC

TGTGACCTCC GAGTCCTCAG

TAAACTGCTT

AGCCAGTGCC CAGAGGTTCA

CCCTTTGCCT

AGCTTGGGAG AATGGAAAAC

CCAGATGGAG

GTGACCCTTC TGCTGGAGGG

AGTGATGGCA

WO 97/12985 PCTIUJS96/1 5774 GCACGGGGAC AACTGGGACC CACTTGCCTC TCATCCCTCC TGGGGCAGCT

TTCTGGACAG

840 GTCCGTCTCC TCCTTGGGGC CCTGCAGAGC CTCCTTGGAA CCC!AGCTTCC

TCCACAGGGC

900 AGGACCACAG CTCACAAGGA

TCCCAAT

927 INFORMATION FOR SEQ ID NO: 154: SEQUENCE

CHARACTERISTICS:

LENGTH: 906 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)-- (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 154: GCTAACTGCT CTATAATGAT CGATGAAATT ATACATCACT

TA.AAGAGACC

ACCTGCACCT

TTGCTGGACC

120

CGACTTCCAA

180

ATTGAGGCAA.

240 CGACATCCpJA 300

TATCTGGTTA

360

CCGGGTGAAC

420

CATAAATCTC

480

GGAAAGGTGC

540

GGCAACATGG

600

CGAACAJACCT

ACCTGGAGAG

TTCTTCGTAA

TCATCATCAA

CCCTTGAGCA

CGTCTGGTCC

CAAACATGGA

GTTTCCTGAT

CGTCTCCCGC

CAATGACGAA

CTTCGTAAGG

TCTCCAACCA

GGCAGGTGAC

AGCGCAGGAA

AATCTCTACT

TCCCAATGCC

GCTTGTAGGA

TCCGCCTGCT

GACGTCTCTA TCCTGATGGA

CCGAAACCTT

GCTGTCAAGA ACTTAGAAAA

TGCATCAGGT

TGTCTGCCCT CTGCCACGGC

CGCACCCTCT

TGGCAAGAAT TCCGGGAAAA

ACTGACGTTC

CAACAGTACG TAGAGGGCGG

TGGAGGCTCC

ATCAACCCGT CTCCTCCOTC

TAAAGAATCT

ATCTTCCTGA GCTTCCAACA

CCTGCTCCGA

GGGTCCACCC TCTGCGTCAG

GGAATTCGGC

TGTGACCTCC GAGTCCTCAG TAAACTGCTT WO 97/12985 PCT/US96/1 5774 CGTGACTCCC ATGTCCTTCA CAGCAGACTG AGCCAGTGCC

CAGAGGTTCA

660 ACACCTGTCC TGCTGCCTGC TGTGGACTTT AGCTTGGGAG

AATGGAAAAC

720 GAGACCAAGG CACAGGACAT TCTGGGAGCA GTGACCCTTC

TGCTGGAGGG

780 GCACGGGGAC AACTGGGACC CACTTGCCTc TCATCCCTCc

TGGGGCAGCT

840 GTCCGTCTCC TCCTTGGGGC CCTGCAGAGC CTCCTTGGjA

CCCAGGGCAG

900

CACAAG

906 INFORMATION FOR SEQ ID NO: 155: SEQUENCE

CHARACTERISTICS:

LENGTH: 993 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)"

CCCTTTGCCT

CCAGATGGAG

AGTGATGGCA

TTCTGGACAG

GACCACAGCT

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 155: ATGGCTAACT GCTCTATAAT GATCGATGAA ATTATACATC

ACTTAAAGAG

CCTTTGCTGG ACCCGAACAA CCTCAATGAC GAAGACGTCT

CTATCCTGAT

120 CTTCGACTTC CAAACCTGGA GAGCTTCGTA AGGGCTGTCA

AGAACTTAGA

180 GGTATTGAGG CAATTCTTCG TAATCTCCAA CCATGTCTGC

CCTCTGCCAC

240 TCTCGACATC CAATCATCAT CAAGGCAGGT GACTGGCAAG

AATTCCGGGA

300 TTCTATCTGG TTACCCTTGA GCAAGCGCAG GAACAACAGT

ACGTAGAGGG

360

ACCACCTGCA

GGATCGAAAC

AAATGCATCA

GGCCGCACCC

AAAACTGACG

CGGTGGAGGC

WO 97/12985 PCT/US96/1 5 7 7 4 TCCCCGGGTG AACCGTCTGG TCCAATCTCT ACTATCAACC

CGTCTCCT

420 TCTCATAAAT CTCCAAACAT GTCTTACAAG CTGTGCCACC

CCGAGGAG

480 GGACACTCTC TGGGCATCCC CTGGGCTCCC CTGAGCTCCT

GCCCCAGC(

540 CTGGCAGGCT GCTTGAGCCA ACTCCATAGC GGCCTTTTCC

TCTACCAGC

600 GCCCTGGAAG GGATATCCCC CGAGTTGGGT CCCACCTTGG

ACACACTGC

660 GCCGACTTTG CCACCACCAT CTGGCAGCAG ATGGAAGAAC

TGGGAATGG

720 CAGCCCACCC AGGGTGCCAT GCCGGCCTTC GCCTCTGCTT TCCAGCGC6 780 GTCCTGGTTG CTAGCCATCT GCAGAGCTTC CTGGAGGTGT

CGTACCGCG

840 CTTGCGCAGC CCGGCGGCGG CTCTGACATG GCTACACCAT

TAGGCCCTG(

900 CCCCAGAGCT TCCTGCTCAA GTCTTTAGAG CAAGTGAGGA

AGATCCAGG(

960 GCGCTCCAGG AGAAGCTGTG TGCCACCTAA

TAA

993 INFORMA~TION FOR SEQ ID NO: 156: SEQUENCE

CHARACTERISTICS:

LENGTH: 993 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc ="DNA (synthetic)"

C

C

G

A

CGTCTAAAGAJA

P' GGTGCTGCTC

GGCCCTGCAG

GCTCCTGCAG

GCTGGACGTC

CCCTGCCCTG

GGCAGGAGGG

TCTACGCCAC

CAGCTCCCTG

CGATGGCGCA

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 156: ATGGCTAACT GCTCTATAAT GATCGATGAA ATTATACATC ACTTAAAGAG

ACCACCTGCA

CCTTTGCTGG ACCCGAACAJA CCTCAATGAC GAAGACGTCT CTATCCTGAT

GGATCGAC

120 WO 97/12985 PCT/US96/1 5774

CTTCGACTTC

180

GGTATTGAGG

240

TCTCGACATC

300

CAAACCTGGA

CAATTCTTCG

CAATCATCAT

GAGCTTCGTA

TAATCTCCAJ\

CAAGGCAGGT

AGGGCTGTCA

CCATGTCTGC

GACTGGCAAG

AGAACTTAGA

CCTCTGCCAC

AATTCCGGGA

AAATGCATCA

GCCGCACCC

AAAACTGACG

TTCTATCTGG

360

TCCCCGGGTG

420

TCTCATAAAT

480

GACGTCGCCG

540

GCCCTGCAGC

600

GGAGGGGTCC

660

CGCCACCTTG

720

TCCCTGCCCC

780

GGCGCAGCGC

840

GTGCTGCTCG

900

GCCCTGCAGC

960 TTAcCCTTGP

AACCGTCTGC

CTCCAAACAT

ACTTTGCCAC

CCACCCAGGG

TGGTTGCTAG

CGCAGCCCGG

AGAGCTTCCT

TCCAGGAGAA

GACACTCTCT

TGGCAGGCTG

GCAAGCGCAG

GAACAACAGT

TCCAATCTCT

GTCTCCCGAG

CACCATCTGG

TGCCATGCCG

CCATCTGCAG

CGGCGGCTCT

GCTCAAGTCT

GCTGTGTCC

GGGCATCCCC

CTTGAGCCAA

ACTATCAACC

TTGGGTCCCA

CAGCAGATGG

GCCTTCGCCT

AGCTTCCTGG

GACATGGCTA

TTAGAGCAAG

ACGTAGAGGG

CGTCTCCTCC

CCTTGGACAC

AAGAACTGGG

CTGCTTTCCA

AGGTGTCGTA

CACCATTAGG

CGGTGGAGGC

GTCTAAAGAA

ACTGCAGCTG

AATGGCCCCT

GCGCCGGGCA

CCGCGTTCT.A

CCCTGCCAGC

TGAGGAAGAT CCAGGGCGAT ACCTACAAGC TGTGCCACCC CGAGGAGCTG

TGGGCTCCCC

CTCCATAGCG

TGAGCTCCTG

GCCTTTTCCT

CCCCAGCCAG

CTACCAGGGG

CTCCTGCAGG CCCTGGAAGG GATATCCTAA

TAA

993 INFORMATION FOR SEQ ID NO: 157: Wi SEQUENCE

CHARACTERISTICS:

LENGTH: 993 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear WO 97/12985 PTU9/57 380 (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic),- (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 157: ATGGCTAACT GCTCTATAAT GATCGATGAA ATTATACATC ACTTAAAGAG

ACCACCTGCA

CCTTTGCTGG ACCCGAACpJA CCTCAATGAC GAAGACGTCT CTATCCTGAT

GGATCGAC

120 CTTCGACTTC CAAACCTGGA GAGCTTCGTA AGGGCTGTCA AGAACTTACA

AAATGCATCA

180 GGTATTGAGG CAATTCTTCG TAATCTCCAA CCATGTCTGC CCTCTGCCAC

GGCCGCACCC

240 TCTCGACATC CAATCATCAT CAAGGCAGGT GACTGGCAAG AATTCCGGGA

AAAACTCACG

300 TTCTATCTGG TTACCCTTGA GCAAGCGCAG GAACAACAGT ACGTAGAGGG

CGGTGGAGGC

360 TCCCCGGGTG AACCGTCTGG TCCAATCTCT ACTATCAACC CGTCTCCTCC

GTCTAAAGAA

420 TCTCATAAAT CTCCAAACAT GTCTTCTGCT TTCCAGCGCC GGGCAGGAGG

GGTCCTGCTT

480 GCTAGCCATC TGCAGAGCTT CCTGGAGGTG TCGTACCGCG TTCTACGCCA

CCTTGCGCAG

540 CCCGGCGGCG GCTCTGACAT GGCTACACCA TTAGGCCCTG CCAGCTCCCT

GCCCCAGAGC

600 TTCCTGCTCA AGTCTTTAGA GCAAGTGAGG AAGATCCAGG GCGATGGCGC

AGCGCTCCAG

660 GAGAAGCTGT GTGCCACCTA CAAGCTGTGC CACCCCGAGG AGCTGGTGCT

GCTCGGACAC

720 TCTCTGGGCA TCCCCTGGGC TCCCCTGAGC TCCTGCCCCA GCCAGGCCCT

CCAGCTGGCA

780 GGCTGCTTGA GCCAACTCCA TAGCGGCCTT TTCCTCTACC AGGGGCTCCT

GCAGGCCCTG

840 GAAGGGATAT CCCCCGAGTT GGGTCCCACC TTGGACACAC TGCAGCTGGA

CGTCGCCGAC

900 WO 97/12985 PCTIUS96/1 5774 381 TTTGCCACCA CCATCTGGCA GCAGATGGAA GAACTGGGAA TGGCCCCTGC CCTGCAGC

CC

960 ACCCAGGGTG CCATGCCGGC CTTCGCCTAA

TAA

993 INFORMATION FOR SEQ ID NO: 158: SEQUENCE

CHARACTERISTICS:.

LENGTH: 993 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 158: ATGGCTAACT GCTCTATAAT GATCGATGAA ATTATACATC ACTTAAAGAG

ACCACCTGCA

CCTTTGCTGG

120

CTTCGACTTC

180

GGTATTGAGG

240

TCTCGACATC

300

TTCTATCTGG

360

TCCCCGGGTG

420

TCTCATAAAT

480

CCGGCCTTCG

540

CAGAGCTTCC

600

TCTGACATGG

660

ACCCGAACAA

CAAACCTGGA

CAATTCTTCG

CAATCATCAT

TTACCCTTGA

AACCGTCTGG

CTCCAAACAT

CCTCTGCTTT

TGGAGGTGTC

CCTCAATGAC!

GAGCTTCGTA

TAATCTCCAA

CAAGGCAGGT

GCA.AGCGCAG

TCCAATCTCT

GTCTATGGCC

CCAGCGCCGG

GTACCGCGTT

GAAGACGTCT

AGGGCTGTCA

CCATGTCTGC

GACTGGCAAG

GAACAACAGT

ACTATCAACC

CCTGCCCTGC

GCAGGAGGGG

CTACGCCACC

CTATCCTGAT

AGAACTTAGA

CCTCTGCCAC

AATTCCGGGA

ACGTAGAGGG

CGTCTCCTCC

AGCCCACCCA

TCCTGGTTGC

TTGCGCAGCC

GGATCGAAAC

AAATGCATCA

GGCCGCACCC

AAAACTGACG

CGGTGGAGGC

GTCTAAAGAA

GGGTGCCATG

TAGCCATCTG

CGGCGGCGGC

CCTGCTCAAG

CTACACCATT AGGCCCTGCC AGCTCCCTGC

CCCAGAGCTT

WO 97/12985 PCT[US96/157 7 4 TCTTTAGAGC AAGTGAGGAA GATCCAGGGC GATGGCGCAG

CGCTCCAGGA

720 GCCACCTACA AGCTGTGCCA CCCCGAGGAG CTGGTGCTGC

TCGGACACTC

780 CCCTGGGCTC CCCTGAGCTC CTGCCCCAGC CAGGCCCTGC

AGCTGGCAGG

840 CAACTCCATA GCGGCCTTTT CCTCTACCAG GGGCTCCTGC

AGGCCCTGGA

900 CCCGAGTTGG GTCCCACCTT GGACACACTG CAGCTGGACG

TCGCCGACTT

960 ATCTGGCAGC AGATGGAAGA ACTGGGATAA

TAA

993 INFORMATION FOR SEQ ID NO: 159: Wi SEQUENCE

CHARACTERISTICS:

LENGTH: 993 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)"

GAAGCTGTGT

TCTGGGCATC

CTGCTTGAGC

AGGGATATCC

TGCCACCACC

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 159: ATGGCTAACT GCTCTATAAT GATCGATGAA ATTATACATC

ACTTAAAGAG

CCTTTGCTGG ACCCGAACAA CCTCAATGAC GAAGACGTCT

CTATCCTGAT

120 CTTCGACTTC CAAACCTGGA GAGCTTCGTA AGGGCTGTCA

AGAACTTAGA

180 GGTATTGAGG CAATTCTTCG TAATCTCCAA CCATGTCTGC

CCTCTGCCAC

240 TCTCGACATC CAATCATCAT CAAGGCAGGT GACTGGCAAG

AATTCCGGGA

300 TTCTATCTGG TTACCCTTGA GCAAGCGCAG GAACAACAGT

ACGTAGAGGG

360

ACCACCTGCA

GGATCGAAAC

AAATGCATCA

GGCCGCACCC

AAAACTGACG

CGGTGGAGGC

WO 97/12985 PCTIUS96/1577 4

TCCCCGGGTC

420 TCTCATAAAIl 480

CAGCGCCGGG

540

TACCGCGTTC

600

GGCCCTGCCA

660

ATCCAGGGCG

720

CCCGAGGAGC

780

TGCCCCAGCC

840

CTCTACCAGG

900

GACACACTGC

960

AACCGTCTG(

CTCCAAACA]

CAGGAGGGG'I

TACGCCACC'I

GCTCCCTGCC

ATGGCGCAGC

TGGTGCTGCT

AGGCCCTGCA

GGCTCCTGCA

AGCTGGACGT

3TCCAATCTC9I P' GTCTACCCAC-

CCTGGTTGCT

TGCGCAGCcC

CCAGAGCTTC

GCTCCAGGAG

CGGACACTCT

GCTGGCAGGC

GGCCCTGGAA

CGCCGACTTT

ACTATCAACC

GGTGCCATGC

AGCCATCTGC

GGCGGCGGCT

CTGCTCAAGT

A-AGCTGTGTG

CTGGGCATCC

TGCTTGAGCC

GGGATATCCC

C

GCCACCACCA q

CGTCTCCTCC

CGGCCTTCGC

AGAGCTTCCT

CTGACATGGC

CTTTAGAGCA

CCACCTACAA

CCTGGGCTCC-

%ACTCCATAG

~CGAGTTGGG 9J

~CTGGCAGCA

GTCTAAAGAA

CTCTGCTTTC

GGAGGTGTCG

TACACCATTA

AGTGAGGAAG

GCTGTGCCAC

CCTGAGCTCC

GGCCTTTTC

CCCACCTTG

7 ATGGAAGAA CTGGGAATGG CCCCTGCCCT GCAGCCCTAA

TAA

993 INFORMA~TION FOR SEQ ID NO: 160: Wi SEQUENCE

CHARACTERISTICS:

LENGTH: 1027 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic), (Xi) SEQUENCE DESCRIPTION: SEQ ID NO: 160: ATGGCTACAC CATTGGGCCC TGCCAGCTCC CTGCCCCAGA GCTTCCTGCT

CAAGTCTTTA

GAGCAAGTGA GGAAGATCCA GGGCGATGGC GCAGCGCTCC AGGAGAAGCT GTGTGCCACC 120 WO 97/12985 PCT/US96/1 5774 TACAAGCTGT

GCCACCCCGA

180 GCTCCCCTGA

GCTCCTGCCC

240 CATAGCGGCC

TTTTCCTCTA

300

GGAGCTGGTG

CAGCCAGGCC

CCAGGGGCTC

CTGCTCGGAC

CTGCAGCTGG

CTGCAGGCCC

ACTCTCTGGG

CAGGCTGCTT

TGGAAGGGAT

CATCCCCTGG

GAGCCAACTC

ATCCCCCGAG

TTGGGTCCCA CCTTGGACAC

ACTGCAGCTC

360

CAGCAGATGG

420

GCCTTCGCCT

480

AGCTTCCTGG

540

GACATGGCTA

600

TTAGAGCAAG

660

ACCTACAAGC

720

TGGGCTCCCC

780

CTCCATAGCG

840

GAGTTGGGTC

900

TGGCAGCAGA

960

AAGAACTGGC

CTGCTTTCCP

AGGTGTCGTA

CACCATTGGG

TGAGGAAGAT

TGTGCCACCC

TGAGCTCCTG

GCCTTTTCCT

CCACCTTGGA

TGGAAGAACT

AATGGCCCCI

GCGCCGGGCA

CCGCGTTCTA

CCCTGCCAGC

CCAGGGCGAT

CGAGGAGCTG

CCCCAGCCAG

CTACCAGGGG

CACACTGCAG

GGGA.ATGGCC

GACGTCGCCC

GCCCTGCAGC

GGAGGGGTCC

CGCCACCTTG

TCCCTGCCCC

GGCGCAGCGC

GTGCTGCTCG

GCCCTGCAGC

CTCCTGCAGG,

CTGGACGTCG

ACTTTGCCAC

CCACCCAGGG

TGGTTGCTAG

CGCAGCCCGG

AGAGCTTCCT

TCCAGGAGAA

GACACTCTCT

TGGCAGGCTG

CCCTGGAGG

CCGACTTTGC

CACCATCTGG

TGCCATGCCG

CCATCTGCAG

CGGCGGCTCT

GCTCAAGTCT

GCTGTGTGCC

GGGCATCCCC

CTTGAGCCAA

GATATCCCCC

CACCACCATC

CCTGCCCTGC AGCCCACCCA

TCCTGGTTGC

TAGCCATCTG CAGAGCTTCC TGGAGGTGTC GTACCGCGTT CTACGCCACC

TTGCGCAGCC

1020

CTGATAA

1027 INFORMATION FOR SEQ ID NO: 161: SEQUENCE

CHARACTERISTICS:

LENGTH: 155 amino acids TYPE: amino acid WO 97/12985 PCT/US96/15774 385 STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 161: Ser Pro Ala Pro Pro Ala Cys Asp Leu Arg Val Leu Ser Lys Leu Leu 1 Arg His Gly Gly Leu Val Pro Leu Val 145 Asp Pro Glu Ala Gly Arg Pro Ser 130 Gly Ser Leu Trp Val Pro Leu Gin 115 Phe Gly His Val Leu Pro Thr Pro Lys Thr Gln Thr Leu Leu 70 Thr Cys Leu Leu Leu Gly 100 Gly Arg Thr Gin His Leu Ser Thr Leu 150 His Val Met 55 Leu Ser Ala Thr Leu 135 Cys Ser Leu 40 Glu Glu Ser Leu Ala 120 Arg Arg 25 Leu Glu Gly Leu Gin 105 His Gly Leu Ser Pro Ala Thr Lys Val Met 75 Leu Gly 90 Ser Leu Lys Asp Lys Val Gin Cys Val Asp Ala Gin Ala Ala Gin Leu Leu Gly Pro Asn 125 Arg Phe 140 Pro Phe Asp Arg Ser Thr 110 Ala Leu Glu Ser Ile Gly Gly Gin Ile Met Val Leu Leu Gin Gin Leu Phe Leu Val Arg Glu Phe 155 INFORMATION FOR SEQ ID NO: 162: SEQUENCE CHARACTERISTICS: LENGTH: 309 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 162: WO 97/12985 PCTIUS96/1577 4 Ser Pro Ala Pro Pro Ala Cys Asp Leu Arg Val Leu Ser Lys Leu Leu 1 5 10 Arg Asp Se: Hi~ Gl G1l Lei Val Prc Leu Val 145 Ser Arg His Gly Gly 225 Leu Val s Pro ~Glu iAla 1Gly Arg Pro Ser 130 Gly Pro Asp Pro Glu 210 Ala Gly Arg I Lei Trj Val Pro Leu Gin 115 Phe Gly Ala Ser Leu 195 rrp lal ?ro jeu r His I Pro Lys Thr Thr Leu 100 Gly Gin Ser Pro His 180 Pro Lys 9] Thr L Thr C 2 Leu L 260 Va Tb Thb Lei Cys Leu Arg His I'hr Pro 165 lal Phr 'hr ~eu :ys 45 eu 1 Lei Prc Gir 1Leu 70 Leu Gly Thr Leu Leu 150 Ala Leu Pro Gin Leu 230 Leu Gly i His Val 1Met 55 Leu *Ser *Ala Thr Leu2 135 Cys I Cys I His S Val L 2 Met G 215 Leu G Ser S Ala L Se Le 40 Gli Gli Se Let 120 krg Tal ~sp er eu 00 lu lu er eu r Arg 25 u Leu ui Giu u Gly fLeu Gin 105 His Gly Arg Leu2 Arg 1 185 Leu I Giu T3 Gly v~ Leu L 2 Gin S 265 Th: Va Lei 90 Ser Lys Lys krg 170 .eu >ro ~hr 'al eu 50 er Ser Ala r Lys LMet 75 1Gly Leu Asp Val Phe 155 Val Ser Ala Lys2 Met 1 235 Gly c Leu

L

Gin Val Cys Asp Pro Phe Gli Se

A

Al Gir Leu Prc Arg 140 Gly Leu Gln ltal kla la In 4eu a. Gin i. Ala 1Leu IGly 9Asn 125 Phe Gly Ser Cys Asp 205 Gin Ala2 Leu Gly 9 Asp Arg Ser Thr 110 Ala Leu Asn Lys Pro 190 Phe 1 .sp krgC ~er C 2 IlE Gi) Gly Gin Ile Met Met Leu 175 Giu Ser Ie ;ly ily -i Val Leu Leu Gin *Leu Phe Leu Ala 160 Leu Val Leu Leu Gin 240 Gin 270C Gl Arg Thr Thr 275 Ala His Lys Asp Pro 280 Asn Ala Ile Phe Leu Ser Phe Gin 285 WO 97/12985 PCT/US96/15774 387 His Leu Leu Arg Gly Lys Val Arg Phe Leu Met Leu Val Gly Gly Ser 290 295 300 Thr Leu Cys Val Arg 305 INFORMATION FOR SEQ ID NO: 163: SEQUENCE

CHARACTERISTICS:

LENGTH: 312 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 163: Ser Pro Ala Pro Pro Ala Cys Asp Leu Arg Val Leu Arg His Gly Gly Leu Val Pro Leu Val 145 Asp Pro Glu Ala Gly Arg Pro Ser 130 Gly Ser His Leu Pro Trp Lys Val Thr Pro Thr Leu Leu 100 Gin Gly 115 Phe Gin Gly Ser Val Thr Thr Leu Cys Leu Arg His Thr Leu Pro Gin Leu 70 Leu Gly Thr Leu Leu 150 His Val Met 55 Leu Ser Ala Thr Leu 135 Cys Ser Leu 40 Glu Glu Ser Leu Ala 120 Arg Val Arg 25 Leu Glu Gly Leu Gin 105 His Gly Arg Leu Pro Thr Val Leu 90 Ser Lys Lys Glu Val 170 Ser Ala Lys Met 75 Gly Leu Asp Val Phe 155 Gin Val Ala Ala Gin Leu Pro Arg 140 Gly Ser Cys Asp Gin Ala Leu Gly Asn 125 Phe Asn Lys Pro Phe Asp Arg Ser Thr 110 Ala Leu Met Leu Glu Ser Ile Gly Gly Gin Ile Met Ala Leu Val Leu Leu Gin Gin Leu Phe Leu Ser 160 Pro Ala Pro Pro Ala 165 Cys Asp Leu Arg Leu Ser Lys Leu Leu Arg 175 WO 97/12985 PCTIUS96/15774 Asp Pro Glu Ala 225 Gly Arg Pro Ser Gly 305 Ser Leu Trp 210 Val Pro Leu Gin Phe 290 Gly His Pro 195 Lys Thr Thr Leu Gly 275 Gin Ser Val 180 Thr Thr Leu Cys Leu 260 Arg His Thr Leu His Pro Val Gin Met Leu Leu 230 Leu Ser 245 Gly Ala Thr Thr Leu Leu Leu Cys Ser Arg Leu Leu 200 Glu Glu 215 Glu Gly Ser Leu Leu Gin Ala His 280 Arg Gly 295 Val Arg Leu 185 Pro Thr Val Leu Ser 265 Lys Lys Ser Ala Lys Met Gly 250 Leu Asp Val Gin Val Ala Ala 235 Gin Leu Pro Arg Cys Asp Gin 220 Ala Leu Gly Asn Phe 300 Pro Phe 205 Asp Arg Ser Thr Ala 285 Leu Glu 190 Ser lie Gly Gly Gin 270 Ile Met Val Leu Leu Gin Gin 255 Leu Phe Leu SHis SGly Gly Leu 240 Val Pro Leu Val 310 INFORMATION FOR SEQ ID NO: 164: SEQUENCE CHARACTERISTICS: LENGTH: 313 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) Ser 1 Arg His Gly SEQUENCE DESCRIPTION: SEQ ID NO: 164: Pro Ala Pro Pro Ala Cys Asp Leu Arg Val Leu Ser Lys Leu Leu 5 10 Asp Ser His Val Leu His Ser Arg Leu Ser Gin Cys Pro Glu Val 25 Pro Leu Pro Thr Pro Val Leu Leu Pro Ala Val Asp Phe Ser Leu 40 Glu Trp Lys Thr Gin Met Glu Glu Thr Lys Ala Gin Asp Ile Leu 55 WO 97/12985 PCTIUS96/1 5774 Gly Leu Val1 Pro Leu Val 145 Ser Arg His Gly Gly.

225 Leu Val Pro Leu Val 305 Ala Gly Arg Pro Ser 130 Gdy Pro Asp Pro Giu 210 Ala Gly P~ro Ser 290

G

1 y Val Pro Leu Gin 115 Phe Gly Ala Ser Leu 195 Trp Val Pro Leu Gin 275 Phe Gly Thr Thr Leu 100 Gly Gin Ser Pro His 180 Pro Lys Thr Thr Leu 260

G

1 y Gln Leu Cys Leu Arg His Thr Pro 165 Val1 Thr Thr Leu Cys 245 Leu Arg His Leu 70 Leu Gly Thr Leu Leu 150 Ala Leu Pro Gin Leu 230 Leu Gly Thr Leu *Leu Ser Ala Thr Leu 135 Cys Cys His Val Met 215 Leu Ser Ala Thr Leu 295 Cys1 Glu Ser Leu Ala 120 Arg Val Asp Ser Leu 200 Glu Giu Ser ELeu Aa 280 Arg Ja 1 Gly Leu Gin 105 His Gly Arg Leu Arg 185 Leu Giu Gly Leu Gin 265 His Gly Arg Val Let 90 Ser Lys Lys Glu Arg 170 Leu Pro Thr Val Leu 250 Ser L~ys Lys -Met 75 IGly Leu Asp Val Phe 155 Val Ser Ala Lys Met 235 Gly Leu Asp Val Ala Gin Leu Pro Arg 140 Gly Leu Gin Val1 Ala 220 Ala Gin Leu Pro Arg 300 Al a Leu Gly Asn 125 Phe Gly Ser Cys Asp 205 Gin Ala Leu Gly Asn 285 Phe Arc Ser Thr 110 Ala Leu Asn Lys Pro 190 Phe Asp Arg Ser I'hr 270 Ala Leu Gly -Gly Gin Sle Met Met Leu 175 Glu Ser Ile Gly Gly 255 Gin Ile Met Gin Gin Leu Phe Leu Ala 160 Leu Val Leu Leu Gin 240 Gin Leu Phe Leu Ser Thr Leu INFORMATION FOR SEQ ID NO: 165: Wi SEQUENCE CHARACTERISTICS: LENGTH: 316 amino acids TYPE: amino acid WO 97/1 2985 PCT/US96/15 7 7 4 390 STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: Protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 165: Ser Pro Ala Pro Pro Ala Cys Asp Leu Arg Val Leu Ser Lys Leu Leu 1 5 10 Arg Asp Ser His Val Leu His Ser Arg Leu Ser Gln Cys Pro Glu Val 25 His Pro Leu Pro Thr Pro Val Leu Leu Pro Ala Val Asp Phe Ser Leu 40 Gly Glu Trp Lys Thr Gln Met Glu Glu Thr Lys Ala Gln Asp Ile Leu 55 Gly Ala Val Thr Leu Leu Leu Glu Gly Val Met Ala Ala Arg Gly Gln 70 75 Leu Gly Pro Thr Cys Leu Ser Ser Leu Leu Gly Gln Leu Ser Gly Gin 90 Val Arg Leu Leu Leu Gly Ala Leu Gln Ser Leu Leu Gly Thr Gln Leu 100 105 110 Pro Pro Gln Gly Arg Thr Thr Ala His Lys Asp Pro Asn Ala Ile Phe 115 120 125 Leu Ser Phe Gln His Leu Leu Arg Gly Lys Val Arg Phe Leu Met Leu 130 135 140 Val Gly Gly Ser Thr Leu Cys Val Arg Glu Phe Gly Gly Asn Gly Gly 145 150 155 160 Asn Met Ala Ser Pro Ala Pro Pro Ala Cys Asp Leu Arg Val Leu Ser 165 170 175 Lys Leu Leu Arg Asp Ser His Val Leu His Ser Arg Leu Ser Gln Cys 180 185 190 Pro Glu Val His Pro Leu Pro Thr Pro Val Leu Leu Pro Ala Val ASP 195 200 205 Phe Ser Leu Gly Glu Trp Lys Thr Gln Met Glu Glu Thr Lys Ala Gln 210 215 220 Asp Ile Leu Gly Ala Val Thr Leu Leu Leu Glu Gly Val Met Ala Ala 225 230 235 240 WO 97/12985 PCTIUS96/'15774 Arg Giy Gin Leu Gly Pro Thr Cys Leu 245 Ser Gly Gin Val Arg LeU Leu Leu Gly 260 265 Thr Gin Leu Pro Pro Gin Gly Arg Thr 275 280 Aia Ile Phe Leu Ser Phe Gin His Leu 290 295 Leu Met Leu Vai Gly Gly Ser Thr Leu 305 310 INFORMATION FOR SEQ ID NO: 166: Ci) SEQUENCE

CHARACTERISTICS:

LENGTH: 302 amino acids TYPE: amino acid STRANDEDNESS: singie TOPOLOGY: iinear (ii) MOLECULE TYPE: protein Ser 250 Ala Thr Leu Cys Ser Leu Aia Arg Val 315 Leu Gin His Giy 300 Arg Leu Gly Gin Leu 255 Ser Leu Leu Gly 270 Lys Asp Pro Asn 285 Lys Val Arg Phe (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 166: Asn Cys Ser Ile Met Ile Asp Giu Ile Ile His 1 5 10 Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn 25 Ile Leu Met Asp Arg Asn Leu Arg Leu Pro Asn 40 Arg Ala Val Lys Asn Leu Giu Asn Ala Ser Gly 55 Arg Asn Leu Gin Pro Cys Leu Pro Ser Ala Thr 70 75 His Pro Ile Ile Ile Lys Ala Gly Asp Trp Gin 90 Leu Thr Phe Tyr Leu Val Thr Leu Giu Gin Ala 100 105 Val Giu Gly Giy Gly Gly Ser Pro Gly Gly Giy 115 120 His Leu Asp Giu Leu Giu Ile Giu Ala Ala Glu Phe Gin Giu Ser Gly 125 Lys Asp Ser Ala Pro Arg Gin 110 Gly Arg Val Phe Ilie Ser Giu Gn Gly Pro Ser Val Leu Arg Lys Tyr Ser WO 97/12985 PCT/US96/15774 392 Asn Met Ala Tyr Lys Leu Cys His Pro Glu Glu Leu Val Leu Leu Gly 130 135 140 His Ser Leu Gly Ile 145 Prc 15( Ala Leu Leu Tyr Gly Pro Thr Ile 210 Pro Thr 225 Ala Gly Ser Tyr Gly Ser Gin Gly 290 Gin Gin Thr 195 Trp Gin Gly Arg Gin 275 Asp SLeu Ala G1i 165 Gly Leu Leu 180 Leu Asp Thr Gin Gin Met Gly Ala Met 230 Val Leu Val 245 Val Leu Arg 260 Ser Phe Leu Gly Ala Ala STrp Ala SCys Leu i Gn Ala Leu Gin 200 Glu Glu 215 Pro Ala Ala Ser His Leu Pro Ser Leu 185 Leu Leu Phe His Ala Leu Gin 170 Glu Asp Gly Ala Leu 250 Gin Ser 155 Leu Gly Val Met Ser 235 Gin Ser His Ile Ala Ala 220 Ala Ser Cys Ser Ser Asp 205 Pro Phe Phe Pro Gly Pro 190 Phe Ala Gin Leu Ser Leu 175 Glu Ala Leu Arg Glu 255 Gin 160 Phe Leu Thr Gin Arg 240 Val Pro Ser Gly Gly Ser Gly 270 265 Leu Leu Lys 280 Gin Ser Glu Glu Leu Gin Cys Val 285 Ala Arg Lys Ile Thr 295 INFORMATION FOR SEQ ID NO: 167: SEQUENCE

CHARACTERISTICS:

LENGTH: 317 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 167: Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg Pro 1 5 10 Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp Val Ser 25 WO 97/12985 PCTIUS96/1 5774 Ile Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Giu Ser Phe Arg Arg His Leu Val Thr Met 145 Ser Leu Tyr Pro Ile 225 Thr Gly Tyr Ser Ala Asn Pro Thr Glu Ile 130 Ala Leu Gin Gin Thr 210 Trp Gin Gly Arg Gin 290 *Val Leu Ile Phe Gly 115 Asn Tyr Gly Leu Giy 195 Leu Gin Gly Val Val 275 Ser *Lys *Gin Ile Tyr 100 Gly Pro Lys Ile Ala 180 Leu Asp GinI Ala Leu 260 Leu Phe Asn Pro Ile Leu Gly Ser Leu Pro 165 Gly Leu Thr Met Met 245 Val krg .jeu Leu Cys 70 Lys Val Gly Pro Cys 150 Trp Cys Gin Leu Giu 230 Pro Ala His Leu Gil 55 Leu Ala Thr Ser Pro 135 His Ala Leu Al a Gin 215 Glu Al a Ser Lieu 295 Asn Pro Gly Leu Pro 120 Ser Pro Pro Ser Leu 200 Leu Leu Phe His Ala 280 Ser Ala Ser Asp Giu 105 Gly Lys Giu Leu Gin 185 Giu Asp Gly Aila Leu 265 31n eu Ser Ala Trp 90 Gin Glu Glu Glu Ser 170 Leu Gly Val Met Ser 250 Gin Pro Glu Gly Thr 75 Gin Ala Pro Ser Leu 155 Ser His Ile Ala Ala 235 Ala Ser Ser 'ln Ile Ala Glu Gin Ser His 140 Val Cys Ser Ser Asp 220 Pro Phe Phe2 Gly Val 300 Ci- Ala Phe Glu Gly 125 Lys Leu Pro Gly Pro 205 Phe Ala Gin Leu 3 iy 285 krg Ala Pro Arg Gin 110 Pro Ser Leu Ser Leu 190 Giu Ala Leu Arg Glu 270 Ser Lys Ile Ser Glu Gin Ile Pro Gly Gin 175 Phe Leu Thr Gin Arg 255 V1al Gly Ile Val Leu Arg Lys Tyr Ser Asn His 160 Ala Leu Gly Thr Pro 240 Ala Ser Gly Gin Gly 305 Asp Gly Ala Ala Leu Gin Giu Lys Leu Cys Ala Thr 310 315 WO 97/12985 PCT/US96/1577 4 394 INFORMATION FOR SEQ ID NO: 168: SEQUENCE

CHARACTERISTICS:

LENGTH: 302 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 168: Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg Pro 1 5 10 Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp Val Ser 25 Ile Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu Ser Phe Val 40 Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly Ile Glu Ala Ile Leu 55 Arg Asn Leu Gin Pro Cys Leu Pro Ser Ala Thr Ala Ala Pro Ser Arg 70 75 His Pro Ile Ile Ile Lys Ala Gly Asp Trp Gin Glu Phe Arg Glu Lys 90 Leu Thr Phe Tyr Leu Val Thr Leu Glu Gin Ala Gin Glu Gin Gin Tyr 100 105 110 Val Glu Gly Gly Gly Gly Ser Pro Gly Gly Gly Ser Gly Gly Gly Ser 115 120 125 Asn Met Ala Pro Glu Leu Gly Pro Thr Leu Asp Thr Leu Gin Leu Asp 130 135 140 Val Ala Asp Phe Ala Thr Thr Ile Trp Gin Gin Met Glu Glu Leu Gly 145 150 155 160 Met Ala Pro Ala Leu Gin Pro Thr Gin Gly Ala Met Pro Ala Phe Ala 165 170 175 Ser Ala Phe Gin Arg Arg Ala Gly Gly Val Leu Val Ala Ser His Leu 180 185 190 Gin Ser Phe Leu Glu Val Ser Tyr Arg Val Leu Arg His Leu Ala Gln 195 200 205 WO 97/12985 PCT/US96/15774 395 Pro Ser Gly Gly Ser Gly Gly Ser Gin Ser Phe Leu Leu Lys Ser Leu 210 215 220 Glu Gin Val Arg Lys Ile Gin Gly Asp Gly Ala Ala Leu Gin Glu Lys 225 230 235 240 Leu Cys Ala Thr Tyr Lys Leu Cys His Pro Glu Glu Leu Val Leu Leu 245 250 255 Gly His Ser Leu Gly Ile Pro Trp Ala Pro Leu Ser Ser Cys Pro Ser 260 265 270 Gin Ala Leu Gin Leu Ala Gly Cys Leu Ser Gin Leu His Ser Gly Leu 275 280 285 Phe Leu Tyr Gin Gly Leu Leu Gin Ala Leu Glu Gly Ile Ser 290 295 300 INFORMATION FOR SEQ ID NO: 169: SEQUENCE

CHARACTERISTICS:

LENGTH: 317 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 169: Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg Pro 1 5 10 Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp Val Ser 25 Ile Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu Ser Phe Val 40 Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly Ile Glu Ala Ile Leu 55 Arg Asn Leu Gin Pro Cys Leu Pro Ser Ala Thr Ala Ala Pro Ser Arg 70 75 His Pro Ile Ile Ile Lys Ala Gly Asp Trp Gin Glu Phe Arg Glu Lys 90 Leu Thr Phe Tyr Leu Val Thr Leu Glu Gin Ala Gin Glu Gin Gin Tyr 100 105 110 WO 97/1 2985 PCTIUS96/1 5774 Val Giu Gly Gly Gly Gly Ser Pro 115 120 Thr Ile Asn Pro Ser Pro Pro Ser 130 135 Met Ala Pro Glu Leu Gly Pro Thr 145 150 Ala Asp Phe Ala Thr Thr Ile Trp 165 Ala Pro Ala Leu Gin Pro Thr Gin 180 Ala Phe Gin Arg Arg Ala Gly Gly 195 200 Ser Phe Leu Giu Val Ser Tyr Arg 210 215 Ser Gly Giy Ser Giy Gly Ser Gin 225 230 Gin Val Arg Lys Ile Gin Gly Asp 245 Cys Ala Thr Tyr Lys Leu Cys His 260 His Ser Leu Gly Ile Pro Trp Ala 1 275 280 Ala Leu Gin Leu Ala Gly Cys Leu S 290 295 Leu Tyr Gin Gly Leu Leu Gin Ala L.

305 310 INFORMATION FOR SEQ ID NO: 170: SEQUENCE

CHARACTERISTICS:

LENGTH: 302 amino acids TYPE: amino acid STRANDEDNESS. single TOPOLOGY: linear (ii) MOLECULE TYPE: protein Gi Ly Le.

Gir Gl) 185 Val Val Ser Gy ?ro ~ro ;er eu y Giu Pro s Giu Ser .1 Asp Thr 155 iGin Met 170 Ala Met Leu Val Leu Arg Phe Leu 235 Ala Ala 250 Glu Glu I Leu Ser S Gin Leu H~ 3 Giu Giy I 315 Se Hi 141 Le.

Git- Pro Ala His 220 Leu eu 4eu ;er [is 00 le r Gly 125 s Lys 0 .1 Gln 1Giu Ala Ser 205 Leu Lys Gin Val I 2 Cys P 285 Ser G Ser Pr( Ser Lej Leu Phe 190 His Atla Ser hlu .eu ~ro ly Ile Pro Asp Gly 175 Ala Leu Gin LeuC Lys I 255 Leu G Ser G Leu

P

Ser Asn Val 160 Met Ser Gln Pro 1lu ~eu in he (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 170: WO 97/12985 PCTIUS96/1 5774 Asn Cys Ser Ile Met Ile Asp Giu Ile Ile His His Leu Lys Arg Pro 1 5 10 Pro Ile Arg Arg His Leu Vai Asn Ala 145 Ser Leu Lys Gin Vail 225 Cys SerC Al~ Lei.

Ala Asn Pro Thr Giu Met 130 Phe His Ala Ser Glu 210 eu Pro 31Y 3Pro 1Met Val Leu Ile Phe Gly 115 Aia Ala Leu Gin Leu 195 Lys LeuC Ser C Leu 1 2 Le As~ Ly~c Gir Ile Tyr 100 Gly Met Ser Gln Pro 180 3iu eu liy ~he 60 u Leu Arg Asn 1Pro Ile *Leu *Gly Aia Ala Ser 165 Ser Gin Cys2 His Ala I 245 Leu As~ Asr Let Cys 70 Lys Val Gly Pro Phe 150 Phe la 1 er ~30 ~eu yr 7Pro 1Leu S5 Leu Ala Thr Ser Ala 135 Gin Leu Gly Arg Thr 215 Leu C Gin I Gin G Asi Arc 40 Asr Prc Gil.

Leu Pro 120 Leu Glu Ser 200 ryr 4eu .i Asn 25 1 Leu 1Aia Ser Asp Giu 105 Gly Gin Arg Vai Gly 185 Ile Lys I Ile I Ala G Leu L 265 Lei Pr( Sei Alz Trp 90 Gin Gly Pro Al.a Ser 170 31y 31n 4eu ~ro ;iy ~50 ~eu u Asn 3Asn Gly Thr 75 Gin *Ala *Gly Thr Gly 155 Tyr Ser Gly Cys Trp 235 CysI Gin Asi Lei IlE Ala Glu Gin Ser Gin 140 Gly Arg Gln %.sp iis jeu lia p~ Gi aGli G1i Aiz PhE Gil Giy 125 Gly Val Val Ser Gly 205 Pro Pro Ser Leu Leu 285 u Asp a Ser .1 Ala IPro Arg IGin 110 Gly Ala Leu Leu PheI 190 Ala I Giu C Leu S Gin L 2 Giu G PhE lIE Ser Giu Gin Gly MIet ktrg 175 4 eu ~la 1u er ~eu LSer Val Leu Arg Lys Tyr Ser Pro Ala 160 His Leu Leu Leu Ser 240 His Ile Ser Pro Giu 275 Leu Gly Pro Thr Leu 280 Asp Thr Leu Gin Asp Val Ala WO 97/12985 PCTIUS96/15774 398 Asp Phe Ala Thr Thr Ile Trp Gin Gin Met Glu Glu Leu Gly 290 295 300 INFORMATION FOR SEQ ID NO: 171: SEQUENCE CHARACTERISTICS: LENGTH: 317 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 171: Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg Pro 1 5 10 Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp Val Ser 25 Ile Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu Ser Phe Val 40 Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly Ile Glu Ala Ile Leu 55 Arg Asn Leu Gin Pro Cys Leu Pro Ser Ala Thr Ala Ala Pro Ser Arg 70 75 His Pro Ile Ile Ile Lys Ala Gly Asp Trp Gin Glu Phe Arg Glu Lys 90 Leu Thr Phe Tyr Leu Val Thr Leu Glu Gin Ala Gin Glu Gin Gin Tyr 100 105 110 Val Glu Gly Gly Gly Gly Ser Pro Gly Glu Pro Ser Gly Pro Ile Ser 115 120 125 Thr Ile Asn Pro Ser Pro Pro Ser Lys Glu Ser His Lys Ser Pro Asn 130 135 140 Met Ala Met Ala Pro Ala Leu Gin Pro Thr Gin Gly Ala Met Pro Ala 145 150 155 160 Phe Ala Ser Ala Phe Gin Arg Arg Ala Gly Gly Val Leu Val Ala Ser 165 170 175 His Leu Gin Ser Phe Leu Glu Val Ser Tyr Arg Val Leu Arg His Leu 180 185 190 WO 97/12985 PCT/US96/15774 399 Ala Gin Pro Ser Gly Gly Ser Gly Gly Ser Gin Ser Phe Leu Leu Lys 195 200 205 Ser Leu Glu Gin Val Arg Lys Ile Gin Gly Asp Gly Ala Ala Leu Gin 210 215 220 Glu Lys Leu Cys Ala Thr Tyr Lys Leu Cys His Pro Glu Glu Leu Val 225 230 235 240 Leu Leu Gly His Ser Leu Gly Ile Pro Trp Ala Pro Leu Ser Ser Cys 245 250 255 Pro Ser Gin Ala Leu Gin Leu Ala Gly Cys Leu Ser Gin Leu His Ser 260 265 270 Gly Leu Phe Leu Tyr Gin Gly Leu Leu Gin Ala Leu Glu Gly Ile Ser 275 280 285 Pro Glu Leu Gly Pro Thr Leu Asp Thr Leu Gin Leu Asp Val Ala Asp 290 295 300 Phe Ala Thr Thr Ile Trp Gin Gin Met Glu Glu Leu Gly 305 310 315 INFORMATION FOR SEQ ID NO: 172: SEQUENCE CHARACTERISTICS: LENGTH: 302 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 172: Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg Pro 1 5 10 Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp Val Ser 25 Ile Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu Ser Phe Val 40 Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly Ile Glu Ala Ile Leu 55 Arg Asn Leu Gin Pro Cys Leu Pro Ser Ala Thr Ala Ala Pro Ser Arg 70 75 WO 97/12985 PCT/US96/15774 His Pro Ile lie Ile Lys Ala Leu Val Asn Arg 145 Glu Ser Lys Tyr Gly 225 Leu Gly Leu Gin Thr Glu Met 130 Arg Val Gly Ile Lys 210 lle Ala Leu Asp Gin Phe Gly 115 Ala Ala Ser Gly Gin 195 Leu Pro Gly Leu Thr 275 Met Tyr 100 Gly Thr Gly Tyr Ser 180 Gly Cys Trp Cys Gin 260 Leu Glu Leu Val Thr Gly Gly Ser Gin Gly Ala 135 Gly Val Leu 150 Arg Val Leu 165 Gin Ser Phe Asp Gly Ala His Pro Glu 215 Ala Pro Leu 230 Leu Ser Gin 245 Ala Leu Glu Gin Leu Asp Glu Leu Gly Gly Leu Pro 120 Met Val Arg Leu Ala 200 Glu Ser Leu Gly Val 280 Met Asp Glu 105 Gly Pro Ala His Leu 185 Leu Leu Ser His Ile 265 Ala Trp Gin Gly Ala Ser Leu 170 Lys Gin Val Cys Ser 250 Ser Asp Gin Ala Gly Phe His 155 Ala Ser Glu Leu Pro 235 Gly Pro Phe Glu Gin Ser Ala 140 Leu Gin Leu Lys Leu 220 Ser Leu Glu Ala Phe Glu Gly 125 Ser Gin Pro Glu Leu 205 Gly Gin Phe Leu Thr 285 Arg Gin 110 Gly Ala Ser Ser Gin 190 Cys His Ala Leu Gly 270 Thr Glu Gin Gly Phe Phe Gly 175 Val Ala Ser Leu Tyr 255 Pro Ile Lys Tyr Ser Gin Leu 160 Gly Arg Thr Leu Gin 240 Gin Thr Trp 290 Ala Pro Ala Leu Gin Pro 300 295 INFORMATION FOR SEQ ID NO: 173: SEQUENCE CHARACTERISTICS: LENGTH: 317 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: protein WO 97/12985 PCTJUS96/1 5774 401 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 173: Asn Cys Ser Ile Met Ile Asp Giu Ile Ile His His 4- 5 Leu Lys Ar D Pr Ii, Ar Arc His Leu Val Thr Met 145 Arg Val Gly Ile Lys 225 Ile o Ala Leu g Ala j Asn Pro Thr Glu Ile 130 Ala AlaC Ser Gly s 1 Gin G 210 Leu C Pro T Pr Me Va Lei lE Phe 115 A.sn rhr .yr er .95 ,ys rp o Leu t Asp 1 Lys .1 Gin Ile Tyr 100 Gly Pro Gin Gly Arg\ 180 Gin S Asp G His P Ala P 2 Lei Arc Asr Prc Ile Leu Giy Ser .iy lai rai er liy ro ro 45 .i Asp Asn ILeu Cys 70 Lys Val Giy Pro Ala 150 Leu Leu I Phe I Ala A 2 Giu G 230 Leu S Pro Leu Giu 55 Leu Ala Thr Ser Pro 135 Mqet lai ~rg ~euI l~a I 15 iu L er S Asn Arg 40 Asn Asn 25 Leu Ala Leu Pro Ser Asn Asn Gly Asp Leu Ile Giu Giu Giu Asp 310 Ser Ala Vai Phe Ile Ser Vai Leu Prc Giy Leu Pro 120 Ser Pro kla -'is eu ~00 ~eu Ceu er Se~ Asj Glu 105 Giy Lys Ala Ser Leu 185 Lys Gin Vai Cys Ala Thr 75 Trp Gin 90 Gin Ala Giu Pro Giu Ser Phe Ala 155 His Leu 170 Ala Gin Ser Leu Giu Lys Leu Leu 235 Pro Ser 250 Ala Glu Gin Ser His 140 Ser Gin Pro Giu Leu 220 3 iy Al~ PhE GEu Gly 125 Lys Ala Ser Ser Gin 205 Cys His APro Arg Gin 110 Pro Ser Phe Phe Gly 190 Val Ala Ser Sej Glt Gir Ile Pro Gin Leu 175 Gly Arg Thr Leu rArg iLys 1Tyr Ser Asn Arg 160 Giu Ser Lys Tyr Gly 31n Ala Leu Gin Leu Ala Giy Cys Leu 260 Ser Gin Leu His Ser 265 Gly Leu Phe Leu Tyr Gn Gly 270 WO 97/12985 PCT/US96/157 7 4 402 Leu Leu Gin Ala Leu Glu Gly Ile Ser Pro Glu Leu Gly Pro Thr Leu 275 280 285 Asp Thr Leu Gin Leu Asp Val Ala Asp Phe Ala Thr Thr Ile Trp Gin 290 295 300 Gin Met Glu Glu Leu Gly Met Ala Pro Ala Leu Gin Pro 305 310 315 INFORMATION FOR SEQ ID NO: 174: SEQUENCE

CHARACTERISTICS:

LENGTH: 302 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 174: Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu 1 Pro Ile Arg Arg His Leu Val Asn Ala Leu Ala Asn Pro Thr Glu Met Pro Met Val Leu Ile Phe Gly 115 Ala Leu Asp Lys Gin Ile Tyr 100 Gly Ser Leu Arg Asn Pro Ile Leu Gly Asp Asn Leu Cys 70 Lys Val Gly Pro Leu Glu 55 Leu Ala Thr Ser Asn Arg 40 Asn Pro Gly Leu Pro 120 Asn 25 Leu Ala Ser Asp Glu 105 Gly Leu Pro Ser Ala Trp 90 Gin Gly Asn Asn Gly Thr 75 Gin Ala Gly Asp Leu Ile Ala Glu Gin Ser Glu Glu Glu Ala Phe Glu Gly 125 Lys Asp Ser Ala Pro Arg Gln 110 Gly i Arg Val Phe Ile Ser Glu Gin Gly Pro Ser Val Leu Arg Lys Tyr Ser 130 Ala Phe Gin Arg Arg Ala Gly Gly Val Leu Val Ala 135 140 Ser 145 His Leu Gin Ser Phe 150 Leu Glu Val Ser Tyr 155 Arg Val Leu Arg His 160 WO 97/12985 PCT/US96/15774 Leu Ala Lys Ser Gin Glu Val Leu 210 Cys Pro 225 Ser Gly Ser Pro Asp Phe Pro Ala 290 Gin Pro Leu Glu 180 Lys Leu 195 Leu Gly Ser Gin Leu Phe Glu Leu 260 Ala Thr 275 Leu Gin Ser 165 Gin Cys His Ala Leu 245 Gly Thr Gly Val Ala Ser Leu 230 Tyr Pro Ile Gly Arg Thr Leu 215 Gin Gin Thr Trp Ser Lys Tyr 200 Gly Leu Gly Leu Gin 280 Gly Ile 185 Lys Ile Ala Leu Asp 265 Gin Gly 170 Gin Leu Pro Gly Leu 250 Thr Met Ser Gly Cys Trp Cys 235 Gin Leu Glu Gin Ser Asp Gly His Pro 205 Ala Pro 220 Leu Ser Ala Leu Gin Leu Glu Leu 285 Phe Ala 190 Glu Leu Gin Glu Asp 270 Gly Leu 175 Ala Glu Ser Leu Gly 255 Val Met Leu Leu Leu Ser His 240 Ile Ala Ala Pro Thr Gln Gly Ala Met Pro Ala Phe Ala INFORMATION FOR SEQ ID NO: 175: SEQUENCE CHARACTERISTICS: LENGTH: 317 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) Asn 1 Pro Ile Arg SEQUENCE DESCRIPTION: SEQ ID NO: 175: Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg Pro 5 10 Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp Val Ser 25 Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu Ser Phe Val 40 Ala Val Lys Asn Leu Glu Asn Ala Ser Gly Ile Glu Ala Ile Leu 55 WO 97/12985 PCTIUS96/1577 4 Arg His Leu Val1 Asn Pro Thr Giu Leu Gin Ile Ile Phe Tyr 100 Gly Giy Pro Cys 70 Ile Lys Leu Vai Giy Gly Leu Pro Ala Gly Thr Leu Ser Pro Ser Asp Glu 105 Ala Trp 90 Gin Thr 75 Gn Ala Ala Giu Gin Ala Phe Giu Gly Pro Ser Arg Giu Gli Gin 110 Pro Ile Arg Lys Tyr Ser 115 Giy Giu Pro Ser 120 Thr Met 145 His Ala Ser Giu Leu 225 Pro Gly Pro Phe Ala 305 Ile 130 Ala Leu Gin Leu Lys 210 Leu Ser Leu Glu kl a 290 eu Asn *Ser Gin Pro Giu 195 Leu Gly.

Gin Phe Leu( 275 Thr 'j Gin

I

Pro Ala Ser Ser 180 Gin Cys His Ala Lieu 260 31y rhr ~ro Se~ PhE Phe 165 Gly Val Ala Ser Leu 245 Tyr Pro Ile Thr Pro Gin 150 Leu Gly Arg Thr Leu 230 Gin Gin Thr i Trp C 2 Pro 135 Arg Giu Ser L-ys Tyr 215 Gly Lieu 31 y 4eu 1n ~95 Ser *Arg Val1 Gly Ile 200 Lys Ile Ala LeuI Asp 91 280 Gin I.

Ala

M~

Ly Alz Ser Gdy 185 Gin Leu Pro .71y eu ~65 rhr let [et G1 *Tyi 17( Seit *Gl)y Cys Trp Cys 250 Gin Leu Giu Pro ui Ser IGly 155 Arg Gn Asp His Ala 235 Leu Ala GinI GiuI Ala 1 315 Hi~ 14( Val Val Ser Gly Pro 220 Pro Ser Lieu Lieu Aeu ~00 'he 5Lys Leu *Leu *Phe Ala 205 Giu Leu Gin Giu Asp 285 Gly Ala Ser Val Arg Leu 190 Ala Glu Ser Leu 270 Ifai 4et *Pro Ala His 175 Leu Leu Leu Ser His 255 Ile Ala I Ala

I

Asn Ser 160 Leu Lys Gin Vai Cys 240 Ser 3er .sp ~ro 310 INFORMATION FOR SEQ ID NO: 176: Wi SEQUENCE

CHARACTERISTICS:

LENGTH: 305 amino acids TYPE: amino acid WO 97/12985 PCT/US96/15774 405 STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 176: Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg Pro 1 5 10 10 Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp Val Ser 25 Ile Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu Ser Phe Val 3540 Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly Ile Glu Ala Ile Leu 55 Arg Asn Leu Gin Pro Cys Leu Pro Ser Ala Thr Ala Ala Pro Ser Arg 70 75 75 His Pro Ile Ile Ile Lys Ala Gly Asp Trp Gin Glu Phe Arg Glu Lys 8590 Leu Thr Phe Tyr Leu Val Thr Leu Glu Gin Ala Gin Glu Gin Gin Tyr 100 105 110 Val Glu Gly Gly Gly Gly Ser Pro Gly Gly Gly Ser Gly Gly Gly Ser 115 120 125 Asn Met Ala Tyr Lys Leu Cys His Pro Glu Glu Leu Val Leu Leu Gly 130 135 140 His Ser Leu Gly Ile Pro Trp Ala Pro Leu Ser Ser Cys Pro Ser Gin 145 150 155 160 Ala Leu Gin Leu Ala Gly Cys Leu Ser Gin Leu His Ser Gly Leu Phe 165 170 175 Leu Tyr Gin Gly Leu Leu Gin Ala Leu Glu Gly Ile Ser Pro Glu Leu 180 185 190 Gly Pro Thr Leu Asp Thr Leu Gin Leu Asp Val Ala Asp Phe Ala Thr 195 200 205 Thr Ile Trp Gln Gln Met Glu Glu Leu Gly Met Ala Pro Ala Leu Gin 210 215 220 Pro Thr Gin Gly Ala Met Pro Ala Phe Ala Ser Ala Phe Gin Arg Arg 225 230 235 240 WO 97/12985 PCT/US96/15774 Ala Gly Gly Val Leu Val Ala Ser 245 Ser Tyr Arg Val Leu Arg His Leu 260 Ala Ser Ser Leu Pro Gln Ser Phe 275 280 Arg Lys Ile Gin Gly Asp Gly Ala 290 295 Thr 305 INFORMATION FOR SEQ ID NO: 177: SEQUENCE

CHARACTERISTICS:

LENGTH: 320 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: protein His Leu Gin Ser Phe Leu Glu Val 250 255 Ala Gin Pro Thr Pro Leu Gly Pro 265 270 Leu Leu Lys Ser Leu Glu Gin Val 285 Ala Leu Gin Glu Lys Leu Cys Ala 300 (xi) Asn 1 Pro Ile Arg Arg His Leu Val SEQUENCE DESCRIPTION: SEQ ID NO: 177: Cys Ser Ile Met Ile Asp Glu Ile Ile His 5 10 Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn 25 Leu Met Asp Arg Asn Leu Arg Leu Pro Asn 40 Ala Val Lys Asn Leu Glu Asn Ala Ser Gly 55 Asn Leu Gin Pro Cys Leu Pro Ser Ala Thr 70 75 Pro Ile Ile Ile Lys Ala Gly Asp Trp Gin 90 Thr Phe Tyr Leu Val Thr Leu Glu Gln Ala 100 105 Glu Gly Gly Gly Gly Ser Pro Gly Glu Pro 115 120 His Asp Leu Ile Ala Glu Gin Ser Leu Glu Glu Glu Ala Phe Glu Gly 125 Lys Asp Ser Ala Pro Arg G1n 110 Pro Arg Val Phe Ile Ser Glu Gin Ile Pro Ser Val Leu Arg Lys Tyr Ser WO 97/12985 PCT/US96/15774 Thr Ile Asn Pro Ser Pro 130 Met 145 Ser Leu Tyr Pro Ile 225 Thr Gly Tyr Ser Lys 305 Ala Tyr Leu Gly Gin Leu Gin Gly 195 Thr Leu 210 Trp Gin Gin Gly Gly Val Arg Val 275 Ser Leu 290 Ile Gin Lys Ile Ala 180 Leu Asp Gin Ala Leu 260 Leu Pro Gly Leu Pro 165 Gly Leu Thr Met Met 245 Val Arg Gin Asp Cys 150 Trp Cys Gin Leu Glu 230 Pro Ala His Ser Gly 310 Pro Ser 135 His Pro Ala Pro Leu Ser Ala Leu 200 Gin Leu 215 Glu Leu Ala Phe Ser His Leu Ala 280 Phe Leu 295 Ala Ala Lys Glu Leu Gin 185 Glu Asp Gly Ala Leu 265 Gin Leu Leu Glu Ser His Lys Ser Pro Asn 140 Glu Leu 155 Ser Ser 170 Leu His Gly Ile Val Ala Met Ala 235 Ser Ala 250 Gin Ser Pro Thr Lys Ser Gin Glu 315 Val Cys Ser Ser Asp 220 Pro Phe Phe Pro Leu 300 Lys Leu Pro Gly Pro 205 Phe Ala Gin Leu Leu 285 Glu Leu Leu Ser Leu 190 Glu Ala Leu Arg Glu 270 Gly Gin Cys Gly Gin 175 Phe Leu Thr Gin Arg 255 Val Pro Val Ala His 160 Ala Leu Gly Thr Pro 240 Ala Ser Ala Arg Thr 320 INFORMATION FOR SEQ ID NO: 178: SEQUENCE CHARACTERISTICS: LENGTH: 305 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 178: Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg Pro WO 97/12985 PCTIUS96/15774 1 Pro Ala 5 Pro Leu iLeu Asp Pro Asn Asn Leu Asn Asp Giu Asp 25 30 Val Ser Ile Leu Met Asp Arg Asi

'I

Arg Ala Val Ly.

Arg His Leu Val Asn Val1 145 Met Ser Gin Pro Lys 225 GinC Val I Cys I As2 Pr: Th3 Git Met 130 Ala Al a la Ser I'hr 210 3er 1lu ~eu ~ro n- Leu Phe Gly 115 *Ala *Asp Pro Phe Phe 195 Pro Leu Lys Leu C Ser C 275 Gin Ile Tyr 100 Gly Pro Phe Ala Gin 180 Leu [Leu 31u eu iy lin Asi Prc Ile Leu Gly Glu Ala Leu 165 Arg Giu Gly Glm Cys 245 -us kla 1i Leu Cys 70 Lys 1Val Gly Leu Thr 150 Gln Arg Val Pro Val 230 Ala 9] Ser I Leu

G

Le G1i 55 Le~ AlE Th2i Ser Gly 135 Thr Pro Ala Ser 2,15 krg Thr jeu ~ln 1 Arg Leu Pr 40 aAsn Ala Se Pro Ser Al Gly Asp Trj 90 0 r a Asn Gly Thr 75 Gin Leu Ile Ala Glu Giu Gu Ala Phe Ser Ala Pro Arg Phe Ile Ser Val Leu Arg Leu Giu *Gin 105 Pro Gly Gly 120 Pro Thr Leu Ile Trp Gin Thr Gin Gly 170 Gly Gly Val 185 Tyr Arg Val 200 Ser Ser LeuI Lys Ile Gin Tyr Lys Leu C 250 Gly Ile Pro q 265 Leu Ala Gly C Ala Gin Glu Gln Gln Tyr 110 Gly Ser Gly Gly Gly Ser 125 Asp Thr Leu Gin Leu Asp 140 Gin Met Glu Glu Leu Gly 155 160 Ala Met Pro Ala Phe Ala 175 Eeu Val Ala Ser His Leu 190 Leu Arg His Leu Ala Gln 205 Pro Gin Ser Phe Leu Leu 220 31Y Asp Gly Ala Ala Leu D35 240 YS His Pro Glu Glu Leu 255 ~rp Ala Pro Leu Ser Ser 270 ~ys Leu Ser Gin Leu His Ser Gly Leu Phe Leu Tyr Gin Gly Leu Leu Gin Ala Leu Giu Gly Ile WO 97/12985 PCTIUS96/1 5774 290 Ser 305 INFORMATION FOR SEQ ID NO: 179: SEQUENCE

CHARACTERISTICS:

LENGTH: 320 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 179: Asn Cys Ser Ile Met Ile Asp Gu Ile Ile His His Pro Ile Arg Arg His Leu Val Thr Met 145 Ala Ala Leu Ala Asn Pro Thr Giu Ile 130 Ala Asp Pro Met Val Leu Ile Phe Gly 115 Asn Pro Phe Leu Asp Lys Gin Ile Tyr 100 Gly Pro Giu Ala Leu Arg Asn Pro Ile Leu Gly Ser Leu Asp Asn Leu Cys 70 Lys Val Gly Pro Gly 150 Thr Pro Leu Giu 55 Leu Ala Thr Ser Pro 135 Pro Ile Asn Arg 40 Asn Pro Gly Leu Pro 120 Ser Thr Trp Asn 25 Leu Ala Ser Asp Glu 105 Gly Lys Leu Gln Leu Pro Ser Ala Trp 90 Gin Glu Giu Asp Asn Asn Gly Thr 75 Gin Ala Pro Ser Thr 155 Asp Leu Ile Ala Glu Gin Ser His 140 Leu Leu Giu Glu Giu Ala Phe Glu Gly 125 Lys Gin Lys Asp Ser Ala Pro Arg Gin 110 Pro Ser Leu Arg Val Phe Ile Ser Giu Gin Ile Pro Asp Gly Pro Ser Val Leu Arg Lys Tyr Ser Asn Val 160 Me t 165 Gin I~et Glu Glu I ~eu Ala Pro Ala Leu Gin Pro Thr Gin Gly Ala Met Pro Ala Phe Ala Ser WO 97/12985 PCT/US96/157 74 410 180 185 190 Ala Phe Gin Arg Arg Ala Gly Gly Val Leu Val Ala Ser His Leu Gin 195 200 205 Ser Phe Leu Glu Val Ser Tyr Arg Val Leu Arg His Leu Ala Gin Pro 210 215 220 Thr Pro Leu Gly Pro Ala Ser Ser Leu Pro Gin Ser Phe Leu Leu Lys 225 230 235 240 Ser Leu Glu Gin Val Arg Lys Ile Gin Gly Asp Gly Ala Ala Leu Gin 245 250 255 Glu Lys Leu Cys Ala Thr Tyr Lys Leu Cys His Pro Glu Glu Leu Val 260 265 270 Leu Leu Gly His Ser Leu Gly Ile Pro Trp Ala Pro Leu Ser Ser Cys 275 280 285 Pro Ser Gin Ala Leu Gln Leu Ala Gly Cys Leu Ser Gin Leu His Ser 290 295 300 Gly Leu Phe Leu Tyr Gin Gly Leu Leu Gin Ala Leu Glu Gly Ile Ser 305 310 315 320 INFORMATION FOR SEQ ID NO: 180: SEQUENCE CHARACTERISTICS: LENGTH: 305 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 180: Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg Pro 1 5 10 Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp Val Ser 25 Ile Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu Ser Phe Val 40 Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly Ile Glu Ala Ile Leu 55 WO 97/12985 PCTIUS96II 5774 Arg Asn Leu Gin Pro His Leu Val Asn Ala 145 Ser Leu Phe Ala Glu 225 Leu Gin Giu Pro Thr Glu Met 130 Phe His Ala Leu Ala 210 Glu Ser Leu Gly Ile Phe Gly 115 Aia Ala Leu Gin Leu 195 Leu Leu Ser His Ile 275 Ile Ile Tyr Leu 100 Gly Giy Met Ala Ser Ala Gin Ser 165 Pro Thr 180 Lys Ser Gin Giu Val Leu Cys Pro 245 Ser Gly 260 Ser Pro Cys Leu Pro Lys Ala Gly Val Thr Leu Giy Ser Pro 120 Pro Ala Leu 135 Phe Gin Arg iso Phe Leu Giu Pro Leu Gly Leu Glu Gin 200 Lys Leu Cys 215 Leu Giy His 230 Ser Gin Ala Leu Phe Leu Giu Leu Gly 280 Ser Asp Giu 105 Gly Gin Arg Val Pro 185 Val Ala Ser Leu Tyr 265 Pro Ala Trp 90 Gin Gly Pro Al a Ser 170 Ala Arg Thr Leu Gin 250 Gin Thr Thr 75 Gin Ala Gly Thr Gly 155 Tyr Ser Lys Tyr Gly 235 Leu Gly Leu Al a Giu Gli Ser Gin 140 Gly Arg Ser Ile Lys 220 Ile Ala Leu Asp Ala Phe Giu Gly 125 Gly Val Leu Gin 205 Leu Pro Gly Leu Thr 285 Pro Arg Gin 110 Gly Ala Leu Leu Pro 190 Gly Cys Trp Cys Gin 270 Leu Ser Giu Gin Gly Met Val Arg 175 Gin Asp His Ala Leu 255 Ala Gln Arg Lys Tyr Ser Pro Ala 160 His Ser Gly Pro Pro 240 Ser Leu Leu Asp Val Ala Asp Phe Ala Thr Thr Ile Trp, Gin 290 295 Gly 305 INFORMATION FOR SEQ ID NO: 181: SEQUENCE CHARACTERISTICS: LENGTH: 320 amino acids TYPE: amino acid STRANDEDNESS: single Gin 300 Met Giu Glu Leu WO 97/12985 PCT/US96,'1577 4 412 TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 181: Asn Cys Ser Ile Met Ile Asp Giu Ile Ile His His Leu 1 Ly Pro Ile Arg Arg His Leu Val1 Thr Met 145 Phe His Ala Leu Ala Leu Ala Asn Pro Thr Giu Ile 130 Ala Aa Leu Gln Leu Pro Met Val Leu Ile Phe Gly 115 Asn Met Ser Gin Pro 195 Lys Let Asp Lys Gin Ile Tyr 100 Gly Pro Al1a Aa Ser 180 ['hr ~er 1Leu Arg Asn Pro Ile Leu Gly Ser Pro Phe 165 Phe ProI Led

C

Asp Asn Leu Cys 70 Lys Val1 Giy Pro Aa 150 eu 4 eu Prc Let Gil 55 Leu Ala Thr Ser Pro 135 Leu Arg Glu Gly )Asn 1Arg 40 Asn Pro Gly Leu Pro 120 Ser Gin Arg Val Pro 1 200 Val A Asi 25 Let.

Ala Ser Asp Giu 105 Gly Ljys Pro kla er .85 la ~rg 'i Leu 1Pro Ser *Ala Trp 90 Gin Giu Glu Thr Giy 170 Tyr I Ser Lys Asi Asi Glj Thr 75 Gin Ala Pro Ser 3mn 155 31 ly ~rg er :le 'Asp I Leu Ile -Ala Giu Gin Ser His 140 Gly Val.

ValI Leu 1 GIn. C Giu Glu Giu Ala Phe Giu Gly 125 L.ys Ala eu Aeu ~ro Ily i As1 Sez Ala Pro Arg Gin 110 Pro Ser Met Val krg 190 isp s Arg )Val.

Phe Ile Ser Glu Gin Ile Pro Pro Ala 175 His I Ser I Gly

P.

Pro Ser Val Leu Arg Lys Tyr Ser Asn kla 160 3er jeu ~he la, 210 215 Ala 225 Leu Gin Giu Lys Leu 230 Cys Ala Thr Tyr Lys 235 Leu Cys His Pro Giu 240 WO 97/12985 PCT/tJS96/15774 413 Glu Leu Val Leu Leu Gly His Ser Leu Gly Ile Pro Trp Ala Pro Leu 245 250 255 Ser Ser Cys Pro Ser Gin Ala Leu Gin Leu Ala Gly Cys Leu Ser Gin 260 265 270 Leu His Ser Gly Leu Phe Leu Tyr Gin Gly Leu Leu Gin Ala Leu Glu 275 280 285 Gly Ile Ser Pro Glu Leu Gly Pro Thr Leu Asp Thr Leu Gin Leu Asp 290 295 300 Val Ala Asp Phe Ala Thr Thr Ile Trp Gin Gin Met Glu Glu Leu Gly 305 310 315 320 INFORMATION FOR SEQ ID NO: 182: SEQUENCE CHARACTERISTICS: LENGTH: 305 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 182: Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg Pro 1 5 10 Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp Val Ser 25 Ile Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu Ser Phe Val 40 Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly Ile Glu Ala Ile Leu 55 Arg Asn Leu Gin Pro Cys Leu Pro Ser Ala Thr Ala Ala Pro Ser Arg 70 75 His Pro Ile Ile Ile Lys Ala Gly Asp Trp Gin Glu Phe Arg Glu Lys 90 Leu Thr Phe Tyr Leu Val Thr Leu Glu Gin Ala Gin Glu Gin Gin Tyr 100 105 110 Val Glu Gly Gly Gly Gly Ser Pro Gly Gly Gly Ser Gly Gly Gly Ser 115 120 125 WO 97/12985 PCT/US96/15774 414 Asn Met Ala Thr Gin Gly Ala Met Pro Ala Phe Ala Ser Ala Phe Gin 130 135 140 Arg 145 Glu Gly Gin Cys His 225 Ala Leu Gly Arg Val Pro Val Ala 210 Ser Leu Tyr Pro Ala Ser Ala Arg 195 Thr Leu Gin Gin Thr 275 Gly Gly Val 150 Tyr Arg Val 165 Ser Ser Leu 180 Lys Ile Gin Tyr Lys Leu Gly Ile Pro 230 Leu Ala Gly 245 Gly Leu Leu 260 Leu Asp Thr Leu Val Leu Arg Pro Gin Gly Asp 200 Cys His 215 Trp Ala Cys Leu Gin Ala Leu Gin 280 Ala His Ser 185 Gly Pro Pro Ser Leu 265 Leu Ser Leu 170 Phe Ala Glu Leu Gin 250 Glu His 155 Ala Leu Ala Glu Ser 235 Leu Gly Leu Gin Leu Leu Leu 220 Ser His Ile Gin Pro Lys Gin 205 Val Cys Ser Ser Ser Thr Ser 190 Glu Leu Pro Gly Pro Phe Pro 175 Leu Lys Leu Ser Leu 255 Glu Leu 160 Leu Glu Leu Gly Gin 240 Phe Leu 270 Asp Val Ala Asp Phe Ala Thr 285 Thr Ile Trp Gin Gin Met Glu Glu Leu Gly Met 290 295 Pro 305 INFORMATION FOR SEQ ID NO: 183: SEQUENCE CHARACTERISTICS: LENGTH: 320 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: protein Ala 300 Pro Ala Leu Gin (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 183: Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg Pro 1 5 10 WO 97/12985 WO 9712985PCT/US96/15774 Pro Ile Arg Arg His Leu Val Thr Met 145 Arg Val Pro Val Ala 225 Her Leu Tyr Ala Leu Ala Asn Pro Thr Giu Ile 130 Ala Ala Ser Ala Arg 210 Thr Leu Gin Gin Pro Met Val Leu Ile Phe Gly 115 Asn Thr Gly Tyr Her 195 Lys Tyr Gly Leu Gly 275 Leu Asp Lys Gin Ile Tyr 100 Gly Pro Gin Gly Arg 180 Ser Ile Lys Ile Ala 260 Leu Leu Asp Arg Asn Asn Leu Pro Cys 70 Ile Lys Leu Val Gly Gly Her Pro Gly Ala 150 Val Leu 165 Val Leu Leu Pro Gin Gly Leu Cys 230 Pro Trp 245 Gly Cys Leu Gin Pro Leu Glu 55 Leu Ala Thr Her Pro 135 Met Val Arg Gin Asp 215 His Ala Leu Ala Asn Arg 40 Asn Pro Gly Leu Pro 120 Ser Pro Ala His Her 200 Gly Pro Pro Ser Leu 280 Asn 25 Leu Al a Ser Asp Glu 105 Gly Lys Ala Ser Leu 185 Phe Ala Giu Leu Gin 265 Glu Leu Asn Asp Glu Asp Val Ser Pro Ser Al a Trp 90 Gin Glu Glu Phe His 170 Ala Leu Ala Giu Her 250 Leu Gly Asn Gly Thr 75 Gin Ala Pro Her Ala 155 Leu Gin Leu Leu Leu 235 Her His Ile Leu Ile Ala Glu Gin Her His 140 Her Gin Pro Lys Gin 220 Val Cys Her Her Glu Giu Ala Phe Glu Gly 125 Lys Ala Her Thr Her 205 Glu Leu Pro Gly Pro 285 Her Ala Pro Arg Gin 110 Pro Her Phe Phe Pro 190 Leu Lys Leu Her Leu 270 Glu Phe Ile Her Glu Gin Ile Pro Gin Leu 175 Leu Giu Leu Gly Gin 255 Phe Leu Val Leu Arg Lys Tyr Her Asn Arg 160 Giu Gly Gin Cys His 240 Ala Leu Gly Pro Thr Leu Asp Thr Leu Gln Leu Asp Val Ala Asp Phe Ala Thr Thr 290 295 WO 97/12985 PCT/US96/15774 416 Ile Trp Gin Gin Met Glu Glu Leu Gly Met Ala Pro Ala Leu Gin Pro 305 310 315 320 INFORMATION FOR SEQ ID NO: 184: SEQUENCE CHARACTERISTICS: LENGTH: 305 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 184: Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg Pro 1 5 10 Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp Val Ser 25 Ile Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu Ser Phe Val 40 Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly Ile Glu Ala Ile Leu 55 Arg Asn Leu Gin Pro Cys Leu Pro Ser Ala Thr Ala Ala Pro Ser Arg 70 75 His Pro Ile Ile Ile Lys Ala Gly Asp Trp Gin Glu Phe Arg Glu Lys 90 Leu Thr Phe Tyr Leu Val Thr Leu Glu Gin Ala Gin Glu Gin Gin Tyr 100 105 110 Val Glu Gly Gly Gly Gly Ser Pro Gly Gly Gly Ser Gly Gly Gly Ser 115 120 125 Asn Met Ala Ser Ala Phe Gin Arg Arg Ala Gly Gly Val Leu Val Ala 130 135 140 Ser His Leu Gin Ser Phe Leu Glu Val Ser Tyr Arg Val Leu Arg His 145 150 155 160 Leu Ala Gin Pro Thr Pro Leu Gly Pro Ala Ser Ser Leu Pro Gin Ser 165 170 175 Phe Leu Leu Lys Ser Leu Glu Gin Val Arg Lys Ile Gin Gly Asp Gly WO 97/12985 PCT/US96/15774 417 180 185 190 Ala Ala Leu Gin Glu Lys Leu Cys Ala Thr Tyr Lys Leu Cys His Pro 195 200 205 Glu Glu Leu Val Leu Leu Gly His Ser Leu Gly Ile Pro Trp Ala Pro 210 215 220 Leu Ser Ser Cys Pro Ser Gin Ala Leu Gin Leu Ala Gly Cys Leu Ser 225 230 235 240 Gin Leu His Ser Gly Leu Phe Leu Tyr Gin Gly Leu Leu Gin Ala Leu 245 250 255 Glu Gly Ile Ser Pro Glu Leu Gly Pro Thr Leu Asp Thr Leu Gin Leu 260 265 270 Asp Val Ala Asp Phe Ala Thr Thr Ile Trp Gin Gin Met Glu Glu Leu 275 280 285 Gly Met Ala Pro Ala Leu Gin Pro Thr Gin Gly Ala Met Pro Ala Phe 290 295 300 Ala 305 INFORMATION FOR SEQ ID NO: 185: SEQUENCE CHARACTERISTICS: LENGTH: 320 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 185: Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg Pro 1 5 10 Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp Val Ser 25 Ile Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu Ser Phe Val 40 Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly Ile Glu Ala Ile Leu 55 Arg Asn Leu Gin Pro Cys Leu Pro Ser Ala Thr Ala Ala Pro Ser Arg WO 97/12985 PCTIUS96/1 5774 Gin Pro Ile Ile Ile Ala Gly Asp Trp Glu Phe Arg Giu Leu Val1 Thr Met 145 His Ala Leu Ala Glu 225 Ser Leu Gly Val.

Met2 305 Th2 Gi.

Ile 130 Al a Leu Gin Leu Leu 210 Leu Ser Ile kla -Phe 1Gly 115 Asn Ser Gin Pro Lys 195 Gin Val Cys Ser Ser 275 Asp I Tyr 100 Gly Pro Ala Ser Thr 180 Ser Glu Leu Pro ?ro 'he Lei.

Gl) Ser Phe Phe 165 Pro Leu Lys Leu Ser 245 Leu Glu Ala 1Val Gly Pro Gin 150 Leu Leu Giu Leu Gly 230 Gin Phe Leu Thr Gin 310 Thr Leu Giu Gin Ala 105 Ser Pro 135 Arg Glu Gly Gin Cys 215 His Ala Leu

G

1 y rhr 295 Pro Pro 120 Ser Arg Val1 Pro Val 200 Aia Ser Leu Tyr Pro 280 Ile Glj Lys Aia Ser Ala 185 Arg Thr Leu Gin Gin 265 rhr Trp rGlu Giu Giy Tyr 170 Ser Lys Tyr Gly Leu 250 Gly Leu Gin Pro Ser Gly 155 Arg Ser Ile Lys Ile 235 Ala Leu A~sp Gln Gin Ser His 140 Val Val Leu Gin Leu 220 Pro Gly Leu Thr MetC 300 Glu Gly 125 Lys Leu Lou Pro Gly 205 Cys Trp :ys 3mn jeu lu Gin 110 Pfo Ser Val Arg Gin 190 Asp His Ala Leu Ala 270 Gin Giu Gir Ile Pro Ala His 175 Ser Gly Pro Pro Ser 255 Leu eu jeu 1Tyr Ser Asn Ser 160 Leu Phe Ala Giu Leu 240 Gln Glu Asp Gly kla Pro Ala Leu Thr Gin Gly Ala Met Pro Ala Phe Ala INFORMATION FOR SEQ ID NO: 186: SEQUENCE

CHARACTERISTICS:

LENGTH: 321 amino acids TYPE: amino acid STRANDEDNESS: single WO 97/12985 PCT/US96/15774 419 TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 186: Leu Asp Pro Asn Asn Leu Asn Asp Giu Asp Val Ser Ile Arg Asn Pro Ile Leu Cys Ala Gly Lys 145 Ala Ser Ser Gin Cys 225 Asn Leu Cys Lys Val Ser Pro Pro 130 Ser Phe Phe Giy Val 210 Leu Giu Leu Ala Thr Ile Leu 115 Ile Pro Gin Leu Gly 195 Arg Arg Asn Pro Gly Leu Met 100 Tyr Ser Asn Arg Giu 180 Ser Lys Leu Pro Ala Ser Ser Ala Asp Trp 70 Giu Gin Ile Asp Val Giu Thr Ile Met Ala 150 Arg Ala 165 Val Ser Gly Gly Ile Gin Asn Gly Thr 55 Gin Ala Giu Gly Asn 135 Thr Gly Tyr Ser Gly 215 Leu Ile 40 Ala Giu Gin Ile Gly 120 Pro Gin Gly Arg Gin 200 Asp Glu 25 Glu Ala Phe Glu Ile 105 Gly Ser Gly Val Val 185 Ser Gly 10 Ser Ala Pro Arg Gin 90 His Gly Pro Ala Leu 170 Leu Phe Ala Phe Ile Ser Giu 75 Gin His Ser Pro Met 155 Val Arg Leu Ala Val Leu Arg Lys Gly Leu Pro Ser 140 Pro Ala His Leu Leu 220 Arg Arg His Leu Gly Lys Gly 125 Lys Ala Ser Leu Lys 205 Gin Leu Ala Asn Pro Thr Gly Arg 110 Giu Glu Phe His Ala 190 Ser Glu Met Val Leu Ile Phe Ser Pro Pro Ser Ala Leu 175 Gin Leu Lys Asp Lys Gin Ile Tyr Asn Pro Ser His Ser 160 Gin Pro Giu Leu Ala Thr Tyr Lys Leu Cys His Pro Giu Giu Leu Val Leu Leu Gly 230 235 24n WO 97/12985 PCT/US96/15774 420 His Ser Leu Gly Ile Pro Trp Ala Pro Leu Ser Ser Cys Pro Ser Gin 245 250 255 Ala Leu Gin Leu Ala Gly Cys Leu Ser Gin Leu His Ser Gly Leu Phe 260 265 270 Leu Tyr Gin Gly Leu Leu Gin Ala Leu Glu Gly Ile Ser Pro Glu Leu 275 280 285 Gly Pro Thr Leu Asp Thr Leu Gin Leu Asp Val Ala Asp Phe Ala Thr 290 295 300 Thr Ile Trp Gin Gin Met Glu Glu Leu Gly Met Ala Pro Ala Leu Gin 305 310 315 320 Pro INFORMATION FOR SEQ ID NO: 187: SEQUENCE

CHARACTERISTICS:

LENGTH: 321 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 187: Asn Ala Ser Gly Ile Glu Ala Ile Leu Arg Asn Leu Gin Pro Cys Leu 1 5 10 Pro Ser Ala Thr Ala Ala Pro Ser Arg His Pro Ile Ile Ile Lys Ala 25 Gly Asp Trp Gin Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr 40 Leu Glu Gin Ala Gin Glu Gin Gin Gly Gly Gly Ser Asn Cys Ser Ile 55 Met Ile Asp Glu Ile Ile His His Leu Lys Arg Pro Pro Ala Pro Leu 70 75 Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp Val Ser Ile Leu Met Asp 90 Arg Asn Leu Arg Leu Pro Asn Leu Glu Ser Phe Val Arg Ala Val Lys 100 105 110 WO 97/12985 PCT/US96/15774 Asn Gly Lys 145 Ala Ser Ser Gin Cys 225 His Ala Leu Gly Thr 305 Leu Pro 130 Ser Phe Phe Gly Val 210 Ala Ser Leu Tyr Pro 290 Glu 115 Ile Pro Gin Leu Gly 195 Arg Thr Leu Gin Gin 275 Thr Tyr Val Ser Thr Asn Met Arg Arg 165 Glu Val 180 Ser Gly Lys Ile Tyr Lys Gly Ile 245 Leu Ala 260 Gly Leu Leu Asp Glu Ile Ala 150 Ala Ser Gly Gin Leu 230 Pro Gly Leu Thr Gly Asn 135 Thr Gly Tyr Ser Gly 215 Cys Trp Cys Gin Leu 295 Gly 120 Pro Gin Gly Arg Gin 200 Asp His Ala Leu Ala 280 Gin Gly Gly Ser Pro Gly Glu Pro Ser 125 Ser Gly Val Val 185 Ser Gly Pro Pro Ser 265 Leu Leu Pro Pro Ala Met 155 Leu Val 170 Leu Arg Phe Leu Ala Ala Glu Glu 235 Leu Ser 250 Gin Leu Glu Gly Asp Val Ser 140 Pro Ala His Leu Leu 220 Leu Ser His Ile Ala 300 Lys Ala Ser Leu Lys 205 Gin Val Cys Ser Ser 285 Asp Glu Ser Phe Ala His Leu 175 Ala Gin 190 Ser Leu Glu Lys Leu Leu Pro Ser 255 Gly Leu 270 Pro Glu Phe Ala His Ser 160 Gin Pro Glu Leu Gly 240 Gin Phe Leu Thr Ile Trp Gin Gin Met Glu Glu Leu Gly Met Ala Pro Ala Leu Gin 310 31i o Pro INFORMATION FOR SEQ ID NO: 188: SEQUENCE CHARACTERISTICS: LENGTH: 321 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: protein WO 97/12985 PCT/US96/15774 422 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 188: Ala Pro Ser Arg His Pro Ile Ile Ile Lys Ala Gly Asp Trp Gin Giu 1 Phe Giu Ile Leu Pro Ser Ala Gly Lys 145 Ala Ser Ser Gin Cys 225 His Arg Gin His Asn Asn Gly Thr Pro 130 Ser Phe Phe Gly Val 210 Ala Ser Giu Gin His Asp Leu Ile Aia 115 Ile Pro Gin Leu Gly 195 Arg Thr Leu Lys Gly Leu Giu Giu Giu 100 Ser Asn Arg Giu 180 Ser Lys Tyr Giy Leu Gly Lys Asp Ser Ala Val Thr Met Arg 165 Val Gly Ile Lys Ile 245 Thr Gly Arg Val 70 Phe Ile Giu Ile Ala 150 Ala Ser Gly Gin Leu 230 Pro Phe Ser Pro 55 Ser Val Leu Gly Asn 135 Thr Gly Tyr Ser Gly 215 Cys Trp Tyr Asn 40 Pro Ile Arg Arg Gly 120 Pro Gin Gly Arg Gin 200 Asp His Ala Leu 25 Cys Ala Leu Ala Asn 105 Gly Ser Gly Val Val 185 Ser Gly Pro Pro Val Ser Pro Met Val 90 Leu Gly Pro Ala Leu 170 Leu Phe Ala Glu Leu 250 Thr Ile Leu Asp 75 Lys Gin Ser Pro Met 155 Val Arg Leu Ala Glu 235 Ser Leu Met Leu Arg Asn Pro Pro Ser 140 Pro Ala His Leu Leu 220 Leu Ser Glu Ile Asp Asn Leu Cys Gly 125 Lys Al a Ser Leu Lys 205 Gin Val Cys Gin Asp Pro Leu Giu Leu 110 Giu Giu Phe His Ala 190 Ser Glu Leu Pro Ala Giu Asn Arg Asn Pro Pro Ser Ala Leu 175 Gin Leu Lys Leu Ser Gin Ile Asn Leu Ala Ser Ser His Ser 160 Gin Pro Giu Leu Gly 240 Gin Ala Leu Gin Leu Ala Gly Cys Leu Ser Gin Leu His Ser Gly Leu-Phe 260 265 270 WO 97/12985 WO 9712985PCT/US96/1 5774 Leu Tyr Gin Gly Leu Leu Gin Ala Leu Giu Gly Ile Ser Pro Giu Leu 275 280 285 Gly Pro Thr Leu Asp Thr Leu Gin Leu Asp Val Ala Asp Phe Ala Thr 290 295 300 Thr Ile Trp Gin Gin Met Glu Giu Leu Gly Met Ala Pro Ala Leu Gin 305 310 315 320 Pro INFORMATION FOR SEQ ID NO: 189: SEQUENCE CHARACTERISTICS: LENGTH: 321 amino acids TYPE: amino acid STRAN~DEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 189: Ala Giy Asp Trp Gin Giu Phe Arg Glu Lys Leu Thr Ile Leu Asp Lys Gin Ile Gly Leu Met Leu Arg Asn Pro Ile Pro 130 Glu Ile Asp Asn Leu Cys Lys 115 Ile Gin Asp Pro Leu Glu Leu 100 Tyr Ser Ala Giu Asn Arg Asn Pro Val1 Thr Gin Ile Asn Leu 70 Ala Ser Giu

TIP

Giu Ile Leu 55 Pro Ser Ala Gly Asn 135 Gin His 40 Asn Asn Gly Thr Gly 120 Pro Gin 25 His Asp Leu Ile Ala 105 Gly Ser Gly Leu Giu Giu Giu 90 Ala Gly Pro Gly Lys Asp Ser 75 Ala Pro Ser Pro Thr Gly Arg Vai Phe Ile Ser Pro Ser 140 Phe Ser Pro Ser Val Leu Arg Gly 125 Lys Tyr Asn Pro Ile Arg Arg His 110 Glu Giu Leu Cys Ala Leu Ala Asn Pro Pro Ser Val Ser Pro Met Val Leu Ile Ser His WO 97/12985 PCTJUS96/1 5774 Lys 145 Ala Ser Ser Gin Cys 225 His Ala Leu Gly Ser Pro Asn Met Ala Thr Gin Gly Ala Met Pro Ala Phe Ala Ser Phe Phe Gly Val 210 Ala Ser Leu Tyr Pro 290 Gin Leu Gly 195 Arg Thr Leu Gin Gin 275 Thr Arg Glu 180 Ser Lys Tyr Gly Leu 260 Gly Leu Arg 165 Val Gly Ile Lys Ile 245 Ala Leu Asp Ala Gly Ser Tyr Gly Ser Gin Gly 215 Leu Cys 230 Pro Trp Gly Cys Leu Gin Thr Leu 295 Gly Arg Gin 200 Asp His Ala Leu Ala 280 Gin Val Val 185 Ser Gly Pro Pro Ser 265 Leu Leu 170 Leu Phe Ala Giu Leu 250 Gin Glu Val1 Arg Leu Ala Giu 235 Ser Leu Gly Ala His Leu Leu 220 Leu Ser His Ile Ser Leu Lys 205 Gin Val Cys Ser Ser 285 Asp His Ala 190 Ser Giu Leu Pro Gly 270 Pro Phe Leu 175 Gin Leu Lys Leu Ser 255 Leu Giu Ala Gin Pro Giu Leu Gly 240 Gin Phe Leu T'hr LeU Asp Val Ala 300 Thr Ile Trp Gln Gin Met Giu Giu Leu Giy 305 310 Pro INFORMAVTION FOR SEQ ID NO: 190: SEQUENCE

CHARACTERISTICS:

LENGTH: 329 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: protein Met 315 Ala Pro Ala Leu Gin 320 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 190: Leu Asp Pro Asn Asn Leu Asn Asp Giu Asp Val Ser Ile Leu Met Asp 1 5 10 WO 97/12985 WO 9712985PCTIUS96/1 5774 Arg Asn Pro Ile Leu Gly Ile Gly Ser 145 Gly Val Val Ser Gly 225 Pro Pro S er Asn Leu Cys Lys Val1 Gly His Gly 130 Pro Ala Leu Leu Phe 210 Ala Glu Leu Gin Leu Giu Leu Ala Thr Ser His 115 Ser Pro Met Val1 Arg 195 Leu Ala Glu Ser Leu 275 Arg Asn Pro Gly Leu Gly 100 Leu Pro Ser Pro Ala 180 His Leu Leu Leu Ser 260 His Leu Ala Ser Asp Glu Gly Lys Gly Lys Ala 165 Ser Leu Lys Gin Val 245 Cys Ser Pro Ser Ala Trp 70 Gin Gly Arg Giu Giu 150 Phe His Ala Ser Giu 230 Leu Pro Gly Asn Leu Gly Ile Thr Ala 55 Gin Giu Ala Gin Ser Asn Pro Pro 120 Pro Ser 135 Ser His Ala Ser Leu Gin Gin Pro 200 Leu Giu 215 Lys Leu Leu Gly Ser Gin Leu Phe 280 Ser Ala Pro Arg Gin Ser Pro Pro Ser Phe 170 Phe Giy Val Ala Ser 250 Leu Tyr Phe Ile Ser Giu 75 Gin Ile Leu Ile Pro 155 Gin Leu Gly Arg Thr 235 Leu Gin Gin Val Leu Arg Lys Gly Met Tyr Ser 140 Asn Arg Giu Ser Lys 220 Tyr Gly Leu Gly Leu 300 Ala Asn Pro Thr Gly Asp 110 Giu Ile Ala Ala Ser 190 Gly Gin Leu Pro Gly 270 Leu Lys Gin Ile Tyr Gly Ile Gly Pro Gin 160 Gly Arg Gin Asp His 240 Al a Leu Ala Leu Glu 290 Gly Ile Ser Pro Glu Leu Gly Pro Thr 295 Asp Thr Leu Gin WO 97/12985 PCTIUS96/15774 426 Leu Asp Val Ala Asp Phe Ala Thr Thr Ile Trp Gin Gin Met Glu Glu 305 310 315 320 Leu Gly Met Ala Pro Ala Leu Gin Pro 325 INFORMATION FOR SEQ ID NO: 191: SEQUENCE CHARACTERISTICS: LENGTH: 329 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 191: Asn Ala Ser Gly Ile Glu Ala Ile Leu Arg Asn Leu Gin Pro Cys Leu 1 5 10 Pro Ser Ala Thr Ala Ala Pro Ser Arg His Pro Ile Ile Ile Lys Ala 25 Gly Asp Trp Gin Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr 40 Leu Glu Gin Ala Gin Glu Gin Gin Gly Gly Gly Ser Gly Gly Gly Ser 55 Gly Gly Gly Ser Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His 70 75 Leu Lys Arg Pro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp 90 Glu Asp Val Ser Ile Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu 100 105 110 Glu Ser Phe Val Arg Ala Val Lys Asn Leu Glu Tyr Val Glu Gly Gly 115 120 125 Gly Gly Ser Pro Gly Glu Pro Ser Gly Pro Ile Ser Thr Ile Asn Pro 130 135 140 Ser Pro Pro Ser Lys Glu Ser His Lys Ser Pro Asn Met Ala Thr Gin 145 150 155 160 Gly Ala Met Pro Ala Phe Ala Ser Ala Phe Gin Arg Arg Ala Gly Gly 165 170 175 WO 97/12985 WO 9712985PCTJUS96/15774 427 Val Leu Val Ala Ser His Leu 180 Val Ser Gly 225 Pro Pro Ser Leu Leu 305 Leu Leu Phe 210 Ala Glu Leu Gin Giu 290 Asp Gly Arg 195 Leu Ala Giu Ser Leu 275 Gly Val Met His Leu Leu Leu Ser 260 His Ile Ala Ala Ser Giu 230 Leu Pro Gly Pro Phe 310 Gin Leu 215 Lys Leu Ser Leu Giu 295 Ala Gin Pro 200 Giu Leu Gly Gin Phe 280 Leu Thr Ser 185 Ser Gin Cys His Ala 265 Leu Gly Thr Pro Phe Gly Val1 Ala Ser 250 Leu Tyr Pro Ile Leu Gly Arg Thr 235 Leu Gin Gln Thr Trp 315 Giu Ser Lys 220 Tyr Gly Leu Gly Leu 300 Gin Val1 Gly 205 Ile Lys Ile Ala Leu 285 Asp Gin Ser 190 Gly Gin Leu Pro Gly 270 Leu Thr Met Tyr Ser Giy Cys Trp 255 Cys Gln Leu Giu Arg Gin Asp His 240 Ala Leu Ala Gin Giu 320 Ala Pro Ala Leu Gin INFORMATION FOR SEQ ID NO: 192: SEQUENCE CHARACTERISTICS: LENGTH: 329 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) Ala 1 Phe Glu SEQUENCE DESCRIPTION: SEQ ID NO: 192: Pro Ser Arg His Pro Ile Ile Ile Lys Ala Gly Asp Trp Gln Giu 5 10 Arg Giu Lys Leu Thr Phe Tyr Leu Val Thr Leu Giu Gln Ala Gin 25 Gin Gin Gly Gly Giy Ser Gly Gly Gly Ser Gly Gly Gly Ser Asn 40 WO 97/12985 PCTIUS96/15774 428 Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg Pro Pro 55 Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp Val Ser Ile 70 75 Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu Ser Phe Val Arg 90 Ala Val Lys Asn Leu Glu Asn Ala Ser Gly Ile Glu Ala Ile Leu Arg 100 105 110 Asn Leu Gin Pro Cys Leu Pro Ser Ala Thr Ala Tyr Val Glu Gly Gly 115 120 125 Gly Gly Ser Pro Gly Glu Pro Ser Gly Pro Ile Ser Thr Ile Asn Pro 130 135 140 Ser Pro Pro Ser Lys Glu Ser His Lys Ser Pro Asn Met Ala Thr Gin 145 150 155 160 Gly Ala Met Pro Ala Phe Ala Ser Ala Phe Gin Arg Arg Ala Gly Gly 165 170 175 Val Leu Val Ala Ser His Leu Gin Ser Phe Leu Glu Val Ser Tyr Arg 180 185 190 Val Leu Arg His Leu Ala Gin Pro Ser Gly Gly Ser Gly Gly Ser Gin 195 200 205 Ser Phe Leu Leu Lys Ser Leu Glu Gin Val Arg Lys Ile Gin Gly Asp 210 215 220 Gly Ala Ala Leu Gin Glu Lys Leu Cys Ala Thr Tyr Lys Leu Cys His 225 230 235 240 Pro Glu Glu Leu Val Leu Leu Gly His Ser Leu Gly Ile Pro Trp Ala 245 250 255 Pro Leu Ser Ser Cys Pro Ser Gin Ala Leu Gin Leu Ala Gly Cys Leu 260 265 270 Ser Gin Leu His Ser Gly Leu Phe Leu Tyr Gin Gly Leu Leu Gin Ala 275 280 285 Leu Glu Gly Ile Ser Pro Glu Leu Gly Pro Thr Leu Asp Thr Leu Gin 290 295 300 Leu Asp Val Ala Asp Phe Ala Thr Thr Ile Trp Gin Gin Met Glu Glu 305 310 315 320 Leu Gly Met Ala Pro Ala Leu Gin Pro 325 WO 97/12985 WO 9712985PCTIUS96/115774 429 INFORMATION FOR SEQ ID NO: 193: SEQUENCE CHARACTERISTICS: LENGTH: 299 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 193: Gly Gly Ser Gly Gly Gly Ser Asn Cys Ser Ile Leu Pro Ser Ala Gly Asn Thr Gly 145 Tyr Ser His Asn Asn Gly Thr Gly Pro Gln 130 Gly Arg Gln His Asp Leu Ile Ala Gly Ser 115 Gly Val Val Ser Leu Giu Glu Giu Ala Gly 100 Pro Al a Leu Leu Phe 180 Lys Asp Ser Ala Pro Ser Pro Met Val Arg 165 Leu Arg Val Phe Ile 70 Ser Pro Ser Pro Ala 150 His Leu Pro Ser Val 55 Leu Arg Gly Lys Ala 135 Ser Leu Lys Pro Ile 40 Arg Arg His G lu Giu 120 Phe His Ala Ser Ala 25 Leu Ala Asn Pro Pro 105 Ser Ala Leu Gin Leu 185 10 Pro Met Val Leu Ile 90 Ser His Ser Gin Pro 170 Glu Ile Met Leu Leu Asp Arg Lys Asn Gin Pro 75 Ile Ile Gly Pro Lys Ser Ala Phe 140 Ser Phe 155 Ser Gly Gin Val Ile Asp Asn Leu Cys Lys Ile Pro 125 Gin Leu Gly Arg Asp Pro Leu Giu Leu Tyr Ser 110 Asn Arg Glu Ser Lys 190 Glu Asn Arg Asn Pro Val Thr Met Arg Val Gly 175 Ile Ile Asn Leu Ala Ser Glu Ile Al a Ala Ser 160 Gly Gin Gly Asp Gly Ala Ala Leu Gin Glu Lys Leu-Cys Ala Thr Tyr Lys Leu WO 97/12985 PCT/US96/1 5774 430 Cys His Pro Glu Glu Leu Val Leu Leu Gly His Ser Leu Gly Ile Pro 210 215 220 Trp Ala Pro Leu Ser Ser Cys Pro Ser Gin Ala Leu Gin Leu Ala Gly 225 230 235 240 Cys Leu Ser Gin Leu His Ser Gly Leu Phe Leu Tyr Gin Gly Leu Leu 245 250 255 Gin Ala Leu Glu Gly Ile Ser Pro Glu Leu Gly Pro Thr Leu Asp Thr 260 265 270 Leu Gin Leu Asp Val Ala Asp Phe Ala Thr Thr Ile Trp Gin Gin Met 275 280 285 Glu Glu Leu Gly Met Ala Pro Ala Leu Gin Pro 290 295 INFORMATION FOR SEQ ID NO: 194: SEQUENCE CHARACTERISTICS: LENGTH: 329 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 194: Met Ala Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys 1 5 10 Arg Pro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp 25 Val Ser Ile Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu Ser 40 Phe Val Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly Ile Glu Ala 55 Ile Leu Arg Asn Leu Gin Pro Cys Leu Pro Ser Ala Thr Ala Ala Pro 70 75 Ser Arg His Pro Ile Ile Ile Lys Ala Gly Asp Trp Gin Glu Phe Arg 90 Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu Gin Ala Gin Glu Gin 100 105 110 WO 97/12985 WO 9712985PCTIUS96/15774 Gin Tyr Val Giu Gly Gly Gly 115 Ile Pro 145 Gly Gin Phe Leu Thr 225 Gin Arg Val Asp Leu 305 Ala Ser 130 Asn His Ala Leu Gly 210 Thr Pro Ala Ser Met 290 Leu Leu Thr Met Ser Leu Tyr 195 Pro Ile Thr G ly Tyr 275 Ala Lys Gin Ile Ala Leu Gin 180 Gin Thr Trp Gin Gly 260 Arg Thr Ser Glu Asn Tyr Gly 165 Leu Gly Leu Gin Gly 245 Val Val1 Pro Leu Pro Lys 150 Ile Ala Leu Asp Gin 230 Ala Leu Leu Leu Giu 310 Ser 135 Leu Pro Gly Leu Thr 215 Met Met Val Arg Gly 295 Gin Gly 120 Pro Cys Trp Cys Gin 200 Leu Glu Pro Ala His 280 Pro Val Ala Ser Pro His Ala Leu 185 Ala Gin Giu Ala Ser 265 Leu Ala Arg Thr Pro Gly Glu Pro Ser Gly Pro 125 Ser Pro Pro 170 Ser Leu Leu Leu Phe 250 His Ala Ser Lys Lys Glu 155 Leu Gin Giu Asp Gly 235 Ala Leu Gin Ser Ile 315 Glu 140 Giu Ser Leu Gly Val 220 Met Ser Gin Pro Leu 300 Gin Ser Leu Ser His Ile 205 19Ta Ala Ala Ser Gly 285 Pro Gly His Val Cys Ser 190 Ser Asp Pro Phe Phe 270 Gly Gin Asp Lys Leu Pro 175 Gly Pro Phe Ala Gin 255 Leu Gly Ser Gly Ser Leu 160 Ser Leu Giu Ala Leu 240 Arg Glu Ser Phe Ala 320 Lys Leu Cys 325 INFORMATION FOR SEQ ID NO: 195: SEQUENCE CHARACTERISTICS: LENGTH: 329 amino acids TYPE: amiino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: protein WO 97/12985 PCT/UJS96/15774 432 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 195: Met Ala Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg Pro Val Ser Phe Val Ile Leu Ser Arg Giu Lys Gin Tyr Ile Ser 130 Pro Asn 145 Asp Vai Gly Met Ala Ser Leu Gin 210 Gin Pro 225 Ser Leu Pro Ile Arg Arg His Leu Val1 115 Thr Met Ala Ala Ala 195 Ser Gly Pro Aia Leu Ala Asn Pro Thr 100 Giu Ile Ala Asp Pro 180 Phe Phe Giy Gin Pro Met Val1 Leu Ile Phe Giy Asn Pro Phe 165 Ala Gin Leu Gly Ser 245 Leu Leu Asp Arg Lys Asn 55 Gin Pro 70 Ile Ile Tyr Leu Gly Gly Pro Ser 135 Giu Leu 150 Ala Thr Leu Gin Arg Arg Giu Val 215 Ser Asp 230 Phe Leu Asp Pro 25 Asn Leu 40 Leu Giu Cys Leu Lys Ala Val Thr 105 Gly Ser 120 Pro Pro Gly Pro Thr Ile Pro Thr 185 Ala Gly 200 Ser Tyr Met Ala Leu Lys 10 Asn Arg Asn Pro Gly 90 Leu Pro Ser Thr Trp, 170 Gin Gly Arg Thr Ser 250 Asn Leu Ala Ser 75 Asp Giu Gly Lys Leu 155 Gin Giy Val Vai Pro 235 Leu Leu Pro Ser Ala Trp Gin Glu Giu 140 Asp Gin Ala Leu Leu 220 Leu Glu Asn Asn Gly Thr 8fm Ala Pro 125 Ser Thr Met Met Val 205 Arg Gly Gin Asp Leu Ile Aia Giu Gin 110 Ser His Leu Glu Pro 190 Ala His Pro Val Giu 'Asp Giu Ser Glu Ala Ala Pro Phe Arg Giu Gin Gly Pro Lys Ser Gin Leu 160 Giu Leu 175 Ala Phe Ser His Leu Ala Aia Ser 240 Arg Lys 255 Ile Gin Giy Asp Gly Ala Ala Leu Gin Giu Lys Leu Cys Ala Thr Tyr 260 270 WO 97/12985 PCT/US96/15774 433 Lys Leu Cys His Pro Glu Glu Leu Val Leu Leu Gly His Ser Leu Gly 275 280 285 Ile Pro Trp Ala Pro Leu Ser Ser Cys Pro Ser Gin Ala Leu Gin Leu 290 295 300 Ala Gly Cys Leu Ser Gin Leu His Ser Gly Leu Phe Leu Tyr Gin Gly 305 310 315 320 Leu Leu Gin Ala Leu Glu Gly Ile Ser 325 INFORMATION FOR SEQ ID NO: 196: SEQUENCE CHARACTERISTICS: LENGTH: 329 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 196: Met Ala Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg Val Phe Ile Ser Glu Gin Ile Pro Ser Val Leu Arg Lys Tyr Ser 130 Pro Ile Arg Arg His Leu Val 115 Thr Ala Leu Ala Asn Pro Thr 100 Glu Ile Pro Met Val Leu Ile Phe Gly Asn Leu Asp Lys Gin 70 Ile Tyr Gly Pro Leu Arg Asn 55 Pro Ile Leu Gly Ser 135 Pro 25 Leu Glu Leu Ala Thr 105 Ser Pro 10 Asn Arg Asn Pro Gly 90 Leu Pro Ser Asn Leu Ala Ser Asp Glu Gly Lys Leu Pro Ser Ala Trp Gin Glu Glu 140 Asn Asn Gly Thr Gin Ala Pro 125 Ser Asp Leu Ile Ala Glu Gin 110 Ser His Glu Glu Glu Ala Phe Glu Gly Lys WO 97/12985 PCT/US96/15774 Pro 145 Ala His Pro Val Ala 225 Ser Leu Tyr Pro Ile 305 Thr Asn Ser Leu Ala Arg 210 Thr Leu Gin Gin Thr 290 Trp Gin Met His Ala Ser 195 Lys Tyr Gly Leu Gly 275 Leu Gin Gly Ala Leu Gin 180 Ser Ile Lys Ile Ala 260 Leu Asp Gin Ala Ser Gin 165 Pro Leu Gin Leu Pro 245 Gly Leu Thr Met Met Ala 150 Ser Gly Pro Gly Cys 230 Trp Cys Gin Leu Glu 310 Pro Phe Phe Gly Gin Asp 215 His Ala Leu Ala Gin 295 Glu Gin Leu Gly Ser 200 Gly Pro Pro Ser Leu 280 Leu Leu Arg Arg Ala Gly Gly Val Leu 155 Glu Ser 185 Phe Ala Glu Leu Gin 265 Glu Asp Gly Val 170 Asp Leu Ala Glu Ser 250 Leu Gly Val Ser Met Leu Leu Leu 235 Ser His Ile Ala Tyr Ala Lys Gin 220 Val Cys Ser Ser Asp 300 Arg Thr Ser 205 Glu Leu Pro Gly Pro 285 Phe Val Pro 190 Leu Lys Leu Ser Leu 270 Glu Ala Leu 175 Leu Glu Leu Gly Gin 255 Phe Leu Thr Val 160 Arg Gly Gin Cys His 240 Ala Leu Gly Thr Met Ala Pro Ala Leu Gin Pro 315 320 Ala Phe Ala INFORMATION FOR SEQ ID NO: 197: SEQUENCE CHARACTERISTICS: LENGTH: 329 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 197: Met Ala Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys 1 5 10 WO 97/12985 PCTIUS96/1 5774 Arg Pro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp 4 v Val Phe Ile Ser Glu Gin Ile Pro 145 Pro Ala His Pro Val 225 Ala Ser Leu Ser Val1 Leu Arg Lys Tyr Ser 130 Asn Ala Ser Leu Al a 210 Arg Thr Leu Gln Ile Arg Arg His Leu Val1 115 Thr Met Phe His Ala 195 Ser Lys Tyr Gly Leu 275 Leu Ala Asn Pro Thr 100 Glu Ile Ala Ala Leu 180 Gin Ser Ile Lys Ile 260 Alia Met Val Leu Ile Phe Gly Asn Met Ser 165 Gin Pro Leu Gin Leu 245 Pro Gly Asp Lys Gin 70 Ile Tyr Gly Pro Ala 150 Ala Ser Gly Pro Gly 230 Cys Trp Cys Arg Asn 40 Asn Leu 55 Pro Cys Ile Lys Leu Val Gly Gly 120 Ser Pro 135 Pro Ala Phe Gin Phe Leu Gly Gly 200 Gin Ser 215 Asp Gly His Pro Ala ProI Leu SerC 280 Leu Glu Leu Ala Thr 105 Ser Pro Leu Arg Glu 185 Ser Phe kla flu jeu 65 1ln *Arc *Ast Prc Gly 90 Leu Pro Ser Gin Arg 170 Val Asp Leu Ala Glu 250 Ser Leu Leu Ala Ser 75 Asp Giu Gly Lys Pro 155 Ala Ser Met Leu Leu 235 Leu Ser His IPro Ser Ala Trp Gin Glu Giu 140 Thr Gly Tyr Ala Lys 220 Gin Val Cys SerC Asn Gly Thr Gin Ala Pr'o 125 Ser Gin Gly Arg I'hr 205 Ser 3lu jeu Pro 3 1 y Leu Ile Ala Glu Gin 110 Ser His Gly Val Val 190 Pro Leu Lys Leu Ser 270 Leu Glu Ala Phe Glu Gly Lays Ala Leu 175 Leu Leu Glu .eu fly 2 fin ?he ISer Ala Pro Arg Gin Pro Ser Met 160 Val Arg Gly Gin Cys 240 His Ala Leu Tyr Gin Gly Leu Leu Gin Ala Leu Giu Gly Ile 290 295 Ser 300 Pro Giu Leu Gly WO 97/12985 PCTIUS96/157 7 4 Pro Thr Leu Asp Thr Leu Gin Leu Asp Val Ala Asp Phe Ala Thr Thr 305 310 315 320 Ile Trp Gin Gin Met Glu Giu Leu Gly 325 INFORMATION FOR SEQ TD NO: 198: SEQUENCE

CHARACTERISTICS:

LENGTH: 329 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 198: Met Ala Asn Cys Ser Ile Met Ile Asp Giu Ile Ile His His 1 Arg Val Phe Ile Ser Glu Gin Ile Pro 145 Pro Ser Vai Leu Arg Lys Tyr Ser 130 Asn Pro Ile Arg Arg His Leu Val 115 Thr Met Ala Leu Ala Asn Pro Thr 100 Glu Ile Al a Pro Met Val Leu Ile Phe Giy Asn Thr Leu Leu Asp Arg Lys Asn 55 Gin Pro 70 Ile Ile Tyr Leu Gly Gly Pro Ser 135 Gin Gly 150 Asp Asn 40 Leu Cys Lys Val Gly 120 Pro Pro 25 Leu Giu Leu Ala Thr 105 Ser Pro Asn Arg Asn Pro Gly 90 Leu Pro Ser Asn Leu Ala Ser 75 Asp Glu Gly Lys Leu Pro Ser Ala Trp Gin Giu Asn Asn Gly Thr Gin Ala Pro 125 Asp Leu Ile Ala Giu Gin 110 Ser His Leu Giu Giu Glu Aia Phe Glu Gly Lys Lys Asp Ser Ala Pro Arg Gin Pro 140Se Ala Met Pro Ala Phe Ala Ser Ala Phe 155 1 rn Gin Arg Arg Ala Gly 165 Gly Val Leu Val Ala 170 Ser His Leu Gin Ser Phe 175 WO 97/12985 PCT/US96/15774 Leu Glu Val Ser Tyr Arg Val Leu Arg His Leu Ala Gin 180 185 Pro Gly Gly 190 Gly Ser Gly 225 Pro Pro Ser Leu Leu 305 Leu Ser Phe 210 Ala Glu Leu Gin Glu 290 Asp Gly Asp 195 Leu Ala Glu Ser Leu 275 Gly Val Met Met Leu Leu Leu Ser 260 His Ile Ala Ala Lys Gin Val 245 Cys Ser Ser Asp Thr Ser Glu 230 Leu Pro Gly Pro Phe 310 Pro Leu 215 Lys Leu Ser Leu Glu 295 Ala Leu Leu 200 Glu Leu Gly Gin Phe 280 Leu Thr Gin Gly Gin Cys His Ala 265 Leu Gly Thr Pro Pro Ala Val Arg Ala Thr 235 Ser Leu 250 Leu Gin Tyr Gin Pro Thr Ile Trp 315 Ser Lys 220 Tyr Gly Leu Gly Leu 300 Gin Ser Leu 205 Ile Gin Lys Leu Ile Pro Ala Gly 270 L'eu Leu 285 Asp Thr Gin Met Pro Gin Gly Asp Cys His 240 Trp Ala 255 Cys Leu Gin Ala Leu Gin Glu Glu 320 Ala Pro Ala INFORMATION FOR SEQ ID NO: 199: SEQUENCE CHARACTERISTICS: LENGTH: 319 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) Met 1 Gin Gln SEQUENCE DESCRIPTION: SEQ ID NO: 199: Ala Asn Cys Ser Asn Met Ile Asp Glu Ile Ile Thr His Leu Lys 5 10 Pro Pro Leu Pro Leu Leu Asp Phe Asn Asn Leu Asn Gly Glu Asp 25 Asp Ile Leu Met Asp Asn Asn Leu Arg Arg Pro Asn Leu Glu Ala 40 WO 97/12985 PCTIUS96/157 7 4 438 Phe Asn Arg Ala Val Lys Ser Leu Gin Asn Ala Ser Ala 55 60 Ile Glu Ser Ile Thr Arg Gin Ile Pro 145 Gin Leu Gly Arg Thr 225 LeuC Gin Gin C Thr L 2 TPrp G 305 Lei Ar Lyc Ty2 Ser 130 Asn Arg Glu Ser L~ys 210 Pyr iy .eu fly ~eu 90 in gHi~ Let Val Thr Met Arg Vai Gly 195 Ile Lys Ile Aia Leu 275 Asp Gin As Pr Th G iE Ala Aia Ser 180 Gly Gin Leu Pro Gly 260 Leu Thr Met n Leu Leu 70 0 Ile His r Phe Tyr 0 aGly Gly Asn Pro Thr Gin iso *Gly Gly 165 Tyr Arg Ser Gin Giy Asp Cys His 230 Trp Ala 245 Cys Leu Gin Ala Leu Gin Gluf GiuI Pro Cys Leu Pro Leu Ala Thr Ala Ala pro 75 I i Let Gij Ser 135 Giy Vai Val Ser Gly 215 Pro Pro Ser Lieu eu ?95 jeu eLys aLys Gly 120 *Pro *Ala Leu Leu Phe 200 Aia Giu Leu Gin I Giu C 280 Asp V As] Th 10! Sei Prc Met Val Arg 185 Leu Aa 31u 3er ~eu ~65

T

al p Gil 90 r Let 5 Prc Ser Pro Ala 170 His Leu Leu Leu Ser 250 His Ile Ala {Asp Trp Glu Asn Gly Giu Lys Glu 140 Ala Phe 155 Ser His Leu Ala Lys Ser Gin Giu 220 Val Leu 235 Cys Pro Ser Gly I Ser Pro C Asp Phe

A

As Al~ Pr( 125 Sex Aila Leu Gin Leu 205 Lys Leu 3er .eu 1iu n Glu i. Gin 110 Ser His Ser Gin Pro 190 Giu Leu Gly Gin Phe 270 LeuC Thr Ph Alz Gl Lys Ala Ser 175 Ser Gin Cys Hlis ka 255 eu liy 'hr Arg Gin Pro Ser Phe 160 Phe Gly Val Ala Ser 240 Leu Tyr Pro Ile 300 Gly Met Ala Pro Ala Leu Gin Pro INFORMA~TION FOR SEQ ID NO: 200: SEQUENCE

CHARACTERISTICS:

WO 97/12985 WO 9712985PCTIUJS96/1 5774 439 LENGTH: 322 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 200: Met Ala Asn Cys Ser Asn Met Ile Asp Giu Ile Gin Gin Phe Ile Thr Arg Gin Ile Pro 145 Gin Leu Leu Pro Asp Asn Leu Arg Lys Tyr Ser 130 Asn Arg Giu Gly Pro Ile Arg Lys His Leu Vai 115 Thr Met Arg Val Pro Pro Met Vai Leu Ile Phe Giy Asn Thr Giy 165 Tyr Ser Leu Giu Lys Leu 70 Ile Tyr Gly Pro Gin 150 Gly Arg Ser Leu Asn Ser 55 Pro Ile Leu Gly Ser 135 Giy Val Val Leu Asp Asn Leu Cys Arg Lys Gly 120 Pro Ala Leu Leu Pro 200 Phe Leu Gin Leu Asp Thr 105 Ser Pro Met Val Arg 185 Gin 10 Asn Arg Asn Pro Giy 90 Leu Pro Ser Pro Ala 170 His Ser Asn Arg Ala Leu 75 Asp Giu Gly Lys Ala 155 Ser Leu Phe Ile Leu Pro Ser Ala Trp Asn Giu Giu 140 Phe His Ala Leu His Gly Leu Ile Ala Giu Gin 110 Ser His Ser Gin Pro 190 Lys Leu Giu Giu Giu Ala Phe Ala Gly Lys Ala Ser 175 Thr Ser Lys Asp Ala Ser Pro Arg Gin Pro Ser Phe 160 Phe Pro Leu 195 Giu Gin Val Arg Lys Ile Gin Gly Asp Gly Ala Ala Leu Gin Glu Lys WO 97/12985 PCT/US96/15774 440 Leu Cys Ala Thr Tyr Lys Leu Cys His Pro Glu Glu Leu Val Leu Leu 225 230 235 240 Gly His Ser Leu Gly Ile Pro Trp Ala Pro Leu Ser Ser Cys Pro Ser 245 250 255 Gin Ala Leu Gin Leu Ala Gly Cys Leu Ser Gln Leu His Ser Gly Leu 260 265 270 Phe Leu Tyr Gln Gly Leu Leu Gln Ala Leu Glu Gly Ile Ser Pro Glu 275 280 285 Leu Gly Pro Thr Leu Asp Thr Leu Gln Leu Asp Val Ala Asp Phe Ala 290 295 300 Thr Thr Ile Trp Gin Gin Met Glu Glu Leu Gly Met Ala Pro Ala Leu 305 310 315 320 Gin Pro INFORMATION FOR SEQ ID NO: 201: SEQUENCE CHARACTERISTICS: LENGTH: 319 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 201: Met Ala Asn Cys Ser Asn Met Ile Asp Glu Ile Ile Thr His Leu Lys 1 5 10 Gin Pro Pro Leu Pro Leu Leu Asp Phe Asn Asn Leu Asn Gly Glu Asp 25 Gin Asp Ile Leu Met Glu Asn Asn Leu Arg Arg Pro Asn Leu Glu Ala 40 Phe Asn Arg Ala Val Lys Ser Leu Gin Asn Ala Ser Ala Ile Glu Ser 55 Ile Leu Lys Asn Leu Leu Pro Cys Leu Pro Leu Ala Thr Ala Ala Pro 70 75 Thr Arg His Pro Ile Ile Ile Arg Asp Gly Asp Trp Asn Glu Phe Arg 90 WO 97/12985 PCT/US96/15774 441 Arg Lys Leu Thr Phe Tyr Leu Lys Thr Leu Glu Asn Ala Gin Ala Gin 100 105 110 Gin Tyr Val Glu Gly Gly Gly Gly Ser Pro Gly Glu Pro Ser Gly Pro 115 120 125 Ile Ser Thr Ile Asn Pro Ser Pro Pro Ser Lys Glu Ser His Lys Ser 130 135 140 Pro Asn Met Ala Thr Gin Gly Ala Met Pro Ala Phe Ala Ser Ala Phe 145 150 155 160 Gin Arg Arg Ala Gly Gly Val Leu Val Ala Ser His Leu Gin Ser Phe 165 170 175 Leu Glu Val Ser Tyr Arg Val Leu Arg His Leu Ala Gin Pro Ser Gly 180 185 190 Gly Ser Gly Gly Ser Gin Ser Phe Leu Leu Lys Ser Leu Glu Gin Val 195 200 205 Arg Lys Ile Gin Gly Asp Gly Ala Ala Leu Gin Glu Lys Leu Cys Ala 210 215 220 Thr Tyr Lys Leu Cys His Pro Glu Glu Leu Val Leu Leu Gly His Ser 225 230 235 240 Leu Gly Ile Pro Trp Ala Pro Leu Ser Ser Cys Pro Ser Gln Ala Leu 245 250 255 Gin Leu Ala Gly Cys Leu Ser Gin Leu His Ser Gly Leu Phe Leu Tyr 260 265 270 Gin Gly Leu Leu Gin Ala Leu Glu Gly Ile Ser Pro Glu Leu Gly Pro 275 280 285 Thr Leu Asp Thr Leu Gin Leu Asp Val Ala Asp Phe Ala Thr Thr Ile 290 295 300 Trp Gin Gin Met Glu Glu Leu Gly Met Ala Pro Ala Leu Gin Pro 305 310 315 INFORMATION FOR SEQ ID NO: 202: SEQUENCE CHARACTERISTICS: LENGTH: 322 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: protein WO 97/12985 WO 9712985PCTIUS96/15774 442 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 202: Met 1 Gin Gin Phe Ile Thr Arg Gin Ile Pro 145 Gin Leu Leu Giu Leu 225 Giy Ala Asn Cys Ser Asn Met Ile Asp Gu Ile Ile Thr His Leu Lys Pro Asp Asn Leu Arg Lys Tyr Ser 130 Asn Arg Giu Gly Gin 210 Cys His Pro Ile Arg Lys His Leu Vai 115 Thr Met Arg Val Pro 195 Val Ala Ser Leu Leu Ala Asn Pro Thr 100 Giu Ile Ala Ala Ser 180 Ala Arg Thr Leu Pro Met Val1 Leu Ile Phe Gly Asn Thr Gly 165 Tyr Ser Lys Tyr Gly 245 Leu Asp Lys Leu 70 His Tyr Gly Pro Gin 150 Gly Arg Ser Ile Lys 230 Ile Leu Asn Ser 55 Pro Ile Leu Gly Ser 135 Gly Val Val Leu Gin 215 Leu Pro Asp Asn 40 Leu Cys Lys Lys Gly 120 Pro Ala Leu Leu Pro 200 Gly Cys Trp Phe 25 Leu Gin Leu Asp Thr 105 Ser Pro Met Val Arg 185 Gin Asp His Ala 10 Asn Arg Asn Pro Gly 90 Leu Pro Ser Pro Ala 170 His Ser Gly Pro Pro 250 Asn Arg Ala Leu 75 Asp Giu Gly Lys Aia 155 Ser Leu Phe Aia Glu 235 Leu Leu Pro Ser Ala Trp Asn Glu Glu 140 Phe His Al a Leu Ala 220 Giu Ser Asn Asn Ala Thr Ala Pro 125 Ser Ala Leu Gin Leu 205 Leu Leu Ser Gly Giu Leu Giu Ile Giu Ala Ala Giu Phe Gin Ala 110 Ser Gly His Lys Ser Ala Gin Ser 175 Pro Thr 190 Lys Ser Gin Giu Val Leu Cys Pro 255 Asp Ala Ser Pro Arg Gin Pro Ser Phe 160 Phe Pro Leu Lys Leu 240 Ser Gin Ala Leu Gin Leu Ala Gly Cys Leu Ser Gin Leu His Ser Gly Leu 260 265 270 WO 97/12985 PCT/US96/15774 443 Phe Leu Tyr Gin Gly Leu Leu Gin Ala Leu Glu Gly Ile 275 280 285 Leu Gly Pro Thr Leu Asp Thr Leu Gin Leu Asp Val Ala 290 295 300 Thr Thr Ile Trp Gin Gin Met Glu Glu Leu Gly Met Ala 305 310 315 Gin Pro INFORMATION FOR SEQ ID NO: 203: SEQUENCE CHARACTERISTICS: LENGTH: 306 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: protein Ser Pro Glu Asp Phe Ala Pro Ala Leu 320 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 203: Ala Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Pro Ser Val Leu Arg Lys Tyr Ser Pro Ile Arg Arg His Leu Val Thr 130 Ala Leu Ala Asn Pro Thr Glu 115 Ile Pro Met Val Leu Ile Phe 100 Gly Asn Leu Asp Lys Gin Ile Tyr Gly Pro Leu Arg Asn Pro 70 Ile Leu Gly Ser Asp Asn Leu 55 Cys Lys Val Gly Pro 135 Pro Leu Glu Leu Ala Thr Ser 120 Pro Asn 25 Arg Asn Pro Gly Leu 105 Pro Ser Asn Leu Asn Leu Pro Asn Ala Ser Gly Ser Ala Thr 75 Asp Trp Gin Glu Gin Ala Gly Glu Pro Lys Glu Ser 140 Glu Glu Glu Ala Phe Glu 110 Gly Lys Arg Val Phe Ile Ser Glu Gin Ile Pro UJn 0~11500 PCTIUS96/1 5774 444 Asn Met Giu Val His Pro Leu Pro Thr Pro Val Leu Leu Pro Ala Val Asp Gin Ala Leu Gly 225 Asn Phe Giy 150 155 160 Phe Ser Asp Ile Arg Gly 195 Ser Gly 210 Thr Gin Ala Ile Leu Met Asn Met 275 Leu Leu 180 Gin Gin Leu Phe Leu 260 Ala Gly Giu 165 Gly Ala Leu Gly Val Arg Pro Pro 230 Leu Ser 245 Val Gly Ser Pro Trp Lys Val Thr Pro Thr 200 Leu Leu 215 Gin Gly Phe Gin Gly Ser Ala Pro 280 Thr Lou 185 Cys Leu Arg His Thr 265 Pro Gin 170 Leu Leu Gly Thr Leu 250 Leu Ala Met Leu Ser Ala Thr 235 Leu Cys Cys Giu Glu Ser Leu 220 Ala Arg Val Asp Giu Thr Gly Val 190 Leu Lou 205 Gin Ser His Lys H~y Lys Arg Giu 270 Leu Arg 285 Lys Ala 175 Met Ala Gly Gin Leu Leu Asp Pro 240 Val Arg 255 Phe Gly Val Leu Ser Lys Leu Leu Arg Asp Ser His Val Leu His 290 295 Cys Pro 305 INFORMATION FOR SEQ ID NO: 204: Ci) SEQUENCE

CHARACTERISTICS:

LENGTH: 306 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: protein Ser 300 Arg Leu Ser Gln (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 204: Ala Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg 1 5 10 Pro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Giu Asp Val 25 WO 97/12985 PCT/tJS96/15774 Ser Val Leu Arg Lys Tyr Ser Asn 145 Gly Gly Leu Vai Pro 225 Leu Val Ser Arg His 305 *Ile Arg Arg His Leu Val Thr 130 Met Giu Ala Gly Arg 210 Pro Ser Gly Pro Leu Ala Asn Pro Thr Giu 115 Ile Leu Trp Val Pro 195 Leu Gin Phe Giy Ala Met Val1 Leu Ile Phe 100 Gly Asn Pro Lys Thr 180 Thr Leu Gly Gin Ser 260 Pro Asp Lys Gin Ile Tyr Gly Pro Thr Thr 165 Leu Cys Leu Arg His 245 Thr Pro Arg Asn Pro 70 Ile Leu Gly Ser Pro 150 Gin Leu Leu Gly Thr 230 Leu Leu Ala Asn Leu Arg Leu Pro Asn Leu Glu Ser Phe.

Leu 55 Cys Lys Val Giy Pro 135 Val Met Leu Ser Ala 215 Thr Leu Cys Cys 40 Giu Leu Ala Thr Ser 120 Pro Leu Glu Giu Ser 200 Leu Ala Arg Val Asp 280 Asn Pro Gly Leu 105 Pro Ser Leu Glu Gly 185 Leu Gin His Gly Arg.

265 Leu.

Ala Ser Asp 90 Giu Gly Lys Pro Thr 170 Val1 Leu Ser Lys Lys 250 Glu Arg Ser Ala 75 Trp Gin Glu Giu Ala 155 Lys Met Gly Leu Asp 235 Val Phe Val Gly Thr Gin Ala Pro Ser 140 Val1 Ala Ala Gin Leu 220 Pro Axg Gly Leu Sle Ala Giu Gin Ser 125 Hlis Asp Gin Ala Leu 205 Gly Asn Phe Gly Ser 285 Glu Ala Phe Giu 110 Gly Lys Phe Asp Arg 190 Ser Thr Ala Leu Asn 270 Lys *Ala Pro Arg Gin Pro Ser Ser Ile 175 Gly Gly Gin Ile Met 255 Met Leu Ile Ser Giu Gin Ile Pro Leu 160 Leu Gin Gin Leu Phe 240 Leu Ala Leu Asp 290 Pro Ser His Val Leu Ser Arg Leu Ser Gin 300 Cys Pro Glu Val WO 97/12985 PCT/US96/15774 446 INFORMATION FOR SEQ ID NO: 205: SEQUENCE CHARACTERISTICS: LENGTH: 306 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 205: Ala Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg 1 5 10 Pro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp Val 25 Ser Ile Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu Ser Phe 40 Val Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly Ile Glu Ala Ile 55 Leu Arg Asn Leu Gln Pro Cys Leu Pro Ser Ala Thr Ala Ala Pro Ser 70 75 Arg His Pro Ile Ile Ile Lys Ala Gly Asp Trp Gln Glu Phe Arg Glu 90 Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu Gln Ala Gln Glu Gln Gln 100 105 110 Tyr Val Glu Gly Gly Gly Gly Ser Pro Gly Glu Pro Ser Gly Pro Ile 115 120 125 Ser Thr Ile Asn Pro Ser Pro Pro Ser Lys Glu Ser His Lys Ser Pro 130 135 140 Asn Met Val Leu Leu Pro Ala Val Asp Phe Ser Leu Gly Glu Trp Lys 145 150 155 160 Thr Gln Met Glu Glu Thr Lys Ala Gin Asp Ile Leu Gly Ala Val Thr 165 170 175 Leu Leu Leu Glu Gly Val Met Ala Ala Arg Gly Gin Leu Gly Pro Thr 180 185 190 Cys Leu Ser Ser Leu Leu Gly Gin Leu Ser Gly Gin Val Arg Leu Leu 195 200 205 WO 97/12985 PCT/US96/15774 447 Leu Gly Ala Leu Gin Ser Leu Leu Gly Thr Gin Leu Pro Pro Gin Gly 210 215 220 Arg Thr Thr Ala His Lys Asp Pro Asn Ala Ile Phe Leu Ser Phe Gin 225 230 235 240 His Leu Leu Arg Gly Lys Val Arg Phe Leu Met Leu Val Gly Gly Ser 245 250 255 Thr Leu Cys Val Arg Glu Phe Gly Gly Asn Met Ala Ser Pro Ala Pro 260 265 270 Pro Ala Cys Asp Leu Arg Val Leu Ser Lys Leu Leu Arg Asp Ser His 275 280 285 Val Leu His Ser Arg Leu Ser Gin Cys Pro Glu Val His Pro Leu Pro 290 295 300 Thr Pro 305 INFORMATION FOR SEQ ID NO: 206: SEQUENCE CHARACTERISTICS: LENGTH: 306 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 206: Ala Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg 1 5 10 Pro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp Val 25 Ser Ile Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu Ser Phe 40 Val Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly Ile Glu Ala Ile 55 Leu Arg Asn Leu Gin Pro Cys Leu Pro Ser Ala Thr Ala Ala Pro Ser 70 75 Arg His Pro Ile Ile Ile Lys Ala Gly Asp Trp Gin Glu Phe Arg Glu 90 WO 97/12985 PCTIUS96/1577 4 Lys Tyr Ser Leu Val Thr 130 Thr Giu 115 Ile Phe 100 Gly Asn Tyr Gly Pro Leu Gly Ser Val Gly Pro 135 Thr Ser 120 Pro Leu 105 Pro Ser Giu Gin Gly Giu Lys Giu Ala Pro Ser Gin Ser 125 His Giu 110 Gly Lys Gin Pro Ser Gin Ile Pro Asn Met Ala Val Asp Phe 145 150 Ser Leu Giy Glu Trp Lys Thr Gin Met Glu Giu Thr Lys Ala Gin Asp Ile Leu Gly Ala Val 'Pbr Gly Leu Gin His 225 Gly Arg.

Leu Val Leu Ser 210 Lys Lys Glu Arg Met Gly 195 Leu Asp Val Phe Val Al a 180 Gin Leu Pro Arg Gly 260 Leu 165 Ala Leu Gly Asn Phe 245 Gly Ser Arg Ser Thr Ala 230 Leu Asn Gly Gly Gin 215 Ile Met Met *Gin Gin 200 Leu Phe Leu Ala Leu 185 Val1 Pro Leu Val1 170 Gly Arg Pro Ser Gly 250 Pro Pro Leu Gin Phe 235 Gly Thr Leu Gly 220 Gin Ser Pro Leu Cys ILeu 205 Arg His Thr Leu Leu 190 Gly Thr Leu Leu Leu 175 Ser Ala Thr Leu Cys 255 160 Giu Ser Leu Ala Arg 240 Val1 265 Pro Ala Cys Asp Leu Leu Arg Asp Ser 275 His Val Leu His Ser Arg Leu Ser Gin Cys Pro Glu Vai His Pro Leu 290 295 Leu Pro 305 INFORMATION FOR SEQ ID NO: 207: SEQUENCE

CHARACTERISTICS:

LENGTH: 306 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: protein Pro 300 Thr Pro Val Leu WO 97/12985 PCTIUS96/1 5774 449 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 207: Ala Asn Cys Ser Ile Met Ile Asp Gu Ile Ile His His Leu Lys Ara

I

Pro Ser Val Leu Arg Lys Tyr Ser Asn 145 Lys Met Gly Leu Asp 225 Val Pro Ile Arg Arg His Leu Val Thr 130 Met Ala Ala Gin Leu 210 Pro Arg Ala Leu Ala Asn Pro Thr Giu 115 Ile Asp Gin Ala Leu 195 Giy Asn.

Phe Pro Met Val Leu Ile Phe 100 Gly Asn Phe Asp Arg 180 Ser Thr Ala Leu Leu Asp Lys Gin Ile Tyr Gly Pro Ser Ile 165 Gly Gly Gin Ile Met 245 *Leu Arg Asn Pro 70 Ile Leu Gly Ser Leu 150 Leu Gin Gin Leu Phe 230 Leu Asp Asn Leu 55 Cys Lys Val Giy Pro 135 Gly Gly Leu Val Pro 215 Leu Vli Pro Leu 40 Glu Leu Ala Thr Ser 120 Pro Giu Ala Giy Arg 200 Pro Ser2 Gly Asn 25 Arg Asn Pro Gly Leu 105 Pro Ser Trp Val Pro 185 Leu G1n Phe Gly Asn Leu Ala Ser Asp 90 Giu Gly Lys Lys Thr 170 Thr Leu Giy Gin Ser 250 Leu Pro Ser Ala 75 Trp Gin Glu Glu Thr 155 Leu Cys Leu Arg Hi s 235 Thr Asn Asn Gly Thr Gin Ala Pro Ser 140 Gin Leu Leu Gly Thr 220 Leu Leu Asp Leu Ile Ala blu Gin Ser 125 His Met Leu Ser Ala 205 rhr Leu lys Glu Glu Giu Ala Phe Giu 110 Gly Lys Giu Giu Ser 190 Leu Ala Arg Val Asp Ser Ala Pro Arg Gin Pro Ser Glu Gly 175 Leu Gln Hi s G1y krg 255 Val Phe Ile Ser Giu Gin Ile Pro Thr 160 Val Leu Ser Lys Lys 240 Glu Phe Gly Gly Asn Met Ala Ser Pro Ala Pro Pro Ala Cys 260 rr Asp Leu Arg 270 WO 97/12985 PCTIUS96/15774 450 Val Leu Ser Lys Leu Leu Arg Asp Ser His Val Leu His Ser Arg Leu 275 280 285 Ser Gin Cys Pro Giu Val His Pro Leu Pro Thr Pro Val Leu Leu Pro 290 295 300 Ala Val 305 INFORMATION FOR SEQ ID NO: 208: SEQUENCE

CHARACTERISTICS:

LENGTH: 306 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 208: Ala Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg 1 5 1 fl Pro Ser Val Leu Arg Lys Tyr Ser Pro Ile Arg Arg His Leu Val Thr 130 Ala Leu Ala Asn Pro Thr Glu 115 Ile Pro Met Val Leu Ile Phe 100 Gly Asn Leu Asp Lys Gin Ile Tyr Gly Pro Leu Arg Asn Pro 70 Ile Leu Gly Ser Asp Asn Leu 55 Cys Lys Val Gly Pro Pro Leu 40 Glu Leu Al a Thr Ser 120 Pro Asn 25 Arg Asn Pro Gly Leu 105 Pro Ser Asn Leu Ala Ser Asp 90 Giu Gly Lys Leu Pro Ser Ala 75 Trp Gin Glu Glu Asn Asn Gly Thr Gin Ala Pro Ser 140 Asp Leu Ile Ala Giu Gin Ser 125 His Glu Glu Glu Ala Phe Glu 110 Gly Lys Asp Ser Ala Pro Arg Gn Pro Ser Val Phe Ile Ser Glu Gin Ile Pro Asn 145 Met Gly Giu Trp Lys 150 Thr Gin Met Giu Giu 155 Thr Lys Ala Gin Asp 160 WO 97/12985 PCT/US96/15774 451 Ile Leu Gly Ala Val Thr Leu Leu Leu Glu Gly Val Met Ala Ala Arg 165 170 175 Gly Gin Leu Gly Pro Thr Cys Leu Ser Ser Leu Leu Gly Gin Leu Ser 180 185 190 Gly Gin Val Arg Leu Leu Leu Gly Ala Leu Gin Ser Leu Leu Gly Thr 195 200 205 Gin Leu Pro Pro Gin Gly Arg Thr Thr Ala His Lys Asp Pro Asn Ala 210 215 220 Ile Phe Leu Ser Phe Gin His Leu Leu Arg Gly Lys Val Arg Phe Leu 225 230 235 240 Met Leu Val Gly Gly Ser Thr Leu Cys Val Arg Glu Phe Gly Gly Asn 245 250 255 Met Ala Ser Pro Ala Pro Pro Ala Cys Asp Leu Arg Val Leu Ser Lys 260 265 270 Leu Leu Arg Asp Ser His Val Leu His Ser Arg Leu Ser Gin Cys Pro 275 280 285 Glu Val His Pro Leu Pro Thr Pro Val Leu Leu Pro Ala Val Asp Phe 290 295 300 Ser Leu 305 INFORMATION FOR SEQ ID NO: 209: SEQUENCE

CHARACTERISTICS:

LENGTH: 306 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 209: Ala Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg 1 5 10 Pro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp Val 25 Ser Ile Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu Ser Phe 40 WO 97/12985 PCT/US96/15 7 7 4 Val Arg Ala Val Lys Asn Leu 55 Leu Arg Asn Leu Gin Pro Cys 70 Arg His Pro Ile Ile Ile Lys Lys Leu Thr Phe Tyr Leu Val 100 Tyr Val Giu Gly Gly Gly Gly 115 Ser Thr Ile Asn Pro Ser Pro 1 130 135 Asn Met Gly Pro Thr Cys Leu S 145 150 Gin Val Arg Leu Leu Leu Gly A 165 Leu Pro Pro Gin Gly Arg Thr T 180 Phe Leu Ser Phe Gin His Leu L 195 2 Leu Val Gly Giy Ser Thr Leu C 210 215 Aia Ser Pro Aia Pro Pro Ala C' 225 230 Leu Arg Asp Ser His Val Leu H: 245 Val His Pro Leu Pro Thr Pro Ve 260 Leu Gly Giu Trp, Lys Thr Gin Me 275 28 Leu Gly Ala Val Thr Leu Leu Le 290 295 Gin Leu 305 INFORMATION FOR SEQ ID NO: 210: SEQUENCE

CHARACTERISTICS:

Gi Le Al rh L2( 'r l1a hr eu 00 vs kEs is .u Asn u Pro a Gly r Leu 105 r Pro 0 Ser 7Ser LeuC Ala 185 Arg G Val A Asp L Ser A 2 Leu Lq 265 Giu G~ Glu

G:

Al Se As G1 Gl Ly~ ~is rg eu rg 50 eu lu Ly a SE r Al p Tr u Gi [G1 Gli 1Le~ ISe~ Lys Lys Giu Arg 235 Leu Pro Thr Val r Gly Ilie -a Thr Ala p Gin Glu fl Ala Gin u Pro Ser 125 Li Ser His 140 a Gly tln -Leu Leu Asp Pro I *Vai Arg 205 *Phe Gly G 220 Val Leu S Ser Gin C Ala Val A 2 Lys Ala G.

285 Met Ala A 300 Gi Al Ph Gli Glj Lys Leu fly ~sn ~he liy er ys sp in la u Al a Pr e Ar Il 0 PPr Sei Ser Thr 175 Ala Leu Asn Lys Pro 255 Phe Asp Arg a Ile o Ser g Giu n Gin o le Pro Gly 160 -Gin Ile Met Met Leu 240 Glu Ser Ile Gly WO 97/12985 PCTIUS96/1 5774 453 LENGTH: 306 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 210: Ala Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg 1 Pro Ser Val Leu Arg Lys Tyr Ser Asn 145 Asp Val Phe Pro Ile Arg Arg His Leu Val Thr 130 Met Pro Arg Gly Ala Leu Ala Asn Pro Thr Giu 115 Ile Gly Asn Phe Gly 195 Pro Met Val Leu Ile Phe 100 Gly Asn Thr Ala Leu 180 Asn.

Leu Asp Lys Gin Ile Tyr Gly Pro Gin Ile 165 Met Met Leu Arg Asn Pro 70 Ile Leu Gly Ser Leu 150 Phe Leu Ala Asp Asn Leu 55 Cys Lys Val Gly Pro 135 Pro Leu Val Ser *Pro Leu 40 Glu Leu Ala Thr Ser i2 0 Pro Pro Ser Gly Pro 200 Asn 25 Arg Asn Pro Gly Leu 105 Pro Ser Gin Phe Gly 185 Ala 10 Asn Leu Ala Ser Asp 90 Glu Gly Lys Gly.

Gin 170 Ser Pro Leu Pro Ser Ala 75 Trp Gin Glu Glu Arg 155 His Thr Pro Asn Asn Gly Thr Gin Ala Pro Ser 140 Thr Leu Leu Ala Asp Ile Ala Giu Gln Ser 125 His Thr Leu Cys Cys 205 Giu Giu Glu Ala Phe Glu 110 Gly Lys Ala Arg Val1 190 Asp Asp Ser Al a Pro Arg Gin Pro Ser His Gly 175 Arg Leu Val Phe Ile Ser Giu Gin Ile Pro Lys 160 Lys Glu Arg Vai Leu Ser Lys Leu Leu Arg Asp Ser His Val Leu 220 His Ser Arg Leu WO 97/12985 PCT/US96/15774 454 Ser Gin Cys Pro Glu Val His Pro Leu Pro Thr Pro Val Leu Leu Pro 225 230 235 240 Ala Val Asp Phe Ser Leu Gly Glu Trp Lys Thr Gin Met Glu Glu Thr 245 250 255 Lys Ala Gin Asp Ile Leu Gly Ala Val Thr Leu Leu Leu Glu Gly Val 260 265 270 Met Ala Ala Arg Gly Gin Leu Gly Pro Thr Cys Leu Ser Ser Leu Leu 275 280 285 Gly Gin Leu Ser Gly Gin Val Arg Leu Leu Leu Gly Ala Leu Gin Ser 290 295 300 Leu Leu 305 INFORMATION FOR SEQ ID NO: 211: SEQUENCE CHARACTERISTICS: LENGTH: 306 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 211: Ala Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg 1 5 10 Pro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp Val 25 Ser Ile Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu Ser Phe 40 Val Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly Ile Glu Ala Ile 55 Leu Arg Asn Leu Gin Pro Cys Leu Pro Ser Ala Thr Ala Ala Pro Ser 70 75 Arg His Pro Ile Ile Ile Lys Ala Gly Asp Trp Gin Glu Phe Arg Glu 90 Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu Gin Ala Gin Glu Gin Gin 100 105 110 WO 97/12985 PCTIUS96/15774 Tyr Val Glu Gly Gly Gly Gly Ser 115 19n Pro Gly Glu Pro Ser Gly Pro Ile 125 Ser Asn 145 Ser Gly Pro Asp Pro 225 Glu Ala Gly Thr 130 Met Phe Gly Ala Ser 210 Leu Trp Val Pro Ile Gly Gin Ser Pro 195 His Pro Lys Thr Thr 275 Asn Arg His Thr 180 Pro Val Thr Thr Leu 260 Cys Pro Thr Leu 165 Leu Ala Leu Pro Gin 245 Leu Leu Ser Thr 150 Leu Cys Cys His Val 230 Met Leu Ser Pro 135 Ala Arg Val Asp Ser 215 Leu Glu Glu Ser Pro His Gly Arg Leu 200 Arg Leu Glu Gly Leu 280 Ser Lys Lys Glu 185 Arg Leu Pro Thr Val 265 Leu Lys Asp Val 170 Phe Val Ser Ala Lys 250 Met Gly Glu Pro 155 Arg Gly Leu Gin Val 235 Ala Ala Gin Ser 140 Asn Phe Gly Ser Cys 220 Asp Gin Ala Leu His Ala Leu Asn Lys 205 Pro Phe Asp Arg Ser Lys Ile Met Met 190 Leu Glu Ser Ile Gly 270 Gly Ser Pro Phe Leu 160 Leu Val 175 Ala Ser Leu Arg Val His Leu Gly 240 Leu Gly 255 Gin Leu Gin Val 285 Arg Leu Leu Leu Gly Ala Leu Gin Ser Leu Leu Gly Thr Gin Leu Pro 290 295 300 Pro Gin 305 INFORMATION FOR SEQ ID NO: 212: SEQUENCE CHARACTERISTICS: LENGTH: 306 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 212: WO 97/12985 PCT/US96/1577 4 456 Ala Asri Cjys Ser Ile Met Ile Asp Giu 1 Ile Ile His His Leu Lys Arg Pro S er Val Leu Arg Lys Tyr Ser Asn 145 Leu LeuC Ala C Leu H Pro V; 225 Gin M Leu L Pr

IL

Arc Arc His Leu Val1 Thr 130 eu ~ys [is ral1 e t eu Al Lei i Al Asi Prc *Thr Glu 115 Ile Ala Arg Val Asp 195 Ser Leu Glu Giu a Pro Met Val I Leu Ile Phe 100 Gly Asn His Gly Arg 180 Leu2 Arg I Leu I Glu TI 2 Gly V Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp Val 25 Asj Ly Glr Ile Tyr Gly Pro Lys Lys 165 31U krg 4 eu ~ro 'hr 45 'al p Ar sAs) Pr 70 IiE Let Gil, Ser Asp 150 Val1 Phe Val Ser Ala 230 Lys Met g Asn ni Leu 55 0 Cys a Lys 1Val Gly Pro 135 Pro Arg Gly Leu Gin C 215 Val A Ala G Ala

A

Lei 40 G1i Le-L Ala Thr Ser 120 Pro Asn Phe 31y Jer ~00 :ys ~sp in la u Ar .1 As 1Pr G1~ Lei.

Prc Ser Ala Leu Asn 185 Lys Pro Phe Asp Arg g n Leu Pro Ala Ser Ser Ala 75 Asp Trp 90 Glu Gin Asn Gly Thr Gin Ala.

Leu Ile Ala Glu (11h Giu Giu Ala Phe Ser Phe Ala Ile Pro Ser Arg Glu Gin Gin 110 Gly Glu Lys Glu Ile Phe 155 Met Leu 170 Met Ala Leu Leu Glu Val Ser Leu 235 Ile Leu 250 Gly Gin Prc Sex 140 Leu Val1 Ser Arg His 220

G

1 y fly eu Sei 125 *His *Sex Gly Pro Asp 205 Pro Giu Ala Gly Arg 285 *Gly Lys *Phe *Gly Aa 190 Ser Leu Trp Val Pro Pro Ser Gin Ser 175 Pro His Pro Lys Thr 255 rhr Ile Pro His 160 Thr Pro Val Thr Thr 240 Leu Cys 260 Leu Ser Ser 275 Leu Leu Gly Gin Leu 280 Ser Gly Gin Val Leu Leu Leu WO 97/12985 PCTIUS96/1 5774 457 Gly Ala Leu Gin Ser Leu Leu Gly Thr Gln Leu Pro Pro Gin Gly Arg 290 295 300 Thr Thr 305 INFORMATION FOR SEQ ID NO: 213: SEQUENCE CHARACTERISTICS: LENGTH: 306 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 213: Ala Asn Cys Ser Ile Met Ile Asp Glu Ile Ile Pro Ser Val Leu Arg Lys Tyr Ser Asn 145 Pro Ile Arg Arg His Leu Val Thr 130 Met Ala Leu Ala Asn Pro Thr Glu 115 Ile Asp Pro Met Val Leu Ile Phe 100 Gly Asn Pro Leu Asp Lys Gin Ile Tyr Gly Pro Asn Leu Arg Asn Pro 70 Ile Leu Gly Ser Ala 150 Asp Asn Leu 55 Cys Lys Val Gly Pro 135 Ile Pro Asn 25 Leu Arg 40 Glu Asn Leu Pro Ala Gly Thr Leu 105 Ser Pro 120 Pro Ser Phe Leu Asn Leu Leu Pro Ala Ser Ser Ala 75 Asp Trp 90 Glu Gin Gly Glu Lys Glu Ser Phe 155 His Asn Asn Gly Thr Gin Ala Pro Ser 140 Gin His Asp Leu Ile Ala Glu Gin Ser 125 His His Leu Glu Glu Glu Ala Phe Glu 110 Gly Lys Leu Lys Asp Ser Ala Pro Arg Gin Pro Ser Leu Arg Val Phe Ile Ser Glu Gin Ile Pro Arg 160 Gly Lys Val Arg Phe Leu Met Leu Val Gly Gly Ser Thr Leu Cys.Val 165 170 175 WO 97/12985 PCT/US96/15774 458 Arg Glu Phe Gly Gly Asn Met Ala Ser Pro Ala Pro Pro Ala Cys Asp 180 185 190 Leu Arg Val Leu Ser Lys Leu Leu Arg Asp Ser His Val Leu His Ser 195 200 205 Arg Leu Ser Gin Cys Pro Glu Val His Pro Leu Pro Thr Pro Val Leu 210 215 220 Leu Pro Ala Val Asp Phe Ser Leu Gly Glu Trp Lys Thr Gin Met Glu 225 230 235 240 Glu Thr Lys Ala Gin Asp Ile Leu Gly Ala Val Thr Leu Leu Leu Glu 245 250 255 Gly Val Met Ala Ala Arg Gly Gln Leu Gly Pro Thr Cys Leu Ser Ser 260 265 270 Leu Leu Gly Gin Leu Ser Gly Gin Val Arg Leu Leu Leu Gly Ala Leu 275 280 285 Gin Ser Leu Leu Gly Thr Gin Leu Pro Pro Gin Gly Arg Thr Thr Ala 290 295 300 His Lys 305 INFORMATION FOR SEQ ID NO: 214: SEQUENCE CHARACTERISTICS: LENGTH: 306 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 214: Ala Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg 1 5 10 Pro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp Val 25 Ser Ile Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu Ser Phe 40 Val Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly Ile Glu Ala Ile 55 WO 97/12985 PCTIUS96/1 5774 Leu Arg Asn Leu Gin Arg Lys Tyr Ser Asn 145 Arg Gly Leu Gin Val1 225 Ala Ala Gin Leu Pro His Leu Val1 Thr 130 Met Phe Gly Ser Cys 210 Asp Gin Ala Leu Gly 290 Asn Pro Thr Glu 115 Ile Ala Leu Asn Lys 195 Pro Phe Asp Arg Ser 275 Thr Ile Phe 100 Gly Asn Ile Met Met 180 Leu Giu Ser Ile Gly 260 Gly Ile Tyr Gly Pro Phe Leu 165 Ala Leu Val Leu Leu 245 Gin Gin Pro Cys Leu Ile Lys Ala Leu Val Thr Gly Gly Ser 120 Ser Pro Pro 135 Leu Ser Phe 150 Val Gly Gly Ser Pro Ala Arg Asp Ser 200 Hi-s Pro Leu 215 Gly Giu Trp 230 Gly Ala Val Leu Gly Pro Val Arg Leu 280 Pro Ser Aia Thr Ala Ala Pro Ser Gly Leu 105 Pro Ser Gin Ser Pro 185 His Pro Lys Thr Thr 265 Leu Asp 90 Glu Gly Lys His Thr 170 Pro Val Thr Thr Leu 250 Cys Leu Trp Gin Giu Giu Leu 155 Leu Ala Leu Pro Gin 235 Leu Leu Gly Gin Ala Pro Ser 140 Leu Cys Cys His Val 220 Met Leu Ser Ala Giu Gin Ser 125 His Arg 'Va 1 Asp Ser 205 Leu Giu Glu Ser Leu 285 Phe Giu 110 Gly Lys Gly Arg Leu 190 Arg Leu Glu Gly Leu 270 Gin Arg Gin Pro Ser Lys Giu 175 Arg Leu Pro Thr Val 255 Leu Ser Glu Gin Ile Pro Val1 160 Phe Val1 Ser Ala Lys 240 Met Gly Leu Gin Leu Pro Pro Gin Gly Arg Thr Thr Ala His Lys Asp 305 INFORMATION FOR SEQ ID NO: 215: SEQUENCE CHARACTERISTICS: LENGTH: 305 amino acids TYPE: amino acid STRANDEDNESS: single WO 97/12985 PCT/US96,'157 7 4 TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) Ala Pro Ser Val Leu Arg Lys Tyr Ser AsnI 145 Asp Gin I Ala I SEQUENCE DESCRIPTION: SEQ ID NO: 215: Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg Pr Ili Arc Arc His Leu Val rhr 130 qe t ?he ~sp ~rg oAla SLeu Ala Asn Pro Thr Giu 115 Ile Giu Ser IleI GlyC Prc Met Val Leu Ile Phe 100 Gly Asn Vl eu jeu in )Let Asr Lys Gin Ile Tyr Gly Pro His Gly 165 Gly Leu iLeu Arg Asn Pro 70 Ile Leu Gly Ser Pro 150 Giu Ala N Gly I Asi Ast Lei.

55 Cys Lys Val Gly Pro 1.35 Leu P'rp al1 ~ro pPrc I Leu 40 iGiu Leu Ala Thr Ser 120 Pro Pro Lys Thr Thr 200 Leu )Asn 25 Arg Asn Pro Gly Leu 105 Pro Ser Thr Thr C 1 Leu L 185 Cys L~ Leu

G

Asn Leu Ala Ser Leu Pro Ser Ala Asi Asi Gi 60 Thr Asp 90 Giu Gly Lys ?ro ;in .70 jeu ~eu ny Trp Gin Giu Giu Val 155 Met Leu Ser Ala Gin Ala Pro Ser 140 Leu Giu Giu Ser n Asp I Leu f 1ie Ala Glu Gn Ser 125 His Leu Gly Leu L 205 Gn

S

G1i Gl Gli Aia Phe Giu 110 Gly Ljys Pro Phr Tai jeu er uAsp 1 Ser 1Ala Pro Arg Gin Pro Ser Ala Lys2 175 Met I Gly C Leu

L

Val Phe Ile Ser Glu Gin Ile Pro Val 160 klia la 1n ieu 195 Leu Ser Gly Gin Vai Arg Leu 210 215 220u Giy 225 Thr Gin Leu Pro Pro 230 Gin Gly Arg Thr Thr 235 Ala His Lys Asp.

Pro 240 WO 97/12985 PCT/US96/15774 461 Asn Ala Ile Phe Leu Ser Phe Gin His Leu Leu Arg Gly Lys Val Arg 245 250 255 Phe Leu Met Leu Val Gly Gly Ser Thr Leu Cys Val Arg Glu Phe Gly 260 265 270 Asn Met Ala Ser Pro Ala Pro Pro Ala Cys Asp Leu Arg Val Leu Ser 275 280 285 Lys Leu Leu Arg Asp Ser His Val Leu His Ser Arg Leu Ser Gin Cys 290 295 300 Pro 305 INFORMATION FOR SEQ ID NO: 216: SEQUENCE

CHARACTERISTICS:

LENGTH: 305 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 216: Ala Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg 1 5 10 Pro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp Val 25 Ser Ile Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu Ser Phe 40 Val Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly Ile Glu Ala Ile 55 Leu Arg Asn Leu Gin Pro Cys Leu Pro Ser Ala Thr Ala Ala Pro Ser 70 75 Arg His Pro Ile Ile Ile Lys Ala Gly Asp Trp Gin Glu Phe Arg Glu 90 Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu Gin Ala Gin Glu Gin Gin 100 105 110 Tyr Val Glu Gly Gly Gly Gly Ser Pro Gly Glu Pro Ser Gly Pro Ile 115 120 125 WO 97/12985 PCTIUS96/1 5774 Ser Asn 145 Thr Ile 130 Met Leu Asn Pro Pro Thr Ser Pro 150 Pro 135 Val1 Pro Leu Ser Lys Leu Pro Glu Ala Ser 140 Val His Asp Lys Phe Pro Leu Gly Glu Trp Lys Thr 165 Gin Met Glu Glu Thr Lys Ala Gin Asp Ile Leu 170 Gly Leu Val Pro 225 Leu Val Pro Ala Gly Arg 210 Pro Ser Gly Ala Val1 Pro 195 Leu Gin Phe Gly Pro 275 Thr 180 Thr Leu Gly Gin Ser 260 Pro Leu Cys Leu Arg His 245 Thr Ala Leu Leu Gly Thr 230 Leu Leu Leu Ser Ala 215 Thr Leu Cys Glu Ser 200 Leu Ala Arg Val Gly 185 Leu Gin His Gly Arg 265 Arg Val Met Leu Gly Ser Leu Lys Asp 235 Lys Val 250 Glu Phe Val Leu Ala Gin Leu 220 Pro Arg Gly Ser Ala Leu 205 Gly Asn Phe Asn Arg 190 Ser Thr Ala Leu Met 270 175 *Gly Gly Gin Ile Met 255 Ala Gin Gin Leu Phe 240 Leu Ser Arg 280 LysLe Asp Ser His Val Leu His Ser Arg Leu Ser Gin 290 295 Pro 305 INFORMATION FOR SEQ ID NO: 217: SEQUENCE

CHARACTERISTICS:

LENGTH: 305 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: protein Cys 300 Pro Giu Val His (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 217: Ala Asn Cys Ser Ile Met Ile Asp Giu Ile Ile His His Leu Lys Arg 1 5 10 WO 97/12985 PCT/US96/15774 Pro Ser Pro Ile Ala Leu Pro Met Leu Asp Lys Gin Leu Arg Asp Asn Pro Leu Asn 25 Arg Asr Leu Leu Pro Asn Asn Asp Leu Val Leu Arg Lys Tyr Ser Asn 145 Thr Leu Cys Leu Arg 225 His I Thr I Ala C Arg Arg Ala Asn Va1 Leu Leu 55 Cys Glu Leu Asn Pro Ala Ser Ser Ala 75 Trp Gly Thr Gin Ile Ala Glu Glu Glu Glu Ala Phe Asp Val Ser Phe Ala Ile Pro Ser Arg Glu 70 His Leu Va1 Thr 130 Met Gin Leu Leu ly 210 [hr .eu .eu :ys Pr Thi Gli- 115 Ile Val Met Leu Ser 195 Ala Thr Leu Cys Asp o Ile Phe 100 1 Gly Asn Leu Glu Glu 180 Ser Leu Ala I Arg C Val 260 Leu A I 1 Tyrt Gl Pro Leu Glu 165 Gly Leu Gln iis ;ly ~rg irg a Ile Leu Gly Ser Pro 150 Thr Vai Leu Ser Lys I 230 Lys Glu i Val L Ly Val Glj Pro 135 Ala Lys Met 3iy Leu 215 ksp al he leu s Ala Thr Ser 120 Pro Va1 Ala Ala Gin 200 Leu Pro Arg Gly Ser I Gi] Let 105 Pro Sex Asp Gin Ala 185 Leu Gly Asn Phe ksn 265 -ys Asp 90 1 Glu Gly Lys Phe Asp 170 Arg Ser Thr Ala Leu b 250 Met I! Leu L G1r Gli.

Glu Sex 155 Ile Gly 3 iy 31n Ile !35 det la ,eu I Al Pr( I Sel 14C Leu Leu Gin Gin Leu 220 Phe Leu Ser Arg a Gin SSer 125 His 1 Gly Gly Leu Val 205 Pro Leu Val Pro I Asp c Gi G1 Lys Glu Ala Gly 190 Arg Pro Ser 31y la ;er ,Gin Pro Ser 1 Trp Val 175 Pro Leu Gin Phe Gly 255 Pro I His I Gin Ile Pro Lys 160 Thr Thr Leu Gly 3Gl 240 Ser ?ro al 275 285 Leu His 290 Ser Arg Leu Ser Gin 295 Cys Pro Glu Val His Pro Leu 300 Pro Thr WO 97/12985 PCT/US96/1 5 7 7 4 464 Pro 305 INFORMATION FOR SEQ ID NO: 218: SEQUENCE

CHARACTERISTICS:

LENGTH: 305 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 218: Ala Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg 1 5 10 Pro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp Val 25 Ser Ile Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu Ser Phe 40 Val Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly Ile Glu Ala Ile 55 Leu Arg Asn Leu Gln Pro Cys Leu Pro Ser Ala Thr Ala Ala Pro Ser 70 75 Arg His Pro Ile Ile Ile Lys Ala Gly Asp Trp Gin Glu Phe Arg Glu 90 Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu Gin Ala Gin Glu Gin Gin 100 105 110 Tyr Val Glu Gly Gly Gly Gly Ser Pro Gly Glu Pro Ser Gly Pro Ile 115 120 125 Ser Thr Ile Asn Pro Ser Pro Pro Ser Lys Glu Ser His Lys Ser Pro 130 135 140 Asn Met Ala Val Asp Phe Ser Leu Gly Glu Trp Lys Thr Gin Met Glu 145 150 155 160 Glu Thr Lys Ala Gin Asp Ile Leu Gly Ala Val Thr Leu Leu Leu Glu 165 170 175 Gly Val Met Ala Ala Arg Gly Gin Leu Gly Pro Thr Cys Leu Ser Ser 180 185 190 WO 97/12985 PCT/US96/15774 465 Leu Leu Gly Gin Leu Ser Gly Gin Val Arg Leu Leu Leu Gly Ala Leu 195 200 205 Gin Ser Leu Leu Gly Thr Gin Leu Pro Pro Gin Gly Arg Thr Thr Ala 210 215 220 His Lys Asp Pro Asn Ala Ile Phe Leu Ser Phe Gin His Leu Leu Arg 225 230 235 240 Gly Lys Val Arg Phe Leu Met Leu Val Gly Gly Ser Thr Leu Cys Val 245 250 255 Arg Glu Phe Gly Asn Met Ala Ser Pro Ala Pro Pro Ala Cys Asp Leu 260 265 270 Arg Val Leu Ser Lys Leu Leu Arg Asp Ser His Val Leu His Ser Arg 275 280 285 Leu Ser Gin Cys Pro Glu Val His Pro Leu Pro Thr Pro Val Leu Leu 290 295 300 Pro 305 INFORMATION FOR SEQ ID NO: 219: SEQUENCE CHARACTERISTICS: LENGTH: 305 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 219: Ala Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg 1 5 10 Pro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp Val 25 Ser Ile Leu Met Asp Arg Asn Leu.Arg Leu Pro Asn Leu Glu Ser Phe 40 Val Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly Ile Glu Ala Ile 55 Leu Arg Asn Leu Gin Pro Cys Leu Pro Ser Ala Thr Ala Ala Pro Ser 70 75 WO 97/12985 PCTJUS96/1 5774 Arg His Pro Ile Ile Ile Lys Ala Gly Asp Trp Gin Giu Phe Arg Giu Lys Tyr Ser Asn 145 Lys Met Gly Leu Asp 225 Val Phe Leu Leu Val Thr 130 Met Aia Ala Gin Leu 210 Pro Arg Gly Ser Thr Giu Ile Asp Gin Ala Leu 195 Gly Asn Phe Asn Lys 275 Phe 100 Gly Asn Phe Asp Arg 180 Ser Thr Ala Leu Met 260 Leu Tyr Gly Pro Ser Ile 165 Gly Gly Gin Ile Met 245 Ala Leu Leu Gly Ser Leu 150 Leu Gin Gin Leu Phe 230 Leu Ser Arg *Val *Gly Pro 135 Gly Gly Leu Val Pro 21i5 Leu Val Pro Asp Thr L 1 Ser P 120 Pro S Giu T Ala V Gly P: 1; Arg L 200 Pro G Ser P1 Gly GZ Ala Pj Ser Hj 280 90 eu 05 ro er rp al ro 85 ln le Ly 55 Ls Ciu Gly Lys Lys Thr 170 Thr Leu Gly Gin Ser 250 Pro Val Gin Giu Giu Thr 155 Leu Cys Leu Arg His 235 Thr Ala Leu Ala Pro Ser 140 Gin Leu Leu Gly Thr 220 Leu Leu Cys His Gin Ser 125 His Met Leu Se'r Aia 205 Thr Leu Cys Asp Ser 285 Giu 110 Gly Lys Giu Glu Ser 190 Leu Ala Arg Val Leu 270 Arg Gin Pro Ser Giu Giy 175 Leu Gin His Giy Arg 255 Arg Leu Gin Ile Pro Thr 160 Val Leu Ser Lys Lys 240 Giu Val Ser Gin Cys Pro Glu Val His Pro Leu Pro Thr Pro 290 295 Vai 305 INFORMATION FOR SEQ ID NO: 220: SEQUENCE CHARACTERISTICS: LENGTH: 365 amino acids TYPE: amino acid STRANDEDNESS: singie TOPOLOGY: iinear (ii) MOLECULE TYPE: protein Leu Leu Pro Ala WO 97/12985 PCTIUS96/15774 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 220: Ala Asn Cys Ser Ile Met Ile Asp Giu Ile Ile His His Leu Lys Arg Pro Ser Val Leu Arg Lys Tyr Ser Asn 145 Ile Gly Gly Gin Ile 225 Pro Ile Arg Arg His Leu Val1 Thr 130 Met Leu Gin Gin Leu 210 Phe Ala Leu Ala Asn Pro Thr Giu 115 Ile Gly Gly Leu Val 195 Pro Leu Pro Met Val Leu Ile Phe 100 Gly Asn Giu Ala Gly 180 Arg Pro Ser Leu Asp Lys Gin Ile Tyr Gly Pro Trp Val 165 Pro Leu Gin Phe Leu Arg Asn Pro 70 Ile Leu Gly Ser Lys 150 Thr Thr Leu Gly Gin 230 Asp Asn Leu 55 Cys Lys Val Gly Pro 135 Thr Leu Cys Leu Arg 215 H~is Pro Leu 40 Glu Leu Ala Thr Ser 120 Pro Gin Leu Leu Gly 200 Thr Leu IAsn 25 Arg Asn Pro Gly Leu 105 Pro Ser Met Leu Ser 185 Ala Thr Leu Asn Leu Ala Ser Asp 90 Giu Gly Lys Giu Giu 170 Ser Leu !kia krg Leu Pro Ser Ala 75 Trp, Gin Giu Giu Giu 155 Gly Leu Gin His Gly 235 Asn Asn Gly Thr Gin Ala Pro Ser 140 Thr Val Leu Ser [Lys 220 [Lys *Asp Leu Ile Ala Giu Gin Ser 125 His Lys Met Gly.

Leu 205 Asp Val Giu Giu Giu Ala Phe Giu 110 Gly Lys Ala Ala Gin 190 Leu Pro Arg Asp Ser Ala Pro Arg Gin Pro Ser Gin Ala 175 Leu Gly Asn Phe Val Phe Ilie Ser Giu Gn Ile Pro Asp 160 Arg Ser Thr Ala Leu Met Leu Val Gly Giy Ser Thr Leu Cys 245 Val 250 Arg Giu Phe Gly Asn Met 255 WO 97/12985 PCT/US96/15774 468 Ala Ser Pro Ala Pro Pro Ala Cys Asp Leu Arg Val Leu Ser Lys Leu 260 265 270 Leu Arg Asp Ser His Val Leu His Ser Arg Leu Ser Gin Cys Pro Glu 275 280 285 Val His Pro Leu Pro Thr Pro Val Leu Leu Pro Ala Val Asp Phe Ser 290 295 300 Leu 305 INFORMATION FOR SEQ ID NO: 221: SEQUENCE CHARACTERISTICS: LENGTH: 305 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 221: Ala Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg 1 5 10 Pro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp Val 25 Ser Ile Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu Ser Phe 40 Val Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly Ile Glu Ala Ile 55 Leu Arg Asn Leu Gin Pro Cys Leu Pro Ser Ala Thr Ala Ala Pro Ser 70 75 Arg His Pro Ile Ile Ile Lys Ala Gly Asp Trp Gin Glu Phe Arg Glu 90 Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu Gin Ala Gin Glu Gin Gin 100 105 110 Tyr Val Glu Gly Gly Gly Gly Ser Pro Gly Glu Pro Ser Gly Pro Ile 115 120 125 Ser Thr Ile Asn Pro Ser Pro Pro Ser Lys Glu Ser His Lys Ser Pro 130 135 140 WO 97/12985 PCT/US96/15774 Asn Met Gly Pro Thr Gin Leu Phe Leu Ser 225 Arg His Gly Val Pro Leu Val 210 Pro Asp Pro Glu Arg Pro Ser 195 Gly Ala Ser Leu Trp 275 Leu Gin 180 Phe Gly Pro His Pro 260 Lys Leu 165 Gly Gin Ser Pro Val 245 Thr Thr Cys Leu Ser 150 Leu Gly Ala Arg Thr Thr His Leu Leu 200 Thr Leu Cys 215 Ala Cys Asp 230 Leu His Ser Pro Val Leu Gin Met Glu 280 Ser Leu Ala 185 Arg Val Leu Arg Leu 265 Glu Leu Gin 170 His Gly Arg Arg Leu 250 Pro Thr Leu 155 Ser Lys Lys Glu Val 235 Ser Ala Lys Gly Leu Asp Val Phe 220 Leu Gin Val Ala Gin Leu Pro Arg 205 Gly Ser Cys Asp Gin 285 Leu Gly Asn 190 Phe Asn Lys Pro Phe 270 Asp Ser Thr 175 Ala Leu Met Leu Glu 255 Ser Ile Gly 160 Gin Ile Met Ala Leu 240 Val Leu Leu Gly Ala Val Thr Leu Leu Leu Glu Gly Val Met Ala Ala Arg Gly Gin 290 295 Leu 305 INFORMATION FOR SEQ ID NO: 222: SEQUENCE CHARACTERISTICS: LENGTH: 305 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: protein 300 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 222: Ala Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg 1 5 .10 Pro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp Val 25 r- WO 97/12985 PCTIUS96/1 5774 470 Ser Ile Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu Ser Phe 40 Val Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly Ile Glu Ala Ile 55 Leu Arg Asn Leu Gin Pro Cys Leu Pro Ser Ala Thr Ala Ala Pro Ser 70 75 Arg His Pro Ile Ile Ile Lys Ala Gly Asp Trp Gin Glu Phe Arg Glu 90 Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu Gin Ala Gin Glu Gin Gin 100 105 110 Tyr Val Glu Gly Gly Gly Gly Ser Pro Gly Glu Pro Ser Gly Pro Ile 115 120 125 Ser Thr Ile Asn Pro Ser Pro Pro Ser Lys Glu Ser His Lys Ser Pro 130 135 140 Asn Met Gly Thr Gin Leu Pro Pro Gin Gly Arg Thr Thr Ala His Lys 145 150 155 160 Asp Pro Asn Ala Ile Phe Leu Ser Phe Gin His Leu Leu Arg Gly Lys 165 170 175 Val Arg Phe Leu Met Leu Val Gly Gly Ser Thr Leu Cys Val Arg Glu 180 185 190 Phe Gly Asn Met Ala Ser Pro Ala Pro Pro Ala Cys Asp Leu Arg Val 195 200 205 Leu Ser Lys Leu Leu Arg Asp Ser His Val Leu His Ser Arg Leu Ser 210 215 220 Gin Cys Pro Glu Val His Pro Leu Pro Thr Pro Val Leu Leu Pro Ala 225 230 235 240 Val Asp Phe Ser Leu Gly Glu Trp Lys Thr Gin Met Glu Glu Thr Lys 245 250 255 Ala Gin Asp Ile Leu Gly Ala Val Thr Leu Leu Leu Glu Gly Val Met 260 265 270 Ala Ala Arg Gly Gin Leu Gly Pro Thr Cys Leu Ser Ser Leu Leu Gly 275 280 285 Gin Leu Ser Gly Gin Val Arg Leu Leu Leu Gly Ala Leu Gin Ser Leu 290 295 300 Leu 305 WO 97/12985 WO 9712985PCTIUS96/15774 471 INFORMATION FOR SEQ ID NO: 223: SEQUENCE CHARACTERISTICS: LENGTH: 305 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 223: Ala Asn Cys Ser Ile Met Ile Asp Giu Ile Ile His His Leu Lys Arg

I

Pro Ser Val Leu Arg Lys Tyr Ser Asn 145 Ser Gly Pro Ile Arg Arg His Leu Val Thr 130 Met Phe Gly Ala Leu Ala Asn Pro Thr Glu 115 Ile Gly Gin Ser Pro Met Val Leu Ile Phe 100 Gly Asn Arg His Thr 180 5 Leu Asp Lys Gin Ile Tyr Gly Pro Thr Leu 165 Leu Leu Arg Asn Pro 70 Ile Leu Gly Ser Thr 150 Leu Cys Asp Asn Leu 55 Cys Lys Val1 Gly Pro 135 Ala Arg Val Pro Leu 40 Giu Leu Ala Thr Ser 120 Pro His Gly Arg Asn 25 Arg Asn Pro Gly Leu 105 Pro Ser Lys Lys Giu 185 10 Asn Leu Ala Ser Asp 90 Giu Gly Lys Asp Val 170 Phe Leu Pro Ser Ala 75 Trp Gin Giu Giu Pro 155 Arg Gly Asn Asn Gly Thr Gin Ala Pro Ser 140 Asn Phe Asn Asp Leu I le Ala Giu Gin Ser 125 His Ala Leu Met Leu 205 Giu Giu Giu Ala Phe Giu 110 Giy Lys Ile Met Ala 190 Asp Ser Ala Pro Arg Gln Pro Ser Phe Leu 175 Ser Val Phe Ile Ser Giu Gin Ile Pro Leu 160 Val Pro Ala Pro Pro Ala Cys Asp Leu Arg Vai Leu Ser Lys 195 )on Leu Arg Asp WO 97/12985 PCT/US96/15774 472 Ser His Val Leu His Ser Arg Leu Ser Gin Cys Pro Glu Val His Pro 210 215 220 Leu Pro Thr Pro Val Leu Leu Pro Ala Val Asp Phe Ser Leu Gly Glu 225 230 235 240 Trp Lys Thr Gin Met Glu Glu Thr Lys Ala Gin Asp Ile Leu Gly Ala 245 250 255 Val Thr Leu Leu Leu Glu Gly Val Met Ala Ala Arg Gly Gin Leu Gly 260 265 270 Pro Thr Cys Leu Ser Ser Leu Leu Gly Gin Leu Ser Gly Gin Val Arg 275 280 285 Leu Leu Leu Gly Ala Leu Gin Ser Leu Leu Gly Thr Gln Leu Pro Pro 290 295 300 Gin 305 INFORMATION FOR SEQ ID NO: 224: SEQUENCE CHARACTERISTICS: LENGTH: 305 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 224: Ala Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg 1 5 10 Pro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp Val 25 Ser Ile Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu Ser Phe 40 Val Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly Ile Glu Ala Ile 55 Leu Arg Asn Leu Gin Pro Cys Leu Pro Ser Ala Thr Ala Ala Pro Ser 70 75 Arg His Pro Ile Ile Ile Lys Ala Gly Asp Trp Gin Glu Phe ArgGlu 90 WO 97/1 2985 PCTIUS96/1 5774 473 Lys Leu Thr Phe Tyr Leu Val Thr Leu Giu Gin Aia Gin Giu Gin Gin I Vu 110 Tyr Ser Asn 145 Ser Gly Ala Ser Leu 225 Trp Val Pro Vai Thr 130 Met Phe Gly Pro His 210 Pro Lys Thr Thr Giu 115 Ile Gly Gin Ser Pro 195 Val Thr Thr Leu Cys 275 Gly Asn Arg His Thr 180 Ala Leu Pro Gin Leu 260 Leu Gly Pro Thr Leu 165 Leu Cys His Vali Met 245 Leu Ser Giy Ser Thr 150 Leu Cys Asp Ser Leu 230 Glu Glu Ser Gly Pro 135 Ala Arg Vai Leu Arg 215 Leu Glu Gly Leu Ser 120 Pro His Gly Arg Arg 200 Leu Pro Thr Val1 Leu 280 Pro Ser L-ys Lys Giu 185 Val1 Ser Ala Lys Met 265 Gly Gly Lys Asp Vai 170 Phe Leu Gin Vai Ala 250 Ala Gin Glu Glu Pro 155 Arg Gly Ser Cys Asp 235 Gin Ala Leu Pro Ser 140 Asn Phe Asn Lys Pro 220 Phe Asp Arg Ser Ser 125 His Ala Leu Met Leu 205 Glu Ser Ile Gly Gly 285 Giy Lys Ile Met Ala 190 Leu Val Leu Leu Gin 270 Gin Pro Ile Ser Pro Phe Leu 160 Leu Val 175 Ser Pro Arg Asp His Pro Gly Giu 240 Gly Ala 255 Leu Gly Val Arg Leu Leu Leu Gly Ala Leu Gin Ser Leu Leu Giy Thr Gin Leu Pro Pro 290 295 300 Gin 305 INFORMATION FOR SEQ ID NO: 225: SEQUENCE CHARACTERISTICS: LENGTH: 305 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: protein WO 97/12985 PCTIUS96/1 5774 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 225: Al a Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg Pro Ser Val Leu Arg Lys Tyr Ser Asn 145 Gly Arg Arg Leu Pro 225 Thr Pro Ile Arg Arg His Leu Val Thr 130 Me t Lys Glu Val1 Ser 210 Al a Lys *Ala Leu Ala Asn Pro Thr Glu 115 Ile Asp Val Phe Leu 195 Gin Val Ala Pro Met Val1 Leu Ile Phe 100 Gly Asn Pro Arg Gly 180 Ser Cys Asp Gin Leu Asp Lys Gin Ile Tyr Gly Pro Asn Phe 165 Asn Lys Pro Phe Asp 245 Leu Arg Asn Pro 70 Ile Leu Gly Ser Ala 150 Leu Met Leu Glu Ser 230 Ile Asp Asn Leu 55 Cys Lys Val Gly Pro 135 Ile Met Ala Leu Val 215 Leu Leu Pro Leu 40 Giu Leu Ala Thr Ser 120 Pro Phe Leu Ser Arg.

200 His Gly Giy Asn 25 Arg Asn Pro Gly Leu 105 Pro Ser Leu Val Pro 185 Asp Pro Glu Ala 10 Asn Leu Ala Ser Asp 90 Giu Gly Lys Ser Gly 170 Ala Ser Leu Trp Val1 250 Leu Pro Ser Ala 75 Trp, Gin Giu Glu Phe 155 Gly Pro His Pro Lys 235 Thr Asn Asn Gly Thr Gin Ala Pro Ser 140 Gin Ser Pro Val Thr 220 Thr Leu Asp Leu Ile Ala Giu Gin Ser 125 His His Thr Ala Leu 205 Pro Gin Leu Giu Glu Giu Ala Phe Giu 110 Giy Lys Leu Leu Cys 190 His Val Met Leu Asp Ser Ala Pro Arg Gin Pro Ser Leu Cys 175 Asp Ser Leu Giu Glu 255 Val Phe Ile Ser Glu Gin Ile Pro Arg 160 Val1 Leu A.rg Eeu "lu Val Met Ala Ala Arg Giy Gin Leu Gly Pro Thr Cys Leu Ser Ser Leu 260 270 WO 97/12985 PCT/US96/15774 475 Leu Gly Gin Leu Ser Gly Gin Val Arg Leu Leu Leu Gly Ala Leu Gin 275 280 285 Ser Leu Leu Gly Thr Gin Leu Pro Pro Gin Gly Arg Thr Thr Ala His 290 295 300 Lys 305 INFORMATION FOR SEQ ID NO: 226: SEQUENCE CHARACTERISTICS: LENGTH: 305 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 226: Ala Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg 1 5 10 Pro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp Val 25 Ser Ile Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu Ser Phe 40 Val Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly Ile Glu Ala Ile 55 Leu Arg Asn Leu Gin Pro Cys Leu Pro Ser Ala Thr Ala Ala Pro Ser 70 75 Arg His Pro Ile Ile Ile Lys Ala Gly Asp Trp Gin Glu Phe Arg Glu 90 Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu Gin Ala Gin Glu Gin Gin 100 105 110 Tyr Val Glu Gly Gly Gly Gly Ser Pro Gly Glu Pro Ser Gly Pro Ile 115 120 125 Ser Thr Ile Asn Pro Ser Pro Pro Ser Lys Glu Ser His Lys Ser Pro 130 135 140 Asn Met Ala Ile Phe Leu Ser Phe Gin His Leu Leu Arg Gly Lys Val 145 150 155 160 WO 97/12985 PCTIUS96/15774 476 Arg Phe Leu Met Leu Val Gly Gly Ser Thr Leu Cys Val Arg Glu Phe 165 170 175 Gly Asn Met Ala Ser Pro Ala Pro Pro Ala Cys Asp Leu Arg Val Leu 180 185 190 Ser Lys Leu Leu Arg Asp Ser His Val Leu His Ser Arg Leu Ser Gin 195 200 205 Cys Pro Glu Val His Pro Leu Pro Thr Pro Val Leu Leu Pro Ala Val 210 215 220 Asp Phe Ser Leu Gly Glu Trp Lys Thr Gin Met Glu Glu Thr Lys Ala 225 230 235 240 Gin Asp Ile Leu Gly Ala Val Thr Leu Leu Leu Glu Gly Val Met Ala 245 250 255 Ala Arg Gly Gin Leu Gly Pro Thr Cys Leu Ser Ser Leu Leu Gly Gin 260 265 270 Leu Ser Gly Gin Val Arg Leu Leu Leu Gly Ala Leu Gln Ser Leu Leu 275 280 285 Gly Thr Gin Leu Pro Pro Gin Gly Arg Thr Thr Ala His Lys Asp Pro 290 295 300 Asn 305 INFORMATION FOR SEQ ID NO: 227: SEQUENCE

CHARACTERISTICS:

LENGTH: 309 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 227: Ala Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg 1 5 10 Pro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp Val 25 Ser Ile Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu Ser Phe 40 WO 97/12985 PCTIUJS96/1 5774 Val Arg Ala Val Lys Asri Lea Giu Asn Ala Ser Gly Ile Gia Ala Ile Leu Arg Lys Tyr Ser Asn 145 Gly Giy Leu Val Pro 225 Leu Val Asn Lys Pro 305 Arg His Leu Val1 Thr 130 Met Gia Ala Gly Arg 210 Pro Ser Gly Met Leu 290 Giu Asn Leu Pro Ile Thr Phe 100 Gla Gly 115 Ile Asn Leu Pro Trp Lys Val Thr 180 Pro Thr 195 Lea Leu Gin Gly Phe Gin Giy Ser 260 Ala Ser 275 Leu Arg Val His Gin Ile Tyr Gly Pro Thr Thr 165 Lea Cys Lea Arg His 245 Thr Pro Asp Pro Pro 70 Ile Leu Gly Ser Pro 150 Gin Leu Lea Gly Thr 230 Leu Leu Ala Ser Cys Lys Vai Gly Pro 135 Vai Met Leu Ser Ala 215 Thr Lea Cys Pro Lea Ala Thr Ser 120 Pro Lea Giu Gia Ser 200 Leu Ala Arg Val Pro 280 Pro Gly Lea 105 Pro Ser Leu Giu Gly 185 Lea Gin His Gly Arg 265 Ala Ser Asp 90 Giu Gly Lys Pro Thr 170 Val1 Lea Ser Lys Lys 250 Gia Cys Ala 75 Trp, Gin Gia Gia Aia 155 Lys Met Gly Lea Asp 235 Val Phe Asp Thr Gin Ala Pro Ser 140 Vai Ala Ala Gin Lea 220 Pro Arg Gly Leu Ala Giu Gin Ser 125 His Asp Gin Ala Lea 205 Gly Asn Phe Gly Arg 285 Ala Phe Gia 110 Gly Lys Phe Asp Arg 190 Ser Thr Ala Lea Asn 270 Vai Pro Arg Gin Pro Ser Ser Ile 175 Giy Gly Gin Ile Met 255 Giy Lea Ser Gia Gin Ile Pro Lea 160 Lea Gin Gin Lea Phe 240 Lea Gly Ser His Val Lea His Ser Arg Lea Ser Gin Cys 295 INFORMATION FOR SEQ ID NO: 228: SEQUENCE CHARACTERISTICS: WO 97/12985 PCT/US96/15774 478 LENGTH: 309 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 228: Ala Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg 1 5 10 Pro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp Val 25 Ser Ile Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu Ser Phe 40 Val Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly Ile Glu Ala Ile 55 Leu Arg Asn Leu Gin Pro Cys Leu Pro Ser Ala Thr Ala Ala Pro Ser 70 75 Arg His Pro Ile Ile Ile Lys Ala Gly Asp Trp Gin Glu Phe Arg Glu 90 Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu Gin Ala Gin Glu Gin Gin 100 105 110 Tyr Val Glu Gly Gly Gly Gly Ser Pro Gly Glu Pro Ser Gly Pro Ile 115 120 125 Ser Thr Ile Asn Pro Ser Pro Pro Ser Lys Glu Ser His Lys Ser Pro 130 135 140 Asn Met Leu Pro Thr Pro Val Leu Leu Pro Ala Val Asp Phe Ser Leu 145 150 155 160 Gly Glu Trp Lys Thr Gin Met Glu Glu Thr Lys Ala Gin Asp Ile Leu 165 170 175 Gly Ala Val Thr Leu Leu Leu Glu Gly Val Met Ala Ala Arg Gly Gin 180 185 190 Leu Gly Pro Thr Cys Leu Ser Ser Leu Leu Gly Gin Leu Ser Gly Gin 195 200 205 Val Arg Leu Leu Leu Gly Ala Leu Gin Ser Leu Leu Gly Thr Gin Leu 210 215 220 WO 97/12985 PCT/US96/15774 479 Pro Pro Gin Gly Arg Thr Thr Ala His Lys Asp Pro Asn Ala Ile Phe 225 230 235 240 Leu Ser Phe Gin His Leu Leu Arg Gly Lys Val Arg Phe Leu Met Leu 245 250 255 Val Gly Gly Ser Thr Leu Cys Val Arg Glu Phe Gly Gly Asn Gly Gly 260 265 270 Asn Met Ala Ser Pro Ala Pro Pro Ala Cys Asp Leu Arg Val Leu Ser 275 280 285 Lys Leu Leu Arg Asp Ser His Val Leu His Ser Arg Leu Ser Gln Cys 290 295 300 Pro Glu Val His Pro 305 INFORMATION FOR SEQ ID NO: 229: SEQUENCE CHARACTERISTICS: LENGTH: 309 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 229: Ala Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg 1 5 10 Pro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp Val 25 Ser Ile Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu Ser Phe 40 Val Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly Ile Glu Ala Ile 55 Leu Arg Asn Leu Gin Pro Cys Leu Pro Ser Ala Thr Ala Ala Pro Ser 70 75 Arg His Pro Ile Ile Ile Lys Ala Gly Asp Trp Gin Glu Phe Arg Glu 90 Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu Gin Ala Gin Glu Gin Gin 100 105 110 WO 97/12985 PCT/US96/1577 4 480 Tyr Val Glu Gly Gly Gly Gly Ser Pro Gly Glu Pro Ser Gly Pro Ile 115 120 125 Ser Thr Ile Asn Pro Ser Pro Pro Ser Lys Glu Ser His Lys Ser Pro 130 135 140 Asn Met Val Leu Leu Pro Ala Val Asp Phe Ser Leu Gly Glu Trp Lys 145 150 155 160 Thr Gin Met Glu Glu Thr Lys Ala Gin Asp Ile Leu Gly Ala Val Thr 165 170 175 Leu Leu Leu Glu Gly Val Met Ala Ala Arg Gly Gin Leu Gly Pro Thr 180 185 190 Cys Leu Ser Ser Leu Leu Gly Gin Leu Ser Gly Gin Val Arg Leu Leu 195 200 205 Leu Gly Ala Leu Gin Ser Leu Leu Gly Thr Gin Leu Pro Pro Gin Gly 210 215 220 Arg Thr Thr Ala His Lys Asp Pro Asn Ala Ile Phe Leu Ser Phe Gin 225 230 235 240 His Leu Leu Arg Gly Lys Val Arg Phe Leu Met Leu Val Gly Gly Ser 245 250 255 Thr Leu Cys Val Arg Glu Phe Gly Gly Asn Gly Gly Asn Met Ala Ser 260 265 270 Pro Ala Pro Pro Ala Cys Asp Leu Arg Val Leu Ser Lys Leu Leu Arg 275 280 285 Asp Ser His Val Leu His Ser Arg Leu Ser Gin Cys Pro Glu Val His 290 295 300 Pro Leu Pro Thr Pro 305 INFORMATION FOR SEQ ID NO: 230: SEQUENCE

CHARACTERISTICS:

LENGTH: 309 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 230: Wn 0'7/1')Ggr wn O~11OQAPCTIUS96/1 5774 481 Ala Asn Cys Ser Ile Met Ile Asp Giu Ile Ile His His Leu Lys Arg 1 Pro Ser Val Leu Arg Lys Tyr Ser Asn 145 Glu Gly Leu Gin His 225 Gly Arg Pro Ile Arg Arg His Leu Val1 Thr 130 Met Thr Val Leu Ser 210 Lys Lays 31u Ala Leu Ala Asn Pro Thr Giu 115 Ile Ala Lys Met Gly 195 Leu Asp Val I Phe C 2 Pr Met Val Leu Ile Phe 100 Gly Asn Val Alia kla 180 .ln jeu ?ro ~rg ~60 Leu Asp Lys IGin Ile Tyr Giy Pro Asp Gin 165 Ala Leu Gly Asn Phe 245 Gly Leu Arg Asn Pro 70 Ile Leu Gly Ser Phe 150 Asp Arg Ser l'hr Ala 230 Leu ksn *Asp Asn Leu 55 Cys Lys Val Gly Pro 135 Ser Ile Gly Gly GinI 215 Ile Met I Gly C Prc LeL 40 Git Leu Ala Thr Ser 120 Pro Leu Leu 'ln jeu ?he ~eu Ily Asn 25 1Arg Asn Pro Gly Leu 105 Pro Ser Gly Gly Leu 185 Val ProI Leu Val C 2 Asn D~ 265 Asr Leu Ala Ser Asp 90 Glu Gly Lys Glu Alia 170

G

1 y krg ?ro 3er ily ~50 ~et Let Prc Ser Ala 75 Trp, Gin Giu Giu Trp, 155 Val Pro Leu Gin Phe 235 Gly Ala j Asn Asn 7Gly Thr Gin Ala Pro Ser 140 Lys Thr Thr Leu Gly 220 Gin F Ser TI Ser P AsI LeL Ile Ala Giu Gin Ser 125 His rhr ELeu :ys jeu ~rg lis ~hr ~ro )Giu Giu Ala Phe Giu 110 Gly Lys Gin Leu Leu 190 Gly Thr Leu Leu AlaI AsI Seit Ala Pro Arg Gin Pro Ser Met Leu 175 Ser la I'hr Leu ys 255 ?ro Val Phe Ile Ser Giu Gin Ile Pro Giu 160 Giu Ser Leu Ala Arg 240 Val Pro Ala Cys Asp 275 Leu Arg Val Leu Ser 280 Lys Leu Leu Arg Asp Ser His Val WO 97/12985 PCT/US96/157 7 4 482 Leu His Se Arg Leu Ser Gin Cys Pro Glu Val His Pro Leu Pro Thr 290 295 300 Pro Val Leu Leu Pro 305 INFORMATION FOR SEQ ID NO: 231: SEQUENCE

CHARACTERISTICS:

LENGTH: 309 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 231: Ala Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg 1 5 10 Pro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp Val 25 Ser Ile Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu Ser Phe 40 Val Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly Ile Glu Ala Ile 55 Leu Arg Asn Leu Gin Pro Cys Leu Pro Ser Ala Thr Ala Ala Pro Ser 70 75 Arg His Pro Ile Ile Ile Lys Ala Gly Asp Trp Gin Glu Phe Arg Glu 90 Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu Gin Ala Gin Glu Gin Gin 100 105 110 Tyr Val Glu Gly Gly Gly Gly Ser Pro Gly Glu Pro Ser Gly Pro Ile 115 120 125 Ser Thr Ile Asn Pro Ser Pro Pro Ser Lys Glu Ser His Lys Ser Pro 130 135 140 Asn Met Asp Phe Ser Leu Gly Glu Trp Lys Thr Gin Met Glu Glu Thr 145 150 155 160 Lys Ala Gin Asp Ile Leu Gly Ala Val Thr Leu Leu Leu Glu Gly Val 165 170 175 WO 97/12985 PCT/US96/15774 483 Met Ala Ala Arg Gly Gin Leu Gly Pro Thr Cys Leu Ser Ser Leu Leu 180 185 190 Gly Gin Leu Ser Gly Gin Val Arg Leu Leu Leu Gly Ala Leu Gin Ser 195 200 205 Leu Leu Gly Thr Gin Leu Pro Pro Gin Gly Arg Thr Thr Ala His Lys 210 215 220 Asp Pro Asn Ala Ile Phe Leu Ser Phe Gin His Leu Leu Arg Gly Lys 225 230 235 240 Val Arg Phe Leu Met Leu Val Gly Gly Ser Thr Leu Cys Val Arg Glu 245 250 255 Phe Gly Gly Asn Gly Gly Asn Met Ala Ser Pro Ala Pro Pro Ala Cys 260 265 270 Asp Leu Arg Val Leu Ser Lys Leu Leu Arg Asp Ser His Val Leu His 275 280 285 Ser Arg Leu Ser Gin Cys Pro Glu Val His Pro Leu Pro Thr Pro Val 290 295 300 Leu Leu Pro Ala Val 305 INFORMATION FOR SEQ ID NO: 232: SEQUENCE

CHARACTERISTICS:

LENGTH: 309 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 232: Ala Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg 1 5 10 Pro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp Val 25 Ser Ile Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu Ser Phe 40 Val Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly Ile Glu Ala Ile 55 WO 97/12985 PCTIUS96/157 7 4 Leu Arg Asn Leu Gin Pro Cys Leu Pro Ser 70 Ala Thr Ala Ala Pro Ser 7 r Arg His Pro Ile Ile Ile Lys Ala Gly Asp Trp Gin Glu 90 Phe Arg Glu Lys Tyr Ser Asn 145 Ile Gly Gly Gin 225 Met Gly Leu Gin C Val P 305 Let Val Thr 130 Met Leu Gin Gin Leu 210 Phe Leu 2 ily 3er ~ys

LSP

iTh: -Gli Giy Leu Val 195 Pro Leu Val Asn Lys 275 Pro Phe r Ph -i Gl Asi Git Ala Gly 180 Arg Pro Ser Gly Met 260 Leu Glu Ser e Tyr 0 Ir Gly -i Pro Trp Val 165 Pro 9J Leu L Gin G Phe G 2 Giy S 245 Ala S Leu A Val H.

Leu Lei.

Gli Ser Lays 150 ['hr :hr ~eu ~ly in 30 er er IVa.

Gl~ Prc 135 Thr Leu Cys Leu Arg 215 His Thr 1 Thr SSer 120 Pro Gin Leu Leu Giy.

200 Thr Leu Leu Lei.

1 05 Prc Ser Met Leu Ser 185 Aia Thr Leu 2ys 1Glu Gly Lys Giu Glu 170 Ser Leu Ala Arg Val 250 Pro Gin Giu Glu Ala Gin Pro Ser 125 Ser His Glu 110 Gly Lys Gin Pro Ser Gin Ile Pro Giu 155 Gly Leu Gin His Gly 235 krg *Thr *Val Leu Ser Lys 220 Lys Giu Cys Lys Ae~t Giy Leu 205 Asp Val Phe Asp Al a Ala Gin 190 Leu Pro Arg Gly Gir Ala 175 Leu Gly Asn Phe Gly 255 Asp 160 *Arg Ser Thr Ala Leu 240 Asn 265 Le270 a rg is Asp Pro 295 His Pro Val Thr Leu Pro His Val 300 Ser 285 Leu Arg Leu INFORMATION FOR SEQ ID NO: 233: SEQUENCE

CHARACTERISTICS:

LENGTH: 309 amino acids TYPE: amino acid STRANDEDNESS: single WO 97/12985 PCTIUS96/15774 TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 233: Ala Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His LeL Pro Ser Val Leu Arg Lys Tyr Ser Asn 145 Gin Leu Phe Leu Gly 225 Pro Ile Arg Arg His Leu Val Thr 130 Met Val Pro ELeu Val 210 *Ala Leu Ala Asn Pro Thr Giu 115 Ile Giy Arg Pro Ser 195 Gly Pro Met Val Leu Ile Phe 100 Gly Asn Pro Leu Gin 180 Phe Gly Leu Asp Lys Gin Ile Tyr Gly Pro Thr Leu 165 Gly.

Gin Ser Leu Arg Asn Pro 70 Ile Leu Gly Ser Cys 150 Leu Arg His Thr Asp Asn Leu 55 Cys Lys Vai Gly Pro 135 Leu Gly.

Thr Leu Leu 215 Pro Leu 40 Glu Leu Ala Thr Ser 120 Pro Ser Al a Thr £seu 200 Dys Asn 25 Arg Asn Pro Giy Leu 105 Pro Ser Ser Leu Ala 185 Arg Val Asy Lei.

Ala Sex Asp 90 Glu Giy Lys Leu Gin 170 His Gly Arg ~Leu Pro Ser Ala 75 Trp Gin Glu Giu Leu 155 Ser Lys Lys Giu Cys 1 235 Asn Asn Gly Thr Gin Ala Pro Ser 140 21 y Leu ksp la 1 ?he Asr Leu 1 Le Ala Giu Gin Ser 125 His Gin Leu Pro Arg 205 Gly Glu Giu Giu Ala Phe Glu 110 Gly Lys Leu Gly Asn.

190 Phe Gly Ly As1 Ser Ala Pro Arg Gin Pro Ser Ser Thr 175 Al a Lou ksn Arg Val Phe Ile Ser Giu Gn Ilie Pro Gly 160 Gin Ile Met Gly Leu 240 ksn Met Ala Ser Pro Ala Pro Pro Ala ~sp Leu Arg Val- WO 97/12985 PCT/US96/15774 Ser Lys Leu Leu Arg Asp Ser His 245 Cys Pro Glu Val His Pro Leu Pro 260 Asp Phe Ser Leu Gly Glu Trp Lys 275 280 Gin Asp Ile Leu Gly Ala Val Thr 290 295 Ala Arg Gly Gin Leu 305 INFORMATION FOR SEQ ID NO: 234: SEQUENCE

CHARACTERISTICS:

LENGTH: 309 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: protein Val Leu His Ser Arg Let 250 Thr Pro Val Leu Leu Pr 265 27( Thr Gin Met Glu Glu Thr 285 Leu Leu Leu Glu Gly Val 300 I Ser Gin 255 SAla Val Lys Ala Met Ala Lys Arg Asp Val Ser Phe Ala Ile Pro Ser Arg Glu Gin Gin Pro Ile (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 234: Ala Asn Cys Ser Ile Met Ile Asp Glu Ile Ile 1 5 10 Pro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu 25 Ser Ile Leu Met Asp Arg Asn Leu Arg Leu Pro 40 Val Arg Ala Val Lys Asn Leu Glu Asn Ala Ser 55 Leu Arg Asn Leu Gin Pro Cys Leu Pro Ser Ala 70 75 Arg His Pro Ile Ile Ile Lys Ala Gly Asp Trp 90 Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu Gin 100 105 Tyr Val Glu Gly Gly Gly Gly Ser Pro Gly Glu 115 120 His His Asn Asp Asn Leu Gly Ile Thr Ala Gin Glu Ala Gin Pro Ser 125 Leu Glu Glu Glu Ala Phe Glu 110 Gly WO 97/12985 PCT/US96/15774 Ser Thr 130 Asn Met 145 Asp Pro Val Arg Phe Gly Asp Leu 210 Ser Arg 225 Leu Leu Glu Glu Glu Gly Ser Leu 290 Leu Gin 305 Ile Asn Pro Gly Thr Gin Asn Ala Ile 165 Phe Leu Met 180 Gly Asn Gly 195 Arg Val Leu Leu Ser Gin Pro Ala Val 245 Thr Lys Ala 260 Val Met Ala 275 Leu Gly Gin Ser Leu Leu Ser Pro 135 Leu Pro 150 Phe Leu Leu Val Gly Asn Ser Lys 215 Cys Pro 230 Asp Phe Gin Asp Ala Arg Leu Ser 295 Pro Ser Lys Glu Ser His Lys Ser Pro Pro Ser Gly Met 200 Leu Glu Ser Ile Gly 280 Gly Gin Phe Gly 185 Ala Leu Val Leu Leu 265 Gin Gin Gly Gin 170 Ser Ser Arg His Gly 250 Gly Leu Val Arg 155 His Thr Pro Asp Pro 235 Glu Ala Gly Arg Thr Leu Leu Ala Ser 220 Leu Trp Val Pro Leu 300 Thr Leu Cys Pro 205 His Pro Lys Thr Thr 285 Leu Ala Arg Val 190 Pro Val Thr Thr Leu 270 Cys Leu His Gly 175 Arg Ala Leu Pro Gin 255 Leu Leu Gly Lys 160 Lys Glu Cys His Val 240 Met Leu Ser Ala INFORMATION FOR SEQ ID NO: 235: SEQUENCE CHARACTERISTICS: LENGTH: 309 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 235: Ala Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg 1 5 10 WO 97/12985 PCT/US96/15774 488 Pro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp Val 25 Ser Ile Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu Ser Phe 40 Val Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly Ile Glu Ala Ile 55 Leu Arg Asn Leu Gin Pro Cys Leu Pro Ser Ala Thr Ala Ala Pro Ser 70 75 Arg His Pro Ile Ile Ile Lys Ala Gly Asp Trp Gin Glu Phe Arg Glu 90 Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu Gin Ala Gin Glu Gin Gin 100 105 110 Tyr Val Glu Gly Gly Gly Gly Ser Pro Gly Glu Pro Ser Gly Pro Ile 115 120 125 Ser Thr Ile Asn Pro Ser Pro Pro Ser Lys Glu Ser His Lys Ser Pro 130 135 140 Asn Met Gly Arg Thr Thr Ala His Lys Asp Pro Asn Ala Ile Phe Leu 145 150 155 160 Ser Phe Gin His Leu Leu Arg Gly Lys Val Arg Phe Leu Met Leu Val 165 170 175 Gly Gly Ser Thr Leu Cys Val Arg Glu Phe Gly Gly Asn Gly Gly Asn 180 185 190 Met Ala Ser Pro Ala Pro Pro Ala Cys Asp Leu Arg Val Leu Ser Lys 195 200 205 Leu Leu Arg Asp Ser His Val Leu His Ser Arg Leu Ser Gin Cys Pro 210 215 220 Glu Val His Pro Leu Pro Thr Pro Val Leu Leu Pro Ala Val Asp Phe 225 230 235 240 Ser Leu Gly Glu Trp Lys Thr Gin Met Glu Glu Thr Lys Ala Gin Asp 245 250 255 Ile Leu Gly Ala Val Thr Leu Leu Leu Glu Gly Val Met Ala Ala Arg 260 265 270 Gly Gin Leu Gly Pro Thr Cys Leu Ser Ser Leu Leu Gly Gin Leu Ser 275 280 285 Gly Gin Val Arg Leu Leu Leu Gly Ala Leu Gin Ser Leu Leu Gly Thr 290 295 300 WO 97/12985 489 Gin Leu Pro Pro Gin 305 INFORMATION FOR SEQ ID NO: 236: Ci) SEQUENCE

CHARACTERISTICS:

LENGTH: 309 amino acids TYPE: amino acid STRANDEDNESS. single TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 236: PCT/US96/1 5774 Ala Asn Cys Ser Ile Met Ile Asp Giu Ile Ile His ffis Leu Lys Arg Pro Ser Val1 Leu Arg Lys Tyr Ser Asn 145 Leu Pro Ile Arg Arg His Leu Val Thr 130 Met Leu Ala Leu Ala Asn Pro Thr Glu 115 Ile Ala Arg Pro Met Val Leu Ile Phe 100 Gly Asn His Gly Leu Asp Lys Gin Ile Tyr Gly Pro Lys Lys 165 Leu Arg Asn Pro 70 Ile Leu Giy Ser Asp 150 Val Asp Asn Leu 55 Cys Lys Val Gly Pro 135 Pro Arg Pro Leu 40 Giu Leu Ala Thr Ser 120 Pro Asn.

Phe Asn 25 Arg Asn Pro Gly Leu 105 Pro Ser Ala Leu 10 Asn.

Leu Ala Ser Asp 90 Giu Gly Lys Ile Met Leu Pro Ser Ala 75 Trp Gin Giu Glu Phe 155 Leu Asn Asn Gly Thr Gin Ala Pro Ser 140 Leu Val Asp Leu Ile Ala Glu Gin Ser 125 His Ser Giy Glu Giu Giu Ala Phe Giu 110 Gly Lys Phe Gly Asp Ser Ala Pro Arg Gin Pro Ser Gin Ser Val Phe Ile Ser Glu Gin.

Ile Pro His 160 Thr Leu Cys Val Arg Giu Phe Gly Gly ASn Gly Gly Asn Met Ala Ser Pro 180 190 WO 97/12985 PCT/US96/15774 490 Ala Pro Pro Ala Cys Asp Leu Arg Val Leu Ser Lys Leu Leu Arg Asp 195 200 205 Ser His Val Leu His Ser Arg Leu Ser Gin Cys Pro Glu Val His Pro 210 215 220 Leu Pro Thr Pro Val Leu Leu Pro Ala Val Asp Phe Ser Leu Gly Glu 225 230 235 240 Trp Lys Thr Gin Met Glu Glu Thr Lys Ala Gin Asp Ile Leu Gly Ala 245 250 255 Val Thr Leu Leu Leu Glu Gly Val Met Ala Ala Arg Gly Gin Leu Gly 260 265 270 Pro Thr Cys Leu Ser Ser Leu Leu Gly Gin Leu Ser Gly Gin Val Arg 275 280 285 Leu Leu Leu Gly Ala Leu Gin Ser Leu Leu Gly Thr Gin Leu Pro Pro 290 295 300 Gin Gly Arg Thr Thr 305 INFORMATION FOR SEQ ID NO: 237: SEQUENCE

CHARACTERISTICS:

LENGTH: 309 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 237: Ala Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg 1 5 10 Pro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp Val 25 Ser Ile Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu Ser Phe 40 Val Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly Ile Glu Ala Ile 55 Leu Arg Asn Leu Gin Pro Cys Leu Pro Ser Ala Thr Ala Ala Pro Ser 70 75 WO 97/12985 PCTIUS96/15774 Arg His Pro Ile Ile Ile Lys Ala Gly Asp Trp Gin Giu Phe 90 Arg Giu Lys Tyr Ser Asn 145 Gly Arg Ala Leu Pro 225 Gin Leu Leu Gly Thr 305 Leu Thr Vai Glu 115 Thr Ile 130 Met Asp Lys Val Giu Phe Cys Asp 195 His Ser 210 Val Leu Met Giu Leu Giu Ser Ser 275 Aia Leu 290 Thr Ala Phe Tyr Leu Val 100 Giy Gly Gly Gly Asn Pro Ser Pro 135 Pro Asn Ala Ile 150 Arg Phe Leu Met 165 Gly Gly Asn Gly 180 Leu Arg Val Leu Arg Leu Ser Gin 215 Leu Pro Ala Val 230 Giu Thr Lys Ala 245 Gly Val Met Ala 260 Leu Leu Gly Gin Gin Ser Leu Leu 295 His Lys Thr Ser 120 Pro Phe Leu Gly Ser 200 Cys Asp Gin.

Ala.

Leu 280 Leu 105 Pro Ser Leu Val Asn 185 Lys Pro Phe Asp Arg 265 Ser Giu Gly Lys Ser Gly 170 Met Leu Giu Ser Ile 250 Gly Gly Gir Giu Giu Phe 155 Giy Ala Leu Val Leu 235 Leu Gln Gln Ala Pro Ser 140 Gin Ser Ser Arg His 220 Gly Gly Leu Vai Pro 300 Gin Ser 125 His His Thr 15ro Asp 205 Pro Giu Ala

G

1 y Arg 285 Glu 110 Gly Lys Leu Leu Ala 190 Ser Leu Trp, Val Pro 270 Leu Gin Pro Ser Leu Cys 175 Pro His Pro Lys Thr 255 Thr Leu Gin Ile Pro Arg 160 Val Pro Val Thr Thr 240 Leu Cys Leu Giy Thr Gin Leu Pro Gin Giy Arg INFORMATION FOR SEQ ID NO: 238: SEQUENCE

CHARACTERISTICS:

LENGTH: 309 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: protein WO 97/12985 PCT/US96/15774 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 238: Ala Asn Cys Ser Ile Met Ile Asp Giu Ile Ile His His Leu Lys Arg 1 r- Pro Ser Val Leu Arg Lys Tyr Ser Asn 145 Arg Gly Leu Arg Leu 225 Pro Ile Arg Arg His Leu Val Thr 130 Met Phe Giy Arg Leu 210 Pro Ala Leu Ala Asn Pro Thr Gin 115 Ile Ala Len Asn Val 195 SerC Ala I Pro Met Val Len Ile Phe 100 Gly Asn Ile M4et "iy 180 Aeu 31n Tal Leu Asp Lys Gin Ile Tyr Gly Pro Phe Leu 165 Gly Ser Cys Asp Leu Arg Asn Pro 70 Ile Leu Gly Ser Leu 150 Val k.sn ys ?ro ?he ~30 Asp Asn Leu 55 Cys Lys Val Gly Pro 135 Ser Gly Met Leu Gin 215 Ser Prc Leu 40 Glu Len Ala Thr Ser 120 Pro Phe Gly Ala Leu 200 vTa 1 eu Asn 25 1Arg Asn Pro Gly Leu 105 Pro Ser Gin Ser Ser 185 Arg His Gly Asr Leu Ala Ser Asp 90 Gin Gly Lys His Thr 170 Pro Pro 3mu 1Leu Pro Ser Ala 75 Trp Gin Gin Gin Leu 155 Leu Ala Ser Leu Trp I 235 Asr Asr G 1y Thr Gin Ala Pro Ser 140 Leu Cys Pro Hs Pro 220 1AsI 1Lei Giu Gin Ser 125 His Arg Val Pro Val1 205 Thr Thr )Gin 1Gin Glu Ala *Phe *Giu 110 Gly Lys Gly Arg Ala 190 Leu Pro Gin D' Asr Ser Ala Pro Arg Gin Pro Ser L~ys G1u 175 :ys .iis Tal ~et Val Phe Ile Ser Glu Gin Ile Pro Val1 160 Phe Asp Ser Leu Giu Gin Thr Lys Ala Gin 245 Asp Ile Leu Gly Ala 250 Val Thr Leu Leu Len Gin 255 WO 97/12985 PCT/US96/15774 493 Gly Val Met Ala Ala Arg Gly Gln Leu Gly Pro Thr Cys Leu Ser Ser 260 265 270 Leu Leu Gly Gin Leu Ser Gly Gin Val Arg Leu Leu Leu Gly Ala Leu 275 280 285 Gin Ser Leu Leu Gly Thr Gin Leu Pro Pro Gin Gly Arg Thr Thr Ala 290 295 300 His Lys Asp Pro Asn 305 INFORMATION FOR SEQ ID NO: 239: SEQUENCE

CHARACTERISTICS:

LENGTH: 302 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 239: Ala Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg 1 5 10 Pro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp Val 25 Ser Ile Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu Ser Phe 40 Val Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly Ile Glu Ala Ile 55 Leu Arg Asn Leu Gin Pro Cys Leu Pro Ser Ala Thr Ala Ala Pro Ser 70 75 Arg His Pro Ile Ile Ile Lys Ala Gly Asp Trp Gin Glu Phe Arg Glu 90 Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu Gin Ala Gin Glu Gin Gin 100 105 110 Tyr Val Glu Gly Gly Gly Gly Ser Pro Gly Glu Pro Ser Gly Pro Ile 115 120 125 Ser Thr Ile Asn Pro Ser Pro Pro Ser Lys Glu Ser His Lys Ser Pro 130 135 140 WO 97/12985 PCT/US96/15774 494 Asn Met Asp Pro Asn Ala Ile Phe Leu Ser Phe Gin His Leu Leu Arg 145 150 155 160 Gly Lys Val Arg Phe Leu Met Leu Val Gly Gly Ser Thr Leu Cys Val 165 170 175 Arg Glu Phe Gly Gly Asn Met Ala Ser Pro Ala Pro Pro Ala Cys Asp 180 185 190 Leu Arg Val Leu Ser Lys Leu Leu Arg Asp Ser His Val Leu His Ser 195 200 205 Arg Leu Ser Gin Cys Pro Glu Val His Pro Leu Pro Thr Pro Val Leu 210 215 220 Leu Pro Ala Val Asp Phe Ser Leu Gly Glu Trp Lys Thr Gin Met Glu 225 230 235 240 Glu Thr Lys Ala Gin Asp Ile Leu Gly Ala Val Thr Leu Leu Leu Glu 245 250 255 Gly Val Met Ala Ala Arg Gly Gin Leu Gly Pro Thr Cys Leu Ser Ser 260 265 270 Leu Leu Gly Gin Leu Ser Gly Gin Val Arg Leu Leu Leu Gly Ala Leu 275 280 285 Gin Ser Leu Leu Gly Thr Gin Gly Arg Thr Thr Ala His Lys 290 295 300 INFORMATION FOR SEQ ID NO: 240: SEQUENCE

CHARACTERISTICS:

LENGTH: 83 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 240: AATTCCGTCG TAAACTGACC TTCTATCTGA AAACCTTGGA GAACGCGCAG

GCTCAACAGT

ACGTAGAGGG CGGTGGAGGC

TCC

83 INFORMATION FOR SEQ ID NO: 241: WO 97/12985 PCT/US96/15774 495 SEQUENCE CHARACTERISTICS: LENGTH: 82 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 241: CCGGGGAGCC TCCACCGCCC TCTACGTACT GTTGAGCCTG CGCGTTCTCC

AAGTTTTCAG

ATAGAAGGTC AGTTTACGAC

GG

82 INFORMATION FOR SEQ ID NO: 242: SEQUENCE

CHARACTERISTICS:

LENGTH: 8 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 242: Gly Gly Gly Ser Gly Gly Gly Ser 1 INFORMATION FOR SEQ ID NO: 243: SEQUENCE

CHARACTERISTICS:

LENGTH: 12 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 243: Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser WO 97/12985 PCT/US96/15774 496 1 5 INFORMATION FOR SEQ ID NO: 244: SEQUENCE

CHARACTERISTICS:

LENGTH: 7 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 244: Ser Gly Gly Ser Gly Gly Ser 1 INFORMATION FOR SEQ ID NO: 245: SEQUENCE

CHARACTERISTICS:

LENGTH: 6 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 245: Glu Phe Gly Asn Met Ala 1 INFORMATION FOR SEQ ID NO: 246: SEQUENCE

CHARACTERISTICS:

LENGTH: 7 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 246: Glu Phe Gly Gly Asn Asn Ala WO 97/12985 PCT/US96/15774 497 1 INFORMATION FOR SEQ ID NO: 247: SEQUENCE CHARACTERISTICS: LENGTH: 10 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 247: Glu Phe Gly Gly Asn Gly Gly Asn Met Ala 1 5 INFORMATION FOR SEQ ID NO: 248: SEQUENCE CHARACTERISTICS: LENGTH: 309 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 248: Ala Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg 1 5 10 Pro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp Val 25 Ser Ile Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu Ser Phe 40 Val Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly Ile Glu Ala Ile 55 Leu Arg Asn Leu Gin Pro Cys Leu Pro Ser Ala Thr Ala Ala Pro Ser 70 75 Arg His Pro Ile Ile Leu Lys Ala Gly Asp Trp Gln Glu Phe Arg Glu 90 Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu Gin Ala Gin Glu Gln Gin WO 97/12985 Tyr Ser Val Thr Glu 115 Ile 100 Gly Asn Gly Pro Gly Ser Gly Pro Ser 120 Pro 105 Pro Ser IPCT[US96,1 5774 110 Pro Ser Gly Pro le 125 Ser His Lys Ser Pro Gly Lys Giu Glu 130 Asn 145 Gly Gly Leu Val Pro 225 Leu Val Asn Met Glu Ala Gly Arg 210 Pro Ser Gly MEet *Leu Trp Val1 Pro 195 Leu Gin Phe Gly Al a Pro Lys Thr 180 Thr Leu Gly Gin Ser 260 Ser Thr Pro 150 Thr Gin 165 Leu Leu Cys Leu Leu Gly Arg Thr 230 His Leu 245 Thr Leu Pro Ala Val Leu Leu Pro Ala Val Asp Phe 155 Ser Leu Met Leu Ser Ala 215 Thr Leu Dys Pro -Glu *Glu Ser 200 Leu Ala Arg Val Pro 280 Glu Gly 185 Leu Gin His Gly A~rg 265 Thr 170 Val Leu Ser Lys Lys 250 Glu Lys Met Gly Leu Asp 235 Val Phe Ala Ala Gn Leu 220 Pro Arg Gly Asn Ala Leu f Gly Asn Phe Gly Asp Arg 190 Ser Thr Ala Leu Asn 270 Ile 175 Gly Gly Gin Ile Met 255 Gly Leu Gin Gin Leu Phe 240 Leu Gly 275 Ala Ser Asp Leu Arg Val Leu Ser Lys Leu Leu Lys Asp Ser His Val Leu His Ser Arg Leu Ser Gin Cys 290 295 300 Pro Glu Val His Pro 305 INFORMATION FOR SEQ ID NO: 249: Wi SEQUENCE

CHARACTERISTICS:

LENGTH: 459 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc ="DNA (synthetic),, WO 97/12985 PCTJUS961 5774 499 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 249: TCTCCCGCTC CGCCTGCTTG TGACCTCCGA GTCCTCAGTA AACTGCTTCG

TGACTCCCAT

GTCCTTCACA GCAGACTGAG CCAGTGCCCA GAGGTTCAcC CTTTGCCTAC

ACCTGTCCTG

120 CTGCCTGCTG TGGACTTTAG CTTGGGAGAA TGGAAAACCC AGATGGAGGA

GACCAAGGCA

180 CAGGACATTC TGGGAGCAGT GACCCTTCTG CTGGAGGGAG TGATGGCAGC

ACGGGGACA

240 CTGGGACCCA CTTGCCTCTC ATCCCTCCTG GGGCAGCTTT CTGGACAGGT

CCGTCTCCTC

300 CTTGGGGCCC TGCAGAGCCT CCTTGGAACC CAGCTTCCTC CACAGGGCAG

GACCACAGCT

360 CACAAGGATC CCAATGCCAT CTTCCTGAGC TTCCAACACC TGCTCCGAGG

AAAGGTGCGT

420 TTCCTGATGC TTGTAGGAGG GTCCACCCTC

TGCGTCAGG

459 INFORMATION FOR SEQ ID NO: 250: SEQUENCE

CHARACTERISTICS:

LENGTH: 447 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 250: TCTCCCGCTC CGCCTGCTTG TGACCTCCGA GTCCTCAGTA AACTGCTTCG

TGACTCCCAT

GTCCTTCACA GCAGACTGAG CCAGTGCCCA GAGGTTCACC CTTTGCCTAC

ACCTGTCCTG

120 CTGCCTGCTG TGGACTTTAG CTTGGGAGAA TGGAAAACCC AGATGGAGGA

GACCAAGGCA

180 CAGGACATTC TGGGAGCAGT GACCCTTCTG CTGGAGGGAG TGATGGCAGC

ACGGGGACAA

240 WO 97/12985 PCTJUS96/1 5774 500 CTGGGACCCA CTTGCCTCTC ATCCCTCCTG GGGCAGCTTT CTGGACAGGT

CCGTCTCCTC

300 CTTGGGGCCC TGCAGAGCCT CCTTGGAACC CAGGGCAGGA CCACAGCTCA

CAAGGATCCC

360 AATGCCATCT TCCTGAGCTT CCAACACCTG CTCCGAGGAA AGGTGCGTTT

CCTGATGCTT

420 GTAGGAGGGT CCACCCTCTG

CGTCAGG

447 INFORMATION FOR SEQ ID NO: 251: SEQUENCE

CHARACTERISTICS:

LENGTH: 459 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc= "DNA (Synthetic).

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 251: TCCCCAGCGC CGCCTGCTTG TGACCTCCGA GTCCTCAGTA AACTGCTTCG

TGACTCCCAT

GTCCTTCACA GCAGACTGAG CCAGTGCCCA GAGGTTCACC CTTTGCCTAC

ACCTGTCCTG

120 CTGCCTGCTG TGGACTTTAG CTTGGGAGAA TGGAAAACCC AGATGGAGGA

GACCAAGGCA

180 CAGGACATTC TGGGAGCAGT GACCCTTCTG CTGGAGGGAG TGATGGCAGC

ACGGGGACAA

240 CTGGGACCCA CTTGCCTCTC ATCCCTCCTG GGGCAGCTTT CTGGACAGGT

'CCGTCTCCTC

300 CTTGGGGCCC TGCAGAGCCT CCTTGGAACC CAGCTTCCTC CACAGGGCAG

GACCACAGCT

360 CACAAGGATC CCAATGCCAT CTTCCTGAGC TTCCAACACC TGCTCCGAGG

AAAGGTGCGT

420 TTCCTGATGC TTGTAGGAGG GTCCACCCTC

TGCGTCAGG

459 INFORMATION FOR SEQ ID NO: 252: WO 97/12985 PCT/US96/15774 501 SEQUENCE CHARACTERISTICS: LENGTH: 153 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 252: Ser Pro Ala Pro Pro Ala Cys Asp Leu Arg Val Leu Ser Lys Leu Leu 1 5 in Arg Asp His Pro Gly Glu Gly Ala Leu Gly Val Arg Pro Pro Leu Ser 130 Val Gly 145 Ser Leu Trp Val Pro Leu Gin 115 Phe Gly His Pro Lys Thr Thr Leu 100 Gly Gin Ser Val Thr Thr Leu Cys Leu Arg His Thr Leu Pro Gin Leu 70 Leu Gly Thr Leu His Val Met 55 Leu Ser Ala Thr Leu 135 Ser Arg 25 Leu Leu 40 Glu Glu Glu Gly Ser Leu Leu Gln 105 Ala His 120 Arg Gly Leu Pro Thr Val Leu 90 Ser Lys Lys Ser Ala Lys Met 75 Gly Leu Asp Val Gin Val Ala Ala Gln Leu Pro Arg 140 Cys Asp Gin Ala Leu Gly Asn 125 Phe Pro Phe Asp Arg Ser Thr 110 Ala Leu Glu Ser Ile Gly Gly Gin Ile Met Val Leu Leu Gin Gin Leu Phe Leu Leu Cys Val Arg INFORMATION FOR SEQ ID NO: 253: SEQUENCE CHARACTERISTICS: LENGTH: 149 amino acids TYPE: amino acid STRANDEDNESS: single- TOPOLOGY: linear (ii) MOLECULE TYPE: protein WO 97/12985 PCTIUS96/1 5774 (xi) SEQUENCE DESCRIPTION: SEQ ID, NO: 253: Ser Pro Ala Pro Pro Ala Cys Asp Leu Arg Val Leu Ser Arg His Gly Gly Leu Val.

Arg Asp Pro Giu Ala Gly Arg Thr *Ser Leu Trp Val Pro Leu Thr 115 His Pro Lys Thr Thr Leu 100 Ala Val Thr Thr Leu Cys Leu His Leu Pro Gin Leu 70 Leu Gly Lys His Val1 Met 55 Leu Ser Ala Asp Ser Leu 40 Giu Glu Ser Leu *Arg 25 Leu Giu Gly Leu Gin 105 Leu Pro Thr Val Leu 90 Ser Alia Ser Al a Lys Met 75 Gly Leu Gin Val1 Ala 60 Ala Gin Leu Cys Asp Gn Ala Leu Gly -Lys Phe Asp Arg Ser Thr 110 Ser Leu Glu Ser Ile Gly Gly Gin Phe Leu Val Leu Leu Gin Gin Gly Gin 120 125Pe e His Leu Leu Arg Gly Lys Val Arg Phe Leu Met 130 135 Thr Leu Cys Val Arg 145 INFORMATION FOR SEQ ID, NO: 254: SEQUENCE

CHARACTERISTICS:

LENGTH: 153 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: protein Leu 140 Val Gly Gly Ser (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 254: Ser Pro Ala Pro Pro Ala Cys Asp Leu Arg Val Leu Ser Lys Leu Leu 10 Arg Asp Ser His Val Leu His Ser Arg Leu Ser Gin Cys Pro Giu Val WO 97/12985 PCT/US96/15774 503 25 His Pro Leu Pro Thr Pro Val Leu Leu Pro Ala Val Asp Phe Ser Leu 40 Gly Glu Trp Lys Thr Gin Met Glu Glu Thr Lys Ala Gin Asp Ile Leu 55 Gly Ala Val Thr Leu Leu Leu Glu Gly Val Met Ala Ala Arg Gly Gin 70 75 Leu Gly Pro Thr Cys Leu Ser Ser Leu Leu Gly Gin Leu Ser Gly Gin 90 Val Arg Leu Leu Leu Gly Ala Leu Gin Ser Leu Leu Gly Thr Gin Leu 100 105 110 Pro Pro Gin Gly Arg Thr Thr Ala His Lys Asp Pro Asn Ala Ile Phe 115 120 125 Leu Ser Phe Gin His Leu Leu Arg Gly Lys Val Arg Phe Leu Met Leu 130 135 140 Val Gly Gly Ser Thr Leu Cys Val Arg 145 150 INFORMATION FOR SEQ ID NO: 255: SEQUENCE

CHARACTERISTICS:

LENGTH: 64 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 255: GGATCCACCA TGAGCCGCCT GCCCGTCCTG CTCCTGCTCC AACTCCTGGT

CCGCCCCGCC

ATGG

64 INFORMATION FOR SEQ ID NO: 256: SEQUENCE CHARACTERISTICS: LENGTH: 153 amino acids TYPE: amino acid STRANDEDNESS: unknown WO 97/12985 PCT/US96/15774 504 TOPOLOGY: unknown (ii) MOLECULE TYPE: protein (ix) FEATURE: NAME/KEY: Modified-site LOCATION:112 OTHER INFORMATION:/note= "position 112 is deleted or Leu, Ala,VA1, Ile, Pro, Phe, Trp or Met" (ix) FEATURE: NAME/KEY: Modified-site LOCATION:113 OTHER INFORMATION:/note= "positoin 113 is deleted or Pro, Phe, Ala, Val, Leu, Ile, Trp or Met" (ix) FEATURE: NAME/KEY: Modified-site LOCATION:114 OTHER INFORMATION:/note= "position 114 is deleted or Pro, Phe, Ala, Val, Leu, Ile, Trp or Met" (ix) FEATURE: NAME/KEY: Modified-site LOCATION:115 OTHER INFORMATION:/note= "positon 115 is deleted or Gin, Gly, Ser, Thr, Tyr, or Asn" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 256: Ser Pro Ala Pro Pro Ala Cys Asp Leu Arg Val Leu Ser Lys Leu Leu 1 5 10 Arg Asp Ser His Val Leu His Ser Arg Leu Ser Gin Cys Pro Glu Val 25 His Pro Leu Pro Thr Pro Val Leu Leu Pro Ala Val Asp Phe Ser Leu 40 Gly Glu Trp Lys Thr Gin Met Glu Glu Thr Lys Ala Gin Asp Ile Leu 55 Gly Ala Val Thr Leu Leu Leu Glu Gly Val Met Ala Ala Arg Gly Gin 70 75 Leu Gly Pro Thr Cys Leu Ser Ser Leu Leu Gly Gin Leu Ser Gly Gln 90 Val Arg Leu Leu Leu Gly Ala Leu Gin Ser Leu Leu Gly Thr Gin Xaa 100 105 110 Xaa Xaa Xaa Gly Arg Thr Thr Ala His Lys Asp Pro Asn Ala Ile Phe WO 97/12985 PCT/US96/15774 505 115 120 125 Leu Ser Phe Gin His Leu Leu Arg Gly Lys Val Arg Phe Leu Met Leu 130 135 140 Val Gly Gly Ser Thr Leu Cys Val Arg 145 150 INFORMATION FOR SEQ ID NO: 257: SEQUENCE CHARACTERISTICS: LENGTH: 464 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic)" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 257: CCATGGCTAA CTGCTCTATA ATGATCGATG AAATTATACA

TCACTTAAAG

CACCTTTGCT GGACCCGAAC AACCTCAATG ACGAAGACGT

CTCTATCCTG

120 ACCTTCGACT TCCAAACCTG GAGAGCTTCG TAAGGGCTGT

CAAGAACTTA

180 CAGGTATTGA GGCAATTCTT CGTAATCTCC AACCATGTCT

GCCCTCTGCC

240 CCTCTCGACA TCCAATCATC ATCAAGGCAG GTGACTGGCA AGAATTCCGG 300 CGTTCTATCT GGTTACCCTT GAGCAAGCGC AGGAACAACA

GTACGTAGAG

360 GCTCCCCGGG TGAACCGTCT GGTCCAATCT CTACTATCAA

CCCGTCTCCT

420 AATCTCATAA ATCTCCAAAC ATGTAAGGTA CCGCATGCAA

GCTT

464 INFORMATION FOR SEQ ID NO: 258: SEQUENCE CHARACTERISTICS: LENGTH: 419 base pairs TYPE: nucleic acid STRANDEDNESS: single

AGACCACCTG

ATGGATCGAA

GAAAATGCAT

ACGGCCGCAC

GAAAAACTGA

GGCGGTGGAG

CCGTCTAAAG

WO 97/12985 PCTIUS96'1 5774 506 TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid DESCRIPTION: /desc "DNA (synthetic), (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 258: CCATGGCTAA CTGCTCTATA ATGATCGATG AAATTATACA

TCACTTAXAG

CACCTTTGCT GGACCCGAAC AACCTCAATG ACGAAGACGT

CTCTATCCTG

120 ACCTTCGACT TCCAAACCTG GAGAGCTTCG TAAGGGCTGT

CAAGAACTTA

180 CAGGTATTGA GGCAATTCTT CGTAATCTCC AACCATGTCT

GCCCTCTGCC

240 CCTCTCGACA TCCAATCATC ATCAAGGCAG GTGACTGGCA

AGAATTCCGG

300 CGTTCTATCT GGTTACCCTT GAGCAAGCGC AGGAACAACA

GTACGTAGAG

360 GCTCCCCGGG TGGTGGTTCT GGCGGCGGCT CCAACATGTA

AGGTACCGCA

419

AGACCACCTG

ATGGATCGAA

GAAAATGCAT

ACGGCCGCAC

GAAAAACTGA

GGCGGTGGAG

TGCAAGCTT

Claims (57)

1. A hematopoietic protein comprising; an amino acid sequence of the formula: R1-L1-R 2 R2-L1-R1, Rl-R2, or R2-R 1 wherein R 1 and R2 are independently selected from the group consisting of; A polypeptide comprising; a modified human G-CSF amino acid sequence of the formula: Xaa Xaa Leu Leu 30 Ala Xaa Xaa Glu Ala Pro Xaa Leu Leu Gin Xaa Thr 120 Gin Gin Gin Gly 150 Xaa Gly Xaa Xaa Leu Gin Xaa Xaa Leu Ser Ser Gin Ala Leu Leu Gin Met Glu Ala Met Pro Ala Ser Ser Leu Xaa Glu Val Ser Leu Glu Xaa Xaa Pro Glu Xaa Xaa Xaa His Gly Asp Xaa Ala Gin Leu Xaa Pro Ser Ile 110 Val Gly 140 Phe Val Xaa Gly Ser Gly Ser Ala Met Ala Xaa Ala His Xaa Leu Pro Asp Ala Ser Pro Lys Thr Ser Ala Phe Glu Phe Pro Ala Gin Ser Xaa Gin Tyr Lys Xaa Gly Leu Xaa Leu Tyr 100 Leu Gly Ala Xaa 130 Ala Leu Xaa Gin Xaa Gly Leu Ile Leu Gin Pro Thr Gin Xaa Xaa Xaa Pro Ala Gly Thr Ile Pro Xaa Gly Xaa Trp Gly Leu Leu Trp Thr Ala Xa Xa l Gly Gly Val Leu Val Ala Ser Xaa Leu Gin Xaa Phe Leu Xaa Xaa WO 97/12985 PCT/US96/15774 Ser Tyr Arg Val wherein Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa position position position position position position position position position position position position position position position 170 Leu Xaa Xaa Leu Ala Gin Pro (SEQ ID NO:1) 1 is Thr, Ser, Arg, Tyr or Gly; 2 is Pro or Leu; 3 is Leu, Arg, Tyr or Ser; 13 is Phe, Ser, His, Thr or Pro; 16 is Lys, Pro, Ser, Thr or His; 17 is Cys, Ser, Gly, Ala, Ile, Tyr or Arg; 18 is Leu, Thr, Pro, His, Ile or Cys; 22 is Arg, Tyr, Ser, Thr or Ala; 24 is Ile, Pro, Tyr or Leu; 27 is Asp, or Gly; 30 is Ala, Ile, Leu or Gly; 34 is Lys or Ser; 36 is Cys or Ser; 42 is Cys or Ser; 43 is His, Thr, Gly, Val, Lys, TrD. Ala Arg, Cys, or Leu; Xaa at position 44 is Pro, Gly, Arg, Asp, Val, Ala, His, Trp, Gin, or Thr; Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa position position position position position position position position position position position position position position position position position position position position position position position 104 108 115 120 123 144 146 147 156 159 162 163 169 170 is is is is is is is is is is i is is Sis Sis is is is is is is is is is s Glu, Arg, Phe, Arg, Ile or Ala; Leu or Thr; Leu, Phe, Arg or Ser; Leu, Ile, His, Pro or Tyr; Leu or His; Cys or Ser; Gin, Lys, Leu or Cys; Gin, Pro, Leu, Arg or Ser; Cys or Ser; Asp, Gly or Val; Leu, Ala, Val, Arg, Trp, Gin or Gly; Thr, His, Leu or Ala; Gin, Gly, Arg, Lys or His Glu, Arg, Phe or Thr Phe, His, Arg, Pro, Leu, Gin or Glu; Arg or Gin; Arg or Gin; His, Gly or Ser; Ser, Arg, Thr, Tyr, Val or Gly; Glu, Leu, Gly or Trp; Val, Gly, Arg or Ala; Arg, Ser, Leu, Arg or Cys; His, Arg or Ser; wherein optionally 1-11 amino acids from the N-terminus and from the C-terminus can optionally be deleted from said modified human G-CSF amino acid sequence; and WO 97/12985 r/-«nn/r 509 r /USYo/13//4 wherein the N-terminus is joined to the C-terminus directly or through a linker capable of joining the N-terminus to the C-terminus and having new C- and N-termini at amino acids;

38-39

39-40

40-41

41-42

42-43

43-44

45-46

48-49

49-50

52-53

53-54

54-55

55-56

56-57

57-58

58-59

59-60

60-61

61-62

62-63

63-64

64-65

65-66

66-67

67-68

68-69

69-70

70-71

71-72

91-92

92-93

93-94

94-95

95-96

96-97

97-98

98-99

99-100

123-124

124-125

125-126

126-127

128-129 128-129

129-130

130-131

131-132

132-133

133-134

134-135

135-136

136-137

137-138

138-139

139-140

140-141

141-142 or 142-143 respectively; (II) A polypeptide comprising; a modified human IL-3 amino acid sequence of the formula: Ala Pro Met Thr Gln Thr Thr Ser Leu Lys Thr Ser Trp Val Asn Cys Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Asn Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 55 rn WO 97/12985 510 rI..IUS96/15774 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 70 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 85 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 100 105 0 Xaa Phe Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 110 115 120 Xaa Xaa Xaa Gin Gin Thr Thr Leu Ser Leu Ala Ile Phe 5125 130 (SEQ ID NO:2) wherein Xaa at position 17 is Ser, Lys, Gly, Asp, met, Gin, or Arg; Xaa at Position 18 is Asn, Xaa at Position 19 is met, Xaa at Position 20 is Ile, Xaa at Position 21 is Asp, Thr, Ser or Vai; Xaa at position 22 is Giu, Leu, Val or Giy; Xaa at Position 23 is Ile, Leu, Ser, or Arg; Xaa at position 24 is Ile, Xaa at Position 25 is Thr, Xaa at Position 26 is His, Xaa at position 27 is Leu, Xaa at Position 28 is Lys, Xaa at Position 29 is Gin, Xaa at position 30 is Pro, Xaa at Position 31 is pro, His, Leu, Phe, Ile, Cys, Gin, Phe, Lys, Ile, Phe, Arg, Gly, Giu, Arg, Arg, Ala, Arg, Ala, Pro, Gly, or Gin; or Cys; or Ala; Glu, Gin, Asn, Trp, Pro, Ser, Ala, His, Asp, Asn, Gin, Vai, Ala, Gly, Trp, Lys, Phe, Gly, His, Thr, Gly, Arg, As n, His, Asp, Val1, Gly, Phe, Arg, Leu, Leu, Thr, Gly, Arg, Gin, Gly, Thr, Gin, Pro, Gly, Ser, Arg, Arg, Ser, Gly, Arg, Asp, Phe, or Leu; Pro, or Ala; Ala, or Trp; or Ala;- Pro, Val or Trp; or Val; Gin, Ser, Leu, or Lys; Ala, Arg, Leu, or Gin; il s eu, Val, Arg, Gin, Asn, Gly, Ala, or Giu; WO 97/12985 Xaa at position Xaa at position Arg, Ala, Xaa at position Xaa at position Xaa at position Xaa at position Xaa at position Xaa at position Xaa at position Val, Glu, Xaa at position Gin, Arg, Xaa at position Glu, Asn, Xaa at position Trp, Asp, Xaa at position Lys, His, Xaa at position Xaa at position Lys, Thr, Xaa at position Xaa at position Ala, Ile, Xaa at position Xaa at position Xaa at position Xaa at position E Lys, His, 2 Xaa at position Xaa at position E Thr, Ala, Xaa at position 5 Xaa at position 5 511 33 is Pro, Leu, Gin, Ala, Thr, or 34 is Leu, Val, Gly, Ser, Lys, Gl Phe, Ile or Met; 35 is Leu, Ala, Gly, Asn, Pro, G1 36 is Asp, Leu, or Val; 37 is Phe, Ser, Pro, Trp, or Ile; 38 is Asn, or Ala; 40 is Leu, Trp, or Arg; 41 is Asn, Cys, Arg, Leu, His, Mel 42 is Gly, Asp, Ser, Cys, Asn, Ly Phe, Tyr, Ile, Met or Ala; 43 is Glu, Asn, Tyr, Leu, Phe, Asi Thr, Gly or Ser; 44 is Asp, Ser, Leu, Arg, Lys, Thi Gin, Ala or Pro; PCT/US96/15774 Glu; u, Gin, Thr, n, or Val; t, S, or Pro; Thr, Leu, p, Ala, Cys, r, Met, Trp, 45 is Gin, Pro, Phe, Val, Met, Leu, Asn, Arg, Ser, Ala, Ile, Glu or His; 46 is Asp, Phe, Ser, Thr, Cys, Glu, Ala, Tyr, Ile, Val or Gly; 47 is Ile, Gly, Val, Ser, Arg, Pro, 48 is Leu, Ser, Cys, Arg, Ile, His, Ala, Met, Val or Asn; 49 is Met, Arg, Ala, Gly, Pro, Asn, 50 is Glu, Leu, Thr, Asp, Tyr, Lys, Val, His, Phe, Met or Gin; 51 is Asn, Arg, Met, Pro, Ser, Thr, 52 is Asn, His, Arg, Leu, Gly, Ser, 53 is Leu, Thr, Ala, Gly, Glu, Pro, I 54 is Arg, Asp, Ile, Ser, Val, Thr, Ula or Leu; 55 is Arg, Thr, Val, Ser, Leu, or GlI 56 is Pro, Gly, Cys, Ser, Gin, Glu, I Tyr, Phe, Leu, Val or Lys; Thr, Lys, Asn, Gin, or His; Phe, Glu, His, Asn, or Asp; Ser, or His; or Thr; Lys, Ser, Gin, Asn, Arg, His, or Met; 57 is Asn or Gly; 8 is Leu, Ser, Asp, Arg, Gin, Val, or Cys; WO 97/12985 512 Xaa at position 59 is Glu Tyr, His, Leu, Pro, or Arg; PCT/US96/15774 Xa< Xae Xai Xaa Xac Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa a at position 60 is a at position 61 is a at position 62 is Sat position 63 is at position 64 is at position 65 is at position 66 is at position 67 is at position 68 is at position 69 is at position 70 is at position 71 is Trp, or Asn; at position 72 is at position 73 is at position 74 is at position 75 is Gin, or Leu; at position 76 is at position 77 is at position 78 is at position 79 is at position 80 is at position 81 is at position 82 is His, Thr, Ser, A at position 83 is at position 84 is at position 85 is at position 86 is at position 87 is I at position 88 is at position 89 is at position 90 is 1 Ala, Phe, Asn, Arg, Ala, Val, Lys, Ser, Leu, Gin, Asn, Ala, Ser, Ala, Ile, Ser, Asn, His, Tyr, Asn, Thr, Ile, Ala, Val, Ala, Leu, Met, Glu, Glu, Met, Pro, Tyr, Asn, or Thr; Glu, Pro, Lys, Arg, or Ser; Val, Arg, Pro, Thr, Asp, or Ile; Trp, Lys, Ser, His, Pro, or Val; Pro, Ser, or Lys; Pro, His, Leu, Phe, or Ser; Arg, Val, Asn, Glu, or Ser; Phe, Val, Gly, Asn, Ile, Pro, or His; Trp, Ser, Ile, Phe, Thr, or His; Pro, Thr, Glu, Arg, Trp, Gly, or Leu; Val, Trp, Pro, or Ala; Leu, Pro, Arg, Gli,'Thr, Gin, Met, Asp, Thr, Ala, Leu, His, Ser, Asn, Arg, Gly, Thr, Asp; Arg; Pro, Arg, Gly, Ala; Glu, Lys, Gly, Asp, Pro, Trp, Arg, Ser, Ser Ile Leu Lys Asn Leu, Leu, la, Pro, Cys, Leu, Pro, Leu, Ala, rhr, Ala, Val Ser Ala, Thr, Trp, SGin, Gin, Tyr, Ala, Glu, Asn, Cys, Ser, Lys, Asp, Pro, Ala, ,Arg, Ser, Asn, Val, Gly, Lys, Phe, Thr, Gly, Val, Arg, Trp, Arg, Cys, Ser, Asn, Trp, Glu, Pro, Gly, or Asp Thr, or Leu; Glu, Phe, Gly, or Arg; Met, Arg, Ile, Gly, or Asp; Gly, Thr, Leu, Glu, or Arg; Ala, Trp, Arg, Val, or Lys; Trp, Arg, Asp, Glu, Asn, Ile, Met or Val; Trp, Arg, or Met; Arg, Met, or Val; or Gin; Ala, or Lys; or Gly; Val, or Trp; Leu, Val, Glu, His, Asn, or Ser; Thr, Gly, Asp, Ile, or Met; WO 97/12985 Pt CT/US96/15774 513 Xaa at position 91 is Ala, Pro, Ser, Thr, Phe, Leu, Asp, Xaa at position 92 is Pro, Phe, Arg, Ser, Lys, His, Ala, Leu; or His; Gly, Ile or Xaa at position 93 i Xaa at position 94 i Ala, or Pro; Xaa at position 95 i Lys, Ser, Ala, Xaa at position 96 i Xaa at position 97 i Xaa at position 98 i Glu, Gin, Ser, Xaa at position 99 i Gly, Ser, Phe, Xaa at position 100 Xaa at position 101 Tyr, Glu, Asn, Xaa at position 102 Xaa at position 103 Xaa at position 104 Gin, Lys, Ala, Xaa at position 105 Leu, Lys, Ile, Xaa at position 106 Xaa at position 108 Ala or Pro; Xaa at position 109 Xaa at position 110 Ser, or Trp; Xaa at position 111 Xaa at position 112 Xaa at position 113 Lys, Leu, Ile, Thr, Arg, Asp, Ile, Ser, Asn, Ser, Glu, Pro, Leu, Ala, Val, Leu, Gin, or Arg; Lys, His, s His, Gin, Pro, Arg, Val, Leu, Gly, Trp, Phe, Ile, or Tyr; s Pro, Lys, Tyr, Gly, Ile, or Thr; s Ile, Val, Lys, Ala, or Asn; s His, Ile, Asn, Leu, Asp, Ala, Thr, Phe, Met, Val, Lys, Arg, Tyr or Pro; s Ile, Leu, Arg, Asp, Val, Pro, Gin, or His; is Lys, Tyr, Leu, His, Arg, Ile, Ser, is Asp, Pro, Met, Lys, His, Thr, Val, Thr, Asn, Gin, or Pro; Ser, Ala, Gly, Ile, Leu, or Gin; 2, Tyr, is Gly, Leu, Glu, is Asp, or Ser; is Trp, Val, Cys, Phe, or Gly; is Asn, Pro, Ala, Asp, or His; is Glu, Ser, Ala, is Arg, Lys, Asp, Lys, Sei or Pro; Tyr, Thr, Met, Pro, Leu, Phe, Ser, Trp, Gin, Tyr, Arg, Lys, is Leu, is Thr, is Phe, Val or Thr, Ala, Ile, Val, Ser, Asn; Cys, Asn, Pro, Asn, Arg, Gin, Cys, His, Val, Lys, Leu, Glu, Thr, Asp, Tyr, His, Ser, Pro, Thr, Ile, Thr, Ile, Tyr, Leu, Leu, Arg, or Met; Glu, His, Gly, Trp, Trp, Arg, Arg, Ala, Gly, or Pro; Gin, His, Ser, Ser, or Gly; Gin, His, Glu, Ser, or Phe; Tyr, Asp, or Leu; His, Thr, Xaa at position Xaa at position 114 is Tyr, 115 is Leu, WO 97/12985 PrT/1 TQ/ I/1 C7T A 514 *-CT/TV J Trp, or Met; Xaa at position 116 is Lys, Leu, Pro, Thr, Met, Asp, Val, Glu, Arg, Trp, Ser, Asn, His, Ala, Tyr, Phe, Gin, or Ile; Xaa at position 117 is Thr, Ser, Asn, Ile, Trp, Lys, or Pro; Xaa at position 118 is Leu, Ser, Pro, Ala, Glu, Cys, Asp, or Tyr; Xaa at position 119 is Glu, Ser, Lys, Pro, Leu, Thr, Tyr, or Arg; Xaa at position 120 is Asn, Ala, Pro, Leu, His, Val, or Gln; Xaa at position 121 is Ala, Ser, Ile, Asn, Pro, Lys, Asp, or Gly; Xaa at position 122 is Gin, Ser, Met, Trp, Arg, Phe, Pro, His, Ile, Tyr, or Cys; Xaa at position 123 is Ala, Met, Glu, His, Ser, Pro, Tyr, or Leu; wherein from 1 to 14 amino acids can optionally be deleted from the N-terminus and/or from 1 to 15 amino acids can optionally be deleted from the C-terminus of said modified human IL-3 amino acid sequence; wherein from 0 to 44 of the amino acids designated by Xaa are different from the corresponding amino acids of native (1-133) human interleukin-3; and wherein the N-terminus is joined to the C-terminus directly or through a linker capable of joining the N-terminus to the C-terminus and having new C- and N-termini at amino acids; 26-27 49-50 83-84 27-28 50-51 84-85 28-29 51-52 85-86 29-30 52-53 86-87 30-31 53-54 87-88 31-32 54-55 88-89 32-33 64-65 89-90 33-34 65-66 90-91 34-35 66-67 91-92 35-36 67-68 92-93 36-37 68-69 97-98 37-38 69-70 98-99 38-39 70-71 99-100 39-40 71-72 100-101 40-41 72-73 101-102 WO 97/12985 Prlrlir TQq'C /I I 515 C/Tni 41-42 82-83 102-103 or 103-104 respectively; (III) A polypeptide comprising; a modified human c-mpl ligand amino acid sequence of the formula: Se~ol~or~ay~pe~ga~ue~se~ur~pe 1 5 10 Hi~le~serr~ue n~sr~ua~ sProLeuProThrPro 20 25 30 ValLeuLeuProAlaValAspPheSerLeuGlyGluTrpLThrGlneluu 45 50 ThrLysAlaGlnAspIleLeuGlyAlaValThrLeuLeuLeuGiGli~letl 65 70 AlaArgGlya inLeuGlyProThrCysLeuSerSerLeuLeuGlyGlnLeuSGly 85 90 GlnValArgLeuLeuLeuGiyAlaLeuG inS erLeuLeuGlyThrGlnXaaXaaXaa 100 105 110 Xa~yr~rh~ai~ss~os~al~ee~rh~ni 115 120 125 130 LeuLeuArgc lyLysValArgPheLeuMetLeu~~ lGlyGlyS erThrLeuCy sVai 135 140 145 150 Arg (SEQ ID NO:256) 153 wherein; Xaa at position 112 is deleted or Leu, Ala, Val, Ile, Pro, Phe, Trp, or Met; Xaa at position 113 is deleted or Pro, Phe, Ala, Val, Leu, Ile, Trp, or Met; Xaa at position 114 is deleted or Pro, Phe, Ala, Val, Leu, Ile, Trp, or Met; Xaa at position 115 is deleted or Gln, Gly, Ser, Thr, Tyr, WO 97/12985 PCT/UIISQ/l C'7A 516 or Asn; and wherein the N-terminus is joined to the C-terminus directly or through a linker (L2) capable of joining the N-terminus to the C-terminus and having new C- and N-termini at amino acids; 26-27 51-52 108-109 27-28 52-53 109-110 28-29 53-54 110-111 29-30 54-55 111-112 30-31 55-56 112-113 32-33 56-57 113-114 33-34 57-58 114-115 34-35 58-59 115-116 36-37 59-60 116-117 37-38 78-79 117-118 38-39 79-80 118-119 40-41 80-81 119-120 41-42 81-82 120-121 42-43 82-83 121-122 43-44 83-84 122-123 44-45 84-85 123-124 46-47 85-86 124-125 47-48 86-87 125-126 48-49 87-88 126-127 50-51 88-89 or 127-128 respectively; (IV) A polypeptide comprising; a modified human IL-3 amino acid sequence of the formula: Ala Pro Met Thr Gin Thr Thr Ser Leu Lys Thr Ser Trp Val Asn 1 5 10 Cys Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 25 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Asn Xaa Xaa Xaa Xaa Xaa Xaa 40 WO 97/12985 Df'qrfFT 517T~'~,a Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 55 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 70 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 85 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 100 105 Xaa Phe Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 110 115 120 Xaa Xaa Xaa Gin Gin Thr Thr Leu Ser Leu Ala Ile Phe 125 130 (SEQ ID NO:2) wherein Xaa at position 17 is Ser, Lys, Giy, Asp, Met, Gin, or Arg; Xaa at Position 18 is Asn, Xaa at Position 19 is met, Xaa at Position 20 is Ile, Xaa at Position 21 is Asp, Thr, Ser or Val; Xaa at position 22 is Giu, Leu, Val or Gly; Xaa at Position 23 is Ile, Leu, Ser, or Arg; Xaa at Position 24 is Ile, Xaa at position 25 is Thr, Xaa at position 26 is His, Xaa at position 27 is Leu, Xaa at position 28 is Lys, Xaa at position 29 is Gin, His, Phe, Cys, Phe, Leu, Ile, Gin, Lys, Ile, Phe, Arg, Gly, Giu, Arg, Arg, Ala, Arg, Ala, Pro, Gly, or Gin; or Cys; or Ala; Giu, Gin, Asn, Trp, Pro, Ser, Ala, His, Asp, Asn, Gin, Val, Ala, Gly, Trp, Lys, Phe, Gly, His, Thr, Giy, Arg, Asn, Val, Gly, Phe, Arg, Leu, Leu, Arg, Gin, Gly, Thr, Gin, Pro, Ser, Arg, Arg, Ser, Gly, Arg, Phe, or Leu; Pro, or Ala; Ala, or Trp; or Ala; Pro, Val or Trp; or Val; WO 97/12985 PCT/US96/15774 Xaa at position 30 is Pro, His, Thr, Gly, Asp, Gin, Ser, Leu, or Lys; Xaa at position Xaa at position Xaa at position Xaa at position Arg, Ala, Xaa at position Xaa at position Xaa at position Xaa at position Xaa at position Xaa at position Xaa at position Val, Glu, Xaa at position Gin, Arg, Xaa at position Glu, Asin, Xaa at position Trp, Asp, Xaa at position Lys, His, Xaa at position Xaa at position Lys, Thr, Xaa at position Xaa at position Ala, Ile, Xaa at position E Xaa at position E Xaa at position E Xaa at position 5 Lys, His, A Xaa at position 5 Xaa at position 5 31 is Pro, Asp, 32 is Leu, Val, 33 is Pro, Leu, 34 is Leu, Val, Phe, Ile or Met; 35 is Leu, Ala, 36 is Asp, Leu, 37 is Phe, Ser, 38 is Asn, or Al 40 is Leu, Trp, 41 is Asn, Cys, 42 is Gly, Asp, Phe, Tyr, Ile, M 43 is Glu, Asn, Gly, Arg, Gin, Gly, Ala, Gin, Ala, Ser, Arg, Asn, Thr, Lys, Leu, or Gin; Gly, Ala, or Glu; or Glu; Glu, Gin, Thr, Gly, Asn, or Val; Pro, Trp, a; or Arg; Arg, Leu, Ser, Cys, et or Ala Tyr, Leu, Pro, Gin, or Val; or lie; His, Asn, Phe, Met, or Pro; Lys, Thr, Leu, Asp, Ala, Cys, Thr, Gly or Ser; 44 is Asp, Ser, Leu, Arg, Lys, Thr, Met, Gin, Ala or Pro; 45 is Gin, Pro, Phe, Val, Met, Leu, Thr, Asn, Arg, Ser, Ala, Ile, Glu or His; 46 is Asp, Phe, Ser, Thr, Cys, Glu, Asn, Ala, Tyr, Ile, Val or Gly; Trp, Lys, Gin, 47 is Ile, Gly, Val, Ser, Arg, 48 is Leu, Ser, Cys, Arg, Ile, Ala, Met, Val or Asn; 19 is Met, Arg, Ala, Gly, Pro, 50 is Glu, Leu, Thr, Asp, Tyr, Val, His, Phe, Met or Gin; 51 is Asn, Arg, Met, Pro, Ser, 52 is Asn, His, Arg, Leu, Gly, 53 is Leu, Thr, Ala, Gly, Glu, 54 is Arg, Asp, Ile, Ser, Val, Lla or Leu; 5 is Arg, Thr, Val, Ser, Leu, 6 is Pro, Gly, Cys, Ser, Gin, Pro, His, Asn, Lys, Thr, Ser, Pro, Thr, or His; Phe, Glu, His, Asn, or Asp; Ser, or His; or Thr; Lys, Ser, or Met; Gin, Asn, or Gly; Glu, Arg, His, WO 97/12985 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Thr, Ala, Tyr, at position 57 is at position 58 is at position 59 is at position 60 is at position 61 is at position 62 is at position 63 is at position 64 is at position 65 is at position 66 is at position 67 is at position 68 is at position 69 is at position 70 is at position 71 is Trp, or Asn; at position 72 is at position 73 is at position 74 is at position 75 is Gin, or Leu; at position 76 is at position 77 is at position 78 is at position 79 is at position 80 is at position 81 is at position 82 is His, Thr, Ser, 2 at position 83 is at position 84 is at position 85 is at position 86 is at position 87 is 519 PCT/I Phe, Leu, Val or Lys; Asn or Gly; Leu, Ser, Asp, Arg, Gin, Val, or Cys; Glu Tyr, His, Leu, Pro, or Arg; Ala, Ser, Pro, Tyr, Asn, or Thr; Phe, Asn, Glu, Pro, Lys, Arg, or Ser; Asn, His, Val, Arg, Pro, Thr, Asp, or Arg, Tyr, Trp, Lys, Ser, His, Pro, or Ala, Asn, Pro, Ser, or Lys; Val, Thr, Pro, His, Leu, Phe, or Ser; Lys, Ile, Arg, Val, Asn, Glu, or Ser; Ser, Ala, Phe, Val, Gly, Asn, Ile, Pr< Leu, Val, Trp, Ser, Ile, Phe, 'Thr, or Gin, Ala, Pro, Thr, Glu, Arg, Trp, GI Asn, Leu, Val, Trp, Pro, or Ala; Ala, Met, Leu, Pro, Arg, Glu. Thr Gl US96/15774 Ile; Val; o, or His; His; y, or Leu; n, Ser Ala, Ile, Glu, I Ser, Ile, Leu, Lys, Asn, Leu, Leu, Ala, Pro, Cys, Leu, Pro, Leu, Glu, Glu, Met, Lys, Val, Ser, Ala, Thr, Trp, Gin, Gin, Tyr, Ala, Glu, Asn, Cys, Ser, Met, Asp, Thr, Gly, Ala, Arg, Ser, Asn, Val, Gly, Lys, Phe, I Thr, Gly, Val, Arg, Trp, Ala, Leu, Pro, Asp, His, Ser, Arg, Pro, Asn, Gly, Gly, Trp, Arg, Thr, Ala; Arg, Ser, Asp; Arg; Asn, Thr, Glu, Met, Gly, Ala, Trp, le, Trp, Arg, or G Trp, Glu, Pr or Leu; Phe, Gly, or Arg, Ile, Gl Thr, Leu, G1 Trp, Arg, Va Arg, Asp, Gl Met or Val; Arg, or Met; Met, or Val; in; o, Gly, or Asp; Arg; y, or u, or A i, or I u, Asn, sp; Lrg; 'ys; Ala, or Lys; or Gly; WO 97/12985 PCT[US96/157 74 Xaa at position 88 is Ala, Xaa at position 89 is Thr, Xaa at position 90 is Ala, Xaa at position 91 is Ala, Xaa at position 92 is Pro, Leu; Xaa at position 93 is Thr, Xaa at position 94 is Arg, Ala, or Pro; Xaa at position 95 is His, Lys, Asp, Pro, Pro, Phe, Asp, Ile, Arg, Val, or Trp; Cys, Leu, Val, Glu, His, Ser, Thr, Gly, Asp, Ile, Ser, Thr, Phe, Leu, Asp, Arg, Ser, Lys, His, Ala, Ser, Asn, Pro, Ala, Leu, Ser, Glu, Leu, Val, Gln, Asn, or Ser; or Met; or His; Gly, Ile or or Arg; Lys, His, Lys, Ser, Xaa at position Xaa at position Xaa at position Glu, Gln, Xaa at position Gly, Ser, Xaa at position Xaa at position Tyr, Glu, Xaa at position Xaa at position Xaa at position Gln, Lys, Xaa at position Leu, Lys, Xaa at position Xaa at position Ala, Trp, 96 is Pro, 97 is Ile, 98 is His, P E Gin, Pro, Arg, Val, 'he, Ile, or Tyr; Lys, Tyr, Gly, Ile, Val, Lys, Ala, or As Ile, Asn, Leu, Asp, Leu, Gly, or Thr; n; Ala, Thr, Thr, Asn, Gln, or Pro; Ser, Phe, Met, Val, Lys, Arg, Tyr or Pro; 99 is Ile, Leu, Arg, Asp, Val, Pro, Gln, Phe, or His; 100 is Lys, Tyr, Leu, His, Arg, Ile, Ser, 101 is Asp, Pro, Met, Lys, His, Thr, Val, Asn, Ser, Ala, Gly, Ile, Leu, or Gln; 102 is Gly, Leu, Glu, 103 is Asp, or Ser; 104 is Trp, Val, Cys, Ala, Phe, or Gly; 105 is Asn, Pro, Ala, Ile, Asp, or His; 106 is Glu, Ser, Ala, 108 is Arg, Lys, Asp, Ser, Tyr, or Pro; Tyr, Thr, Met, Pro, Leu, Phe, Ser, Trp, Gln, Tyr, Ala or Pro; Xaa at position 109 is Arg, Thr, Pro, Xaa at position 110 is Lys, Ala, Asn, Ser, or Trp; Xaa at position 111 is Leu, Ile, Arg, Xaa at position 112 is Thr, Val, Gln, Xaa at position 113 is Phe, Ser, Cys, Lys, Leu, Glu, Thr, Asp, Tyr, His, Thr, Thr, Tyr, Leu, Ile, Ile, Leu, Arg, Gly, Gln, Ser, Gln, Ser, Tyr, or Pro; His, Ser, or Gly; His, Glu, or Phe; Asp, or Met; Glu, His, Gly, Trp, WO 97/12985 PCT/ITo9/i1 C'7 A 521 Lys, Leu, lie, Val or Asn; Xaa at position 114 is Tyr, Cys, His, Ser, Trp, Arg, or Leu; Xaa at position 115 is Leu, Asn, Val, Pro, Arg, Ala, His, Thr, Trp, or Met; Xaa at position 116 is Lys, Leu, Pro, Thr, Met, Asp, Val, Glu, Arg, Trp, Ser, Asn, His, Ala, Tyr, Phe, Gin, or Ile; Xaa at position 117 is Thr, Ser, Asn, Ile, Trp, Lys, or Pro; Xaa at position 118 is Leu, Ser, Pro, Ala, Glu, Cys, Asp, or Tyr; Xaa at position 119 is Glu, Ser, Lys, Pro, Leu, Thr, Tyr, or Arg; Xaa at position 120 is Asn, Ala, Pro, Leu, His, Val, or Gin; Xaa at position 121 is Ala, Ser, Ile, Asn, Pro, Lys, Asp, or Gly; Xaa at position 122 is Gin, Ser, Met, Trp, Arg, Phe, Pro, His, Ile, Tyr, or Cys; Xaa at position 123 is Ala, Met, Glu, His, Ser, Pro, Tyr, or Leu; wherein from 1 to 14 amino acids can optionally be deleted from the N-terminus and/or from 1 to 15 amino acids can optionally be deleted from the C-terminus of said modified human IL-3 amino acid sequence; and wherein from 1 to 44 of the amino acids designated by Xaa are different from the corresponding amino acids of native (1-133) human interleukin-3; and a colony stimulating factor. and wherein L 1 is a linker capable of linking R 1 to R2; with the proviso that at least R1 or R2 is selected from the polypeptide of formula or (III); and said hematopoietic protein can optionally be immediately preceded by (methionine- 1 (alanine- 1 or (methionine 2 alanine- 1 WO 97/12985 D/UIr]TonT" I f 522 -*luyo/13/7714 2. A hematopoietic protein comprising; an amino acid sequence of the formula: R1-L1-R2, R2-L1-R1, R1-R 2 or R2-R 1 wherein R 1 and R2 are independently selected from the group consisting of; A polypeptide comprising; a modified human G-CSF amino acid sequence of the formula: 1 Xaa Leu Ala Xaa Ala Xaa Leu Xaa Gin Gin Gly Xaa Leu Xaa Glu Pro Leu 90 Gin Thr 120 Gin Gly 150 Gly Xaa Xaa Leu Xaa Leu Ser Ala Leu Met Ala Val Gly Pro Xaa Xaa Gin Glu Xaa Val Ser Ser Gin Leu Leu Glu Gin Xaa Glu Xaa Met Pro Leu Val Ala Glu Xaa Xaa Xaa His Gly Asp Xaa Ala Ala Ser Gin Leu Xaa Pro Ser Ile 110 Val Gly 140 Phe Ser Ser Leu Pro Val Xaa Lys Xaa Ala Thr Gly His Ser Ser Xaa Ala Gly Leu Phe Ser Pro Glu Ala Asp Phe Met Ala Pro Ala Ser Ala Xaa Leu Gln Gin Ser Xaa Gin Tyr Lys Xaa Gly Leu Xaa Leu Tyr 100 Leu Gly Ala Xaa 130 Ala Leu Xaa Gin 160 Xaa Phe Xaa Gly Leu Ile Leu Gln Pro Thr Gin Xaa Leu Xaa Xaa Pro Ala Gly Thr Ile Pro Xaa Xaa Gly Xaa Trp Gly Leu Leu Trp Thr Ala Xaa Ser Tyr 170 Arg Val Leu Xaa Xaa Leu Ala Gin Pro (SEQ ID NO:1) WO 97/12985 PCT/US96/15774 wherein Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa position position position position position position position position position position position position position position position 1 is Thr, Ser, Arg, Tyr or Gly; 2 is Pro or Leu; 3 is Leu, Arg, Tyr or Ser; 13 is Phe, Ser, His, Thr or Pro; 16 is Lys, Pro, Ser, Thr or His; 17 is Cys, Ser, Gly, Ala, Ile, Tyr or Arg; 18 is Leu, Thr, Pro, His, Ile or Cys; 22 is Arg, Tyr, Ser, Thr or Ala; 24 is Ile, Pro, Tyr or Leu; 27 is Asp, or Gly; 30 is Ala, Ile, Leu or Gly; 34 is Lys or Ser; 36 is Cys or Ser; 42 is Cys or Ser; 43 is His, Thr, Gly, Val, Lvs. Trn Ali Arg, Cys, or Leu; Xaa at position 44 is Pro, Gly, Arg, Asp, Val, Ala, His, Trp, Gln, or Thr; Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa position position position position position position position position position position position position position position position position position position position position position position position 46 47 49 50 54 64 67 70 74 104 108 115 120 123 144 146 147 156 159 162 163 169 170 is is is is is is is is is is is is is is is is is is is is is is is Glu, Arg, Phe, Arg, Ile or Ala; Leu or Thr; Leu, Phe, Arg or Ser; Leu, Ile, His, Pro or Tyr; Leu or His; Cys or Ser; Gin, Lys, Leu or Cys; Gin, Pro, Leu, Arg or Ser; Cys or Ser; Asp, Gly or Val; Leu, Ala, Val, Arg, Trp, Gin or Gly; Thr, His, Leu or Ala; Gin, Gly, Arg, Lys or His Glu, Arg, Phe or Thr Phe, His, Arg, Pro, Leu, Gin or Glu; Arg or Gin; Arg or Gin; His, Gly or Ser; Ser, Arg, Thr, Tyr, Val or Gly; Glu, Leu, Gly or Trp; Val, Gly, Arg or Ala; Arg, Ser, Leu, Arg or Cys; His, Arg or Ser; wherein optionally 1-11 amino acids from the N-terminus and from the C-terminus can be deleted from said modified human G-CSF amino acid sequence; and WO 97/12985 524 PCT/US96/15774 wherein the N-terminus is joined to the C-terminus directly or through a linker capable of joining the N-terminus to the C-terminus and having new C- and N-termini at amino acids; 38-39 39-40 40-41 41-42 42-43 43-44 45-46 48-49 49-50 52-53 53-54 54-55 55-56 56-57 57-58 58-59 59-60 60-61 61-62 62-63 63-64 64-65 65-66 66-67 67-68 68-69 69-70 70-71 71-72 91-92 92-93 93-94 94-95 95-96 96-97 97-98 98-99 99-100 123-124 124-125 125-126 126-127 128-129 128-129 129-130 130-131 131-132 132-133 133-134 134-135 135-136 136-137 137-138 138-139 139-140 140-141 141-142 or 142-143 respectively; (II) A polypeptide comprising; a modified human IL-3 amino acid sequence of the formula: Ala Pro Met Thr Gin Thr Thr Ser Leu Lys Thr Ser Trp Val Asn 1 5 10 Cys Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 25 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Asn Xaa Xaa Xaa Xaa Xaa Xaa 40 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa WO 97/12985 pf-r/fTen 52S Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 70 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 85 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 100 105 0 Xaa Phe Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 110 115 120 Xaa Xaa Xaa Gin Gin Thr Thr Leu Ser Leu Ala Ile Phe 125 130 wherein Xaa at position 17 is Ser, Lys, Gly, Asp, Met, Gin, or Arg; Xaa at position 18 is Asn, Xaa at position 19 is Met, Xaa at position 20 is Ile, Xaa at position 21 is Asp, Thr, Ser or Val; Xaa at position 22 is Giu, Leu, Val or Gly; Xaa at position 23 is Ile, Leu, Ser, or Arg; Xaa at Position 24 is Ile, Xaa at position 25 is Thr, Xaa at position 26 is His, Xaa at position 27 is Leu, Xaa at position 28 is Lys, Xaa at position 29 is Gin, Xaa at position 30 is Pro, Xaa at Position 31 is Pro, H4is TLei Phe, Cys, Phe, Ile, Gin, Lys, Ile, Phe, Arg, Gly, Giu, Arg, Arg, Ala, Arg, Ala, Pro, Gly, or Gin; or Cys; or Ala; Giu, Gin, Asn, Trp, Pro, Ser, Ala, His, Asp, Asn, Gin, Vai, Ala, Gly, Trp, Lys, Phe, Gly, His, Thr, Gly, Arg, Asn, His, Asp, Val, Giy, Phe, Arg, Leu, Leu, Thr, Gly, Arg, Gin, Gly, Thr, Gin, Pro, Gly, Ala, Ser, Arg, Arg, Ser, Gly, Arg, Asp, Arg, Phe, or Leu; Pro, or Ala; Ala, or Trp; or Ala; Pro, Val or Trp; or Val; Gin, Ser, Leu, or Lys; Leu, or Gin; L- s ueu, Val, Arg, Gln, Asn, Giy, Ala, or Giu; WO 97/12985 526 PCT/US96/15774 Xaa at position Xaa at position Arg, Ala, Xaa at position Xaa at position Xaa at position Xaa at position Xaa at position Xaa at position Xaa at position Val, Glu, Xaa at position Gin, Arg, Xaa at position Glu, Aasn, Xaa at position Trp, Asp, Xaa at position Lys, His, Xaa at position Xaa at position Lys, Thr, Xaa at position Xaa at position Ala, Ile, Xaa at position Xaa at position E Xaa at position 5 Xaa at position E Lys, his, I Xaa at position 5 Xaa at position 5 Thr, Ala, T Xaa at position 5 Xaa.at position 5 33 is Pro, Leu, Gin, Ala, Thr, or Glu; 34 is Leu, Val, Gly, Ser, Lys, Glu, Gin, Thr, Phe, Ile or Met; 35 is Leu, Ala, Gly, Asn, Pro, Gin, or Val; 36 is Asp, Leu, or Val; 37 is Phe, Ser, Pro, Trp, or Ile; 38 is Asn, or Ala; 40 is Leu, Trp, or Arg; 41 is Asn, Cys, Arg, Leu, His, 42 is Gly, Asp, Ser, Cys, Asn, Phe, Tyr, Ile, Met or Ala; 43 is Glu, Asn, Tyr, Leu, Phe, Thr, Gly or Ser; 44 is Asp, Ser, Leu, Arg, Lys, Gin, Ala or Pro; Met, Lys, Asp, or Pro; Thr, Leu, Ala, Cys, Thr, Met, Trp, 45 is Gin, Asn, Arg, 46 is Asp, Ala, Tyr, 47 is Ile, 48 is Leu, Ala, Met, 49 is Met, 50 is Glu, Val, His, 51 is Asn, 52 is Asn, 53 is Leu, 4 is Arg, la or Leu )5 is Arg, 6 is Pro, yr, Phe, Pro, Phe, Val, Met, Leu, Thr, Ser, Ala, Ile, Glu or His; Phe, Ser, Thr, Cys, Glu, Asn, Ile, Val or Gly; Gly, Val, Ser, Arg, Pro, or H Ser, Cys, Arg, Ile, His, Phe, Val or Asn; Arg, Ala, Gly, Pro, Asn, His, Leu, Thr, Asp, Tyr, Lys, Asn, Phe, Met or Gin; Arg, Met, Pro, Ser, Thr, or H: His, Arg, Leu, Gly, Ser, or T Thr, Ala, Gly, Glu, Pro, Lys, Asp, Ile, Ser, Val, Thr, Gin, Lys, Gin, is; Glu, or Asp; Ser, is; ir; Ser, Asn, or Met; Thr, Val, Ser, Leu, Gly, Cys, Ser, Gin, Leu, Val or Lys; or Gly; Glu, Arg, His, .7 is Asn or Gly; 8 is Leu, Ser, Asp, Arg, Gin, Val, or Cys; WO 97/12985 527 Xaa at position 59 is Glu Tyr, His, Leu, Pro, or Arg; PCT/US96/15774 Xaa at position 60 is Ala, Xaa at position 61 is Phe, Xaa at position 62 is Asn, Xaa at position 63 is Arg, Xaa at position 64 is Ala, Xaa at position 65 is Val, Xaa at position 66 is Lys, Xaa at position 67 is Ser, Xaa at position 68 is Leu, Xaa at position 69 is Gin, Xaa at position 70 is Asn, Xaa at position 71 is Ala, Trp, or Asn; Xaa at position 72 is Ser, Xaa at position 73 is Ala, Xaa at position 74 is Ile, Xaa at position 75 is Glu, Gin, or Leu; Xaa at position 76 is Ser, Xaa at position 77 is Ile, Xaa at position 78 is Leu, Xaa at position 79 is Lys, Xaa at position 80 is Asn, Xaa at position 81 is Leu,. Xaa at position 82 is Leu, His, Thr, Ser, Ala, T Xaa at position 83 is Pro, Xaa at position 84 is Cys, Xaa at position 85 is Leu, Xaa at position 86 is Pro, Xaa at position 87 is Leu, Xaa at position 88 is Ala, Xaa at position 89 is Thr, Xaa at position 90 is Ala, Asn, His, Tyr, Asn, Thr, Ile, Ala, Val, Ala, Leu, Met, Pro, Tyr, Glu, Pro, Val, Arg, Trp, Lys, Pro, Ser, Pro, His, Arg, Val, Phe, Val, Trp, Ser, Pro, Thr, Val, Trp, Leu, Pro, Asn, or Thr; Lys, Arg, or Ser; Pro, Thr, Asp, or Ile; Ser, His, Pro, or Val; or Lys; Leu, Phe, or Ser; Asn, Glu, or Ser; Gly, Asn, Ile, Pro, or His; Ile, Phe, Thr, or His; Glu, Arg, Trp, Gly, or Leu; Pro, or Ala; Arg, Glu, Thr, Gin, His, Asn, Arg, or Asp; Ser, Gly, Thr, or Arg; Glu, Met, Glu, Asp, Ala, Leu, Met, Thr, Pro, Arg, Gly, Ala; Lys, Gly, Asp, Pro, Trp, Arg, Ser, Val, Ser, Ala, Thr, Trp, Gin, Gin, yr, Ala, Glu, Asn, Cys, Ser, Lys, Asp, Pro, Ala, Arg, Ser, Asn, Val, Gly, Lys, Phe, Thr, Gly, Val, Arg, Trp, Arg, Cys, Ser, Asn, Trp, Glu, Pro, Gly, or Asp; Thr, or Leu; Glu, Phe, Gly, or Arg; Met, Arg, Ile, Gly, or Asp; Gly, Thr, Leu, Glu, or Arg; Ala, Trp, Arg, Val, or Lys; Trp, Arg, Asp, Glu, Asn, Ile, Met or Val; Trp, Arg, or Met; Arg, Met, or Val; or Gin; Ala, or Lys; or Gly; Val, or Trp; Leu, Val, Glu, His, Asn, or Ser; Thr, Gly, Asp, Ile, or Met; WO 97/12985 PCT/US96/15774 528 Xaa at position 91 is Ala, Pro, Ser, Thr, Xaa at position 92 is Pro, Phe, Arg, Ser, Leu; Phe, Lys, Pro, Leu, Leu, His, Ala, Val, Asp, Ala, Leu, Gin, or His; Gly, Ile or or Arg; Lys, His, Xaa at position 93 Xaa at position 94 Ala, or Pro; Xaa at position 95 Lys, Ser, Ala, Xaa at position 96 Xaa at position 97 j Xaa at position 98 i Glu, Gin, Ser, Xaa at position 99 i Gly, Ser, Phe, Xaa at position 100 Xaa at position 101 Tyr, Glu, Asn, Xaa at position 102 Xaa at position 103 Xaa at position 104 Gin, Lys, Ala, Xaa at position 105 Leu, Lys, Ile, Xaa at position 106 Xaa at position 108 Ala or Pro; Xaa at position 109 Xaa at position 1100 Ser, or Trp; Xaa at position 111 j Xaa at position 112 i Xaa at position 113 i Thr, Arg, Asp, Ile, Ser, Ser, Asn, Glu, .s His, Gin Trp, Phe, is Pro, Lys s Ile, Val s His, Ile, Phe, Met, ,Pro, Arg, Val, Ile, or Tyr; STyr, Gly, Ile, SLys, Ala, or As Asn, Leu, Asp, Val, Lys, Arg, T Leu, Gly, Thr, Asn, or Thr; n; Ala, Thr, yr or Pro; Pro,'Gin, Ile, Ser, Gin, or Pro; Thr, Val, s Ile, Leu, Arg, Asp, Val, or His; is Lys, Tyr, Leu, His, Arg, is Asp, Pro, Met, Lys, His, Ser, Ala, Gly, Ile, Leu, or Gin; is Gly, Leu, Glu, is Asp, or Ser; is Trp, Val, Cys, Phe, or Gly; is Asn, Pro, Ala, Asp, or His; Lys, Ser, Tyr, or Pro; Tyr, Thr, Met, Pro, Leu, Phe, Ser, Trp, Gin, Tyr, Glu, Arg, Arg, Lys, Leu, Thr, Phe, Ser, Lys, Thr, Ala, Ile, Val, Ser, Asn; Cys, Ala, Asp, Pro, Asn, Arg, Gin, Cys, Lys, Leu, Glu, Thr, Asp, Tyr, His, Thr, Thr, Tyr, Leu, Ile, Ile, Leu, Arg, Gly, Gin, Ser, Gin, Ser, Tyr, or Pro; His, Ser, or Gly; His, Glu, or Phe; Asp, or Met; Glu, His, Gly, Trp, Lys, Leu, Xaa at position Ile, Val or 114 is Tyr, His, Ser, Tr, Ara. or Leu1 Xaa at position 115 is Leu, Asn, Val, Pro, Arg, Ala, His, Thr, WO 97/12985 DC T/UTC'm 529 -iur o Trp, or Met; Xaa at position 116 is Lys, Leu, Pro, Thr, Met, Asp, Val, Glu, Arg, Trp, Ser, Asn, His, Ala, Tyr, Phe, Gin, or Ile; Xaa at position 117 is Thr, Ser, Asn, Ile, Trp, Lys, or Pro; Xaa at position 118 is Leu, Ser, Pro, Ala, Glu, Cys, Asp, or Tyr; Xaa at position 119 is Glu, Ser, Lys, Pro, Leu, Thr, Tyr, or Arg; Xaa at position 120 is Asn, Ala, Pro, Leu, His, Val, or Gin; Xaa at position 121 is Ala, Ser, Ile, Asn, Pro, Lys, Asp, or Gly; Xaa at position 122 is Gin, Ser, Met, Trp, Arg, Phe, Pro, His, Ile, Tyr, or Cys; Xaa at position 123 is Ala, Met, Glu, His, Ser, Pro, Tyr, or Leu; wherein from 1 to 14 amino acids can optionally be deleted from the N-terminus and/or from 1 to 15 amino acids can optionally be deleted from the C-terminus of said modified human IL-3 amino acid sequence; and wherein from 0 to 44 of the amino acids designated by Xaa are different from the corresponding amino acids of native (1-133) human interleukin-3; and wherein the N-terminus is joined to the C-terminus directly or through a linker (L2) capable of joining the N-terminus to the C-terminus and having new C- and N-termini at amino acids; 26-27 49-50 83-84 27-28 50-51 84-85 28-29 51-52 85-86 29-30 52-53 86-87 30-31 53-54 87-88 31-32 54-55 88-89 32-33 64-65 89-90 33-34 65-66 90-91 34-35 66-67 91-92 35-36 67-68 92-93 36-37 68-69 97-98 37-38 69-70 98-99 38-39 70-71 99-100 39-40 71-72 100-101 40-41 72-73 101-102 WO 97/12985 WO 7/1985530 S96/D1 5774 41-42 82-83 102-103 or 103-104 respectively; (III) A polypeptide comprising; a modified human c-mpl ligand amino acid sequence of the formula: S erPraroPr o ay~s~urga uerLysLeuLeuArgAsp 8 er 1 5 10 Hi sValLeuHisserArgLeuS erGlnCys ProGluVaiHi sProLeuProThrPro 20 25 30 ValLeuLeuProAlaValAspPheSerLeuclyGluTrpy~rle~u 45 50 ThrLysAlaGnAspIleLeu~ylyaalahrLe LLui.. l~tl 65 70 AlaArgGlyGlnLeu~ lyProThrCysLeuSerSerLeuLeuGlyGlnLSGly 85 90 GlnValArgL euLeuLeuGlyAlaLeuGlnS erLeuLeuGlyThrGlnaaXaaXaa 100 105 110 Xa~yr~rh~ai~ss~os~al~ee~rh~ni 115, 120 125 130 Le~ur~yy~lr~ee~te~ll~ye~re~sa 135 140 145 150 Arg (SEQ ID NO:256) 153 wherein; Xaa at position 112 is deleted or Leu, Ala, Val, Ile, Pro, Phe, Trp, or Met; Xaa at position 113 is deleted or Pro, Phe, Ala, Val, Leu, Ile, Trp, or Met; Xaa at position 114 is deleted or Pro, Phe, Ala, Val, Leu, Ile, Trp, or Met; Xaa at position 115 is deleted or Gln, Gly, Ser, Thr, Tyr, WO 97/12985 PTUrS9/15 4cci 531 or Asn; and wherein the N-terminus is joined to the C-terminus directly or through a linker (L2) capable of joining the N-terminus to the C-terminus and having new C- and N-termini at amino acids; 52-53 108-109 53-54 109-110 54-55 110-111 55-56 111-112 56-57 112-113 57-58 113-114 58-59 114-115 59-60 115-116 78-79 116-117 79-80 117-118 80-81 118-119 81-82 119-120 82-83 120-121 83-84 121-122 84-85 122-123 85-86 123-124 86-87 124-125 87-88 125-126 88-89 126-127 or 127-128 respectively; (IV) A polypeptide comprising; a modified human IL-3 amino acid sequence of the formula: Ala Pro Met Thr Gin Thr Thr Ser Leu Lys Thr Ser Trp Val Asn 1 5 10 Cys Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 25 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Asn Xaa Xaa Xaa Xaa Xaa Xaa 40 WO 97/12985 532 PCTIUS96/1 5774 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 55 Xaa Xaa Xaa xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 70 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 85 0 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 100 105 Xaa Phe Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 3110 115 120 Xaa Xaa Xaa Gin Gin Thr Thr Leu Ser Leu Ala Ile Phe 125 130 wherein xaa at position 17 is Ser, Lys, Gly, Asp, met, Gin, or Arg; -aa at Position 18 is Asn, Xaa at position 19 is Met, Xaa at Position 20 is Ile, Xaa at Position 21 is Asp, Thr, Ser or Val; Xaa at Position 22 is Giu, Leu, Val or Gly; Xaa at Position 23 is Ile, Leu, Ser, or Arg; Xaa at Position 24 is Ile, Xaa at Position 25 is Thr, Xaa at Position 26 is His, Xaa at Position 27 is Leu, Xaa at Position 28 is Lys, Xaa at Position 29 is Gin, His, Leu, Phe, li e, Cys, Gin, Phe, Lys, Ile, Arg, Glu, Arg, Phe, Gly, Arg, Ala, Arg, Ala, Pro, Gly, or Gin; or Cys; or Ala; Giu, Gin, Asn, Trp, Pro, Ser, Ala, His, Asp, Asn, Gin, Val, Ala, Gly, Trp, Lys, Phe, Gly, His, Thr, Gly, Arg, As n, Val, Gly, Phe, Arg, Leu, Leu, Arg, Gin, Gly, Thr, Gin, Pro, Ser, Arg, Arg, Ser, Gly, Argf, Phe, or Leu; Pro, or Ala; Ala, or Trp; or Ala; Pro, Val or Trp; or Val; WO 97/12985 PCT/US96/15774 Xaa at position 30 is Pro, His, Thr, Gly, Xaa at position 31 is Pro, Asp, Gly, Ala, Xaa at position 32 is Leu, Val, Arg, Gin, Xaa at position 33 is Pro, Leu, Gin, Ala, Xaa at position 34 is Leu, Val, Gly, Ser, Arg, Ala, Phe, Ile or Met; Xaa at position 35 is Leu, Ala, Gly, Asn, Xaa at position 36 is Asp, Leu, or Val; Xaa at position 37 is Phe, Ser, Pro, Trp, Xaa at position 38 is Asn, or Ala; Xaa at position 40 is Leu, Trp, or Arg; Xaa at position 41 is Asn, Cys, Arg, Leu, Asp, Gin, Ser, Leu, or Lys; Arg, Leu, or Gin; Asn, Gly, Ala, or Glu; Thr, or Glu; Lys, Glu, Gin, Thr, Pro, Gin, or Val; or Ile; His, Met, or Pro; Xaa at positio Val, Glu Xaa at positio Gin, Arg, Xaa at position Glu, Asn, Xaa at position Trp, Asp, Xaa at position Lys, His, Xaa at position Xaa at position Lys, Thr, Xaa at position Xaa at position Ala, Ile, Xaa at position Xaa at position Xaa at position Xaa at position Lys, His, n 42 is Gly, Asp, Ser, Cys, Asn, Lys,-Thr, Leu, SPhe, Tyr, Ile, Met or Ala; n 43 is Glu, Asn, Tyr, Leu, Phe, Asp, Ala, Cys, Thr, Gly or Ser; S44 is Asp, Ser, Leu, Arg, Lys, Thr, Met, Trp, Gin, Ala or Pro; 45 is Gin, Pro, Phe, Val, Met, Leu, Thr, Lys, Asn, Arg, Ser, Ala, Ile, Glu or His; 46 is Asp, Phe, Ser, Thr, Cys, Glu, Asn, Gin, Ala, Tyr, Ile, Val or Gly; 47 is Ile, Gly, Val, Ser, Arg, Pro, or His; 48 is Leu, Ser, Cys, Arg, Ile, His, Phe, Glu, Ala, Met, Val or Asn; 49 is Met, Arg, Ala, Gly, Pro, Asn, His, or As 50 is Glu, Leu, Thr, Asp, Tyr, Lys, Asn, Ser, Val, His, Phe, Met or Gin; 51 is Asn, Arg, Met, Pro, Ser, Thr, or His; 52 is Asn, His, Arg, Leu, Gly, Ser, or Thr; 53 is Leu, Thr, Ala, Gly, Glu, Pro, Lys, Ser, 54 is Arg, Asp, Ile, Ser, Val, Thr, Gin, Asn, Ala or Leu; P; or Met; Xaa at position 55 is Arg, Thr, Val, Ser, Leu, or Gly; Xaa at osition 56 is Pro, Gly, Cys, Ser, Gin, Glu, Arg, His, WO 97/12985 534 PCTIUS96/1 5774 Thr, Ala, Tyr, Phe, Leu, Val or Lys; Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaai Xaa Xa Xaa Xaa~ Xaa 4 Xaa a Xaa a Xdaa Xaa a Xaa a Xaa a' Xaa a' Xa a at Xaa at Xaa a t Xaa a t at Position 57 i at Position 58 i at Position 59 i at Position 60 1 at Position 61 i at Position 62 i at Position 63 i~ at Position 64 i~ at Position 65 i, at Position 66 is at Position 67 i s at position 68 i s at Position 69 is It Position 70 is ~t Position 71 is Trp, or Asn; it Position 72 is t Position 73 is .t Position 74 is t Position 75 is Gin, or Leu; t Position 76 is t Position 77 is t Position 78 is tPosition 79 is Position 80 is Position 81 is Position 82 is His, Thr, Ser, A *Position 83 is Position 84 is Position 85 isI Position 86 is S s s 3Asn or Giy; Leu, Ser, Asp, Arg, Gin, Val, or Cys; Glu Tyr, His, Leu, Pro, or Arg; Ala, Ser, Pro, Tyr, Asn, or Thr; Phe, Asn, Giu, Pro, Lys, Arg, or Ser; Asn, His, Val, Arg, Pro, Thr, Asp, or Arg, Tyr, Trp, Lys, Ser, Hi s, Pro, or Ala, Asn, Pro, Ser, or Lys; Val, Thr, Pro, His, Leu, Phe, or Ser; Lys, Ile, Arg, Val, Asn, Giu, or Ser; Ser, Ala, Phe, Val, Gly, Asn, Ile, Pro Leu, Val, Trp, Ser, Ile, Phe,- Thr, or Gin, Ala, Pro, Thr, Giu, Arg, Trp, Gly Asn, Leu, Val, Trp, Pro, or Ala; Ala, Met, Leu, Pro, Arq, Giu, Thr, Gin Ile; Val; I or His; His; or Leu; Ser, Ala, Ile, Giu, Git Gil Met Lys Ser Ile Leu Lys Asn Leu Leu la, Pro, cys, 4eu, Vai Ser Ala Thr Trp, Gin, Tyr, Ala, Giu, Asn, 1Met, LAsp, .Thr, Giy, Ala, Arg, Ser, Asn, Val, Gly, Lys, Phe, Thr, Gly, Val, Ala, Leu, Pro, Asp, His, Ser, Arg, Pro, As n, Gly, Gly, Trp, Arg, or Asp; Thr, or Arg; Ala; Arg, Ser, Asn Thr Giu Met Gly Ala Trp, Trp, G Iu, Or Leu; Phe, Gly, Arg, Ile, Thr, Leu, Trp, Arg, Arg, Asp, Pro, Gly, or Asp; or Arg; Gly, or Asp; GiU, or Arg; Val, or Lys; Giu, Asn, Xaa Xaai Xaa Xaa Trp, Arg, or Met; Arg, Met, or Val; or Gin; Ala, or Lys; or Gly; Xaa at Position 87 is Leu, Ser, Trp, WO 97/12985 PCT/US96/15774 Xaa Xaa Xaa Xaa Xaa at position at position at position at position at position Leu; Ala, Thr, Ala, Ala, Pro, Lys, Asp, Pro, Pro, Phe, Arg, Cys, Ser, Ser, Arg, Ser, Ser, Val, Leu, Thr, Thr, Ser, Asn, Glu, or Trp; Val, Glu, Gly, Asp, Phe, Leu, Lys, His, His, Ile, Asp, Ala, Leu, Gin, Asn, or Ser; or Met; or His; Gly, Ile or Xaa at position 93 Xaa at position 94 Ala, or Pro; Thr, Arg, Asp, Ile, Gin, Phe, Pro, Leu, Ala, Val, or Arg; Lys, His, Xaa at position Lys, Ser, Xaa at position Xaa at position Xaa at position Glu, Gin, Xaa at position Gly, Ser, Xaa at position Xaa at position Tyr, Glu, Xaa at position Xaa at position Xaa at position Gin, Lys, Xaa at position Leu, Lys, Xaa at position Xaa at position 95 is Ala, 96 is 97 is 98 is Ser, His, Trp, Pro, Arg, Ile, or Tyz Val, Leu, Gly, Thr, Asn, Pro, Lys, Tyr, Gly, Ile, or Thr; Ile, Val, Lys, Ala, or Asn;. His, Ile, Asn, Leu, Asp, Ala, Thr, Phe, Met, Val, Lys, Arg, Tyr or Pro; 99 is Ile, Leu, Arg, Asp, Val, Pro, Gin, Phe, or His; 100 is Lys, Tyr, Leu, His, Arg, Ile, Ser, 101 is Asp, Pro, Met, Lys, His, Thr, Val, Asn, Ser, Ala, Gly, Ile, Leu, or Gin; Gin, or Pro; 102 is Gly, 103 is Asp, 104 is Trp, Ala, Phe, or 105 is Asn, Ile, Asp, or 106 is Glu, Leu, Glu, or Ser; Val, Cys, Gly; Pro, Ala, His; Ser, Ala, Lys, Ser, Tyr, or Pro; Tyr, Thr, Met, Pro, Leu, Phe, Ser, Trp, Gin, Tyr, 108 is Arg, Lys, Asp, Ala or Pro; Xaa at position 109 is Arg, Thr, Pro, Xaa at position 110 is Lys, Ala, Asn, Ser, or Trp; Xaa at position 111 is Leu, Ile, Arg, Xaa at position 112 is Thr, Val, Gin, Lys, Leu, Glu, Thr, Asp, Tyr, Thr, Thr, Tyr, Leu, Ile, Ile, Leu, Arg, Gly, Gin, Ser, Gin, or Pro; His, Ser, or Gly; His, Glu, or Met; Glu, His, Ser, or Phe; Xaa at position 113 is Phe, Ser, Cys, His, Gly, Trp, Tyr, Asp, WO 97/12985 536 PCT/US96/157 7 4 Lys, Leu, lie, Val or Asn; Xaa at position 114 is Tyr, Cys, His, Ser, Trp, Arg, or Leu; Xaa at position 115 is Leu, Asn, Val, Pro, Arg, Ala, His, Thr, Trp, or Met; Xaa at position 116 is Lys, Leu, Pro, Thr, Met, Asp, Val, Glu, Arg, Trp, Ser, Asn, His, Ala, Tyr, Phe, Gin, or Ile; Xaa at position 117 is Thr, Ser, Asn, Ile, Trp, Lys, or Pro; Xaa at position 118 is Leu, Ser, Pro, Ala, Glu, Cys, Asp, or Tyr; Xaa at position 119 is Glu, Ser, Lys, Pro, Leu, Thr, Tyr, or Arg; Xaa at position 120 is Asn, Ala, Pro, Leu, His, Val, or Gin; Xaa at position 121 is Ala, Ser, Ile, Asn, Pro, Lys, Asp, or Gly; Xaa at position 122 is Gln, Ser, Met, Trp, Arg, Phe, Pro, His, Ile, Tyr, or Cys; Xaa at position 123 is Ala, Met, Glu, His, Ser, Pro, Tyr, or Leu; wherein from 1 to 14 amino acids can optionally be deleted from the N-terminus and/or from 1 to 15 amino acids can optionally be deleted from the C-terminus of said modified human IL-3 amino acid sequence; and wherein from 1 to 44 of the amino acids designated by Xaa are different from the corresponding amino acids of native (1-133) human interleukin-3; and a colony stimulating factor; and wherein L 1 is a linker capable of linking R 1 to R2; with the proviso that at least R 1 or R2 is selected from the polypeptide of formula (III); and said hematopoietic protein can optionally be immediately preceded by (methionine-1), (alanine-1) or (methionine- 2 alanine-l). WO 97/12985537 PCT/US96/15774 3. The hematopoietic protein as recited in claim 1 wherein the polypeptide of (IV) is selected from the from the group consisting of; Ala Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg Pro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Ala Glu Asp Val Asp Ile Leu Met Glu Arg Asn Leu Arg Leu Pro Asn Leu Glu Ser Phe Val Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly Ile Glu Ala Ile Leu Arg Asn Leu Gin Pro Cys Leu Pro Ser Ala Thr Ala Ala Pro Ser Arg His Pro Ile Ile Ile Lys Ala Gly Asp Trp Gin Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu S Glu Gin Ala Gin Glu Gin Gin (SEQ ID NO:225); Ala Asn Cys jer Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg Pro Pro Asn Pro Leu Leu Asp Pro Asn Asn Leu Asn Ser Glu Asp Met Asp Ile Leu Met Glu Arg Asn Leu Arg Thr Pro Asn Leu Leu Ala Phe Val Arg Ala Val Lys His Leu Glu Asn Ala Ser Gly Ile Glu Ala Ile Leu Arg Asn Leu Gin Pro Cys Leu Pro Ser Ala Thr Ala Ala Pro Ser Arg His Pro Ile Ile Ile Lys Ala Gly Asp Trp Gin Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu Gin Ala Gin Glu Gln Gin (SEQ ID N0:226); 0 Ala Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Val Pro Pro Ala Pro Leu Leu Asp Ser Asn Asn Leu Asn Ser Glu Asp Met Asp Ile Leu Met Glu Arg Asn Leu Arg Leu Pro Asn Leu Leu Ala Phe Val Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly Ile Glu Ala Ile Leu Arg Asn Leu Gin Pro Cys Leu Pro Ser Ala Thr Ala Ala Pro Ser Arg His Pro Ile Ile Ile Lys Ala Gly Asp Trp Gin Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu Gin Ala Gin Glu Gin Gin (SEQ ID N0:227); and WO 97/12985 538 PCT/US96/15774 Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg Pro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp Val Ser Ile Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu Ser Phe Val Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly Ile Glu Ala Ile Leu Arg Asn Leu Gin Pro Cys Leu Pro Ser Ala Thr Ala Ala Pro Ser Arg His Pro Ile Ile Ile Lys Ala Gly Asp Trp Gin Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu Gin Ala Gin Glu Gin Gin (SEQ ID NO:228). 4. The hematopoietic protein as recited in claim 2 wherein the polypeptide of (IV) is selected from the from the group consisting of; Ala Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg Pro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Ala Glu Asp Val Asp Ile Leu Met Glu Arg Asn Leu Arg Leu Pro Asn Leu Glu Ser Phe Val Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly Ile Glu Ala Ile Leu Arg Asn Leu Gin Pro Cys Leu Pro Ser Ala Thr Ala Ala Pro Ser Arg His Pro Ile Ile Ile Lys Ala Gly Asp Trp Gin Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu Gin Ala Gin Glu Gin Gin (SEQ ID NO:225); Ala Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg Pro Pro Asn Pro Leu Leu Asp Pro Asn Asn Leu Asn Ser Glu Asp Met Asp Ile Leu Met Glu Arg Asn Leu Arg Thr Pro Asn Leu Leu Ala Phe Val Arg Ala Val Lys His Leu Glu Asn Ala Ser Gly Ile Glu Ala Ile Leu Arg Asn Leu Gin Pro Cys Leu Pro Ser Ala Thr Ala Ala Pro Ser Arg His Pro Ile Ile Ile Lys Ala Gly Asp Trp Gin Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu Gin Ala Gin Glu Gin Gin (SEQ ID NO:226); Ala Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys WO 97/12985 539 PCT/US96/1 5774 Val Pro Pro Ala Pro Leu Leu Asp Ser Asn Asn Leu Asn Ser Giu Asp Met Asp Ile Leu Met Giu Arg Asn Leu Arg Leu Pro Asn Leu Leu Ala Phe Val Arg Ala Val Ile Giu Ala Ile Leu Arg Asn Thr Ala Ala Pro Ser Arg His Trp Gin Giu Phe Arg Giu Lys Lys Asn Leu Giu Asn Ala Ser Gly Leu Gin Pro Cys Leu Pro Ser Ala Pro Ile Ile Ile Lys Ala Gly Asp Leu Thr Phe Tyr Leu Val Thr Leu Glu Gin Ala Gin Giu Gin Gin (SEQ ID N0:227); cand Asn Pro Vai Ser Giu Ala Gin Cys Pro Ser Phe Ala Ala Giu Ser Ala Ile Va 1 Ile Pro Phe Ile Pro Leu Arg Leu Ser Arg Met Leu Met Ala Arg Arg Ile Leu Asp Va 1 Asn His Asp Asp Arg Lys Leu Pro Giu Pro Asn Asn Gin Ile Ile Asn Leu Leu Pro Ile Asn Arg Giu Cys His Leu Leu As n Leu His Asn Pro Ala Pro Leu Asp Asn Ser Ser Lys Giu Leu Gly Ala Arg Asp Giu Ile Thr lie Tie Lys Ala Gly Asp Trp Lys Leu Thr Phe Tyr Leu Val Thr Leu Clii Gin Ala Gin Giu Gin Gin (SEQ ID N0:228). A hematopojetic protein comprising; sequence of the formula: an amino acid Ri-Ll-R 2 R2-Ll-Rl, Rl-R 2 or R2-Rj wherein Rl is a Polypeptide comprising; a modified human G-CSF amino acid sequence of the formula: 1 Xaa Xaa Xaa Gly Pro Ala Ser Ser Leu Pro Gin Ser Xaa Leu Leu Xad Xaa Xaa Glu Gin Val Xaa Lys Xaa Gin Gly Xaa Gly Ala Xaa Leu Gln Glu Xaa Leu Xaa Ala Thr Tyr Lys Leu Xaa Xaa Xaa Glu Xaa Xaa Val Xaa Xaa Gly His Ser Xaa Gly Ile Pro Trp WO 97/12985 540 PCT/US96/1 5 7 7 4 Ala Pro Leu Ser Ser Xaa Pro Ser Xaa Ala Leu Xaa Leu Ala Gly Xaa Leu Ser Gin Leu His Ser Gly Leu Phe Leu Tyr Gin Gly Leu Leu Gin Ala Leu Xaa Thr Leu Gin 120 Gin Gin Met Glu Gin Gly Ala Met 150 Gly Gly Val Leu Ser Tyr Arg Val i00 Glu Gly Ile Ser Pro Glu Leu Gly Pro Thr Leu 110 Xaa Asp Val Ala Asp Phe Ala Xaa Thr Ile Trp 130 Xaa Xaa Gly Met Ala Pro Ala Leu Gin Pro Thr 140 Pro Ala Phe Ala Ser Ala Xaa Gin Xaa Xaa Ala 160 Val Ala Ser Xaa Leu Gin Xaa Phe Leu Xaa Xaa 170 Leu Xaa Xaa Leu Ala Gin Pro (SEQ ID NO:1) 1 is Thr, Ser, Arg, Tyr or Gly; 2 is Pro or Leu; 3 is Leu, Arg, Tyr or Ser; 13 is Phe, Ser, His, Thr or Pro; 16 is Lys, Pro, Ser, Thr or His; 17 is Cys, Ser, Gly, Ala, Ile, Tyr or Arg; 18 is Leu, Thr, Pro, His, Ile or Cys; 22 is Arg, Tyr, Ser, Thr or Ala; 24 is Ile, Pro, Tyr or Leu; 27 is Asp, or Gly; 30 is Ala, Ile, Leu or Gly; 34 is Lys or Ser; 36 is Cys or Ser; 42 is Cys or Ser; 43 is His, Thr, Glv. Val T.c m -i- wherein Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa position position position position position position position position position position position position position position position 4 i ys, Trp, Ala, Arg, Cys, or Leu; p Xaa at position 44 is Pro, Gly, Arg, Asp, Val, Ala, His, Trp, Gln, or Thr; Xaa at position 46 is Glu, Arg, Phe, Arg, Ile or Ala; Xaa at position 47 is Leu or Thr; Xaa at position 49 is Leu, Phe, Arg or Ser; Xaa at position 50 is Leu, Ile, His, Pro or Tyr; Xaa at position 54 is Leu or His; Xaa at position 64 is Cys or Ser; Xaa at position 67 is Gin, Lys, Leu or Cys; Xaa at position 70 is Gin, Pro, Leu, Arg or Ser; Xaa at position 74 is Cys or Ser; WO 97/12985 PCTIUS96/15774 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa pos.1-ion position position position position position position position position position position position position position 104 108 115 120 123 144 146 147 156 159 162 163 169 170 Asp, Gly or Val; Leu, Ala, Val, Arg, Trp, Gin or Gly; Thr, His, Leu or Ala; Gin, Gly, Arg, Lys or His Glu, Arg, Phe or Thr Phe, His, Arg, Pro, Leu, Gin or Glu; Arg or Gin; Arg or Gin; His, Gly or Ser; Ser, Arg, Thr, Tyr, Val or Gly; Glu, Leu, Gly or Trp; Val, Gly, Arg or Ala; Arg, Ser, Leu, Arg or Cys; His, Arg or Ser; wherein optionally 1-11 amino acids from the N-terminus and from the C-terminus can be deleted from said modified human G-CSF amino acid sequence; and wherein the N-terminus is joined to the C-terminus directly or through a linker capable of joining the N-terminus to the C-terminus and having new C- and N-termini at amino acids; 38-39 39-40 40-41 41-42 42-43 43-44 45-46 48-49 49-50 52-53 53-54 54-55 55-56 56-57 57-58 58-59 59-60 60-61 61-62 62-63 63-64 64-65 65-66 66-67 67-68 68-69 69-70 70-71 71-72 91-92 92-93 93-94 94-95 95-96 96-97 97-98 98-99 99-100 123-124 124-125 125-126 126-127 128-129 128-129 129-130 130-131 131-132 132-133 133-134 134-135 135-136 136-137 137-138 138-139 139-140 140-141 141-142 or 142-143 respectively; WO 97/12985PC/S6I57 542 PTU9/57 wherein R2 is a Polypeptide comprising; a modified human TL-3 amino acid sequence of the formula: Ala Pro Met Thr Gin Thr Thr Ser Leu Lys Thr Ser Trp Val Asn 1 5 10 Cys Xaa Xa.- Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 25 0 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Asn Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 55 Xaa 70 Xaa 85 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 100 Xaa Xaa Xaa Xaa Phe Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 110 115 120 Xaa Xaa Xaa Gin Gin Thr Thr Leu Ser Leu Ala Ile Phe 125 130 (SEQ ID NO:2) wherein Xaa at position 17 is Ser, Lys, Gly, Asp, Met, Gin, or Arg; Xaa at position 18 is Asn, His, Leu, Ile, Phe, Arg, or Gin; Xaa at position 19 is Met, Phe, Ile, Arg, Gly, Ala, or Cys; Xaa at position 20 is Ile, Cys, Gin, Glu, Arg, Pro, or Ala; WO 97/12985 PCT/US96/15774 Xaa at PositI-.n 21 is Asp, Thr, Ser or Val; Xaa at Position 22 is Glu, Leu, Val or Gly; Phe, Lys, Arg, Ala, Gly, Giu, Gi Asn, Trp, Pro, Ser, Ala, His, Asp, Asn, Gin, Xaa at Position 23 is Ile, Leu, Ser, Xaa at positio, Xaa at positioT Xaa at Positior Xaa at Positior Xaa at Position Xaa at position Xaa at Position Xaa at Position Xaa at Position Xaa at Posit-,)n Xaa at Position Arg, Ala, Xaa at Position Xaa at position Xaa at Position Xaa at position Xaa at Position Xaa at position Xaa at Position Val, Giu, Xaa at Position Gin, Arg, Xaa at Position Giu, Asn, Xaa at Position Trp, Asp, Xaa at Position Lys, His, Xaa at Position or Arg; i24 is Ile, Gly, 25 is Thr, His, 126 is His, Thr, 127 is Leu, Gly, L28 is Lys, Arg, 29 is Gin, Asn, 30 is Pro, His, 31 is Pro, Asp, 32 is Leu, Val, 33 is Pro, Leu, 34 is Leu, Val, Phe, Ile or Met;- 35 is Leu, Ala, 36 is Asp, Leu, 37 is Phe, Ser, 38 is Asn, or Al~ 40 is Leu, Trp, 41 is Asn, Cys, 42 is Gly, Asp, I Y rie, Val1, Giy, Phe, Arg, Leu, Leu, Thr, G ly, Arg, Gin, Giy, Arg, Gin, Gly, Thr, Gin, Pro, Gly, Ala, Gin, Ala, Ser, Ser, Arg, Arg, Ser, Gly, Arg, Asp, Arg, As n, Thr, Lys, Phe, or Leu; Pro, or Ala; Ala, or Trp; or Ala; Pro, Val or Trp; or Val; GlJP,Ser, Leu, or Leu, or Gin; Gly, Ala, or Giu; or Gu; Giu, Gin, Thr, Lys; Giy, Asn, Pro, Gin, or Val; or Val; Pro, Trp, or I Arg; krg, Leu, His, er, Cys, Asn, le; Met, Lys, or Pro; Thr, Leu, Phe, Tyr, Ile, Met or Ala; 43 is Giu, Asn, Tyr, Leu, Phe, Asp, Ala, C Thr, Gly or Ser; 44 is Asp, Ser, Leu, Arg, Lys, Thr, Met, Tr Gin, Ala or Pro; 45 is Gin, Pro, Phe, Val, Met, Leu, Thr, Ly Asn, Arg, Ser, Ala, Ile, Glu or His; 46 is Asp, Phe, Ser, Thr, Cys, Glu, Asn, Gl Ala, Tlyr, Ile, Val or Gly; 47 is Ile, Gly, Val, Ser, Arg, Pro, or His; Ps, n, WO 97/12985 PCT/US96/15774 Xaa at position 48 is Leu, Ser, Cys, Arg, Ile, His, Phe, Giu, Lys, Thr, Ala, Xaa at position 49 is Xaa at position 50 is Ala, Ile, Val, I Xaa at position 51 is Xaa at position 52 is Xaa at posit..on 53 is Xaa at position 54 is Lys, His, Ala or Xaa at position 55 is Xaa at position 56 is Thr, Ala, Tyr, P Xaa at position 57 is Xaa at position 58 is Xaa at position 59 is Xaa at position 60 is Xaa at position 61 is Xaa at position 62 is Xaa at position 63 is Xaa at position 64 is Xaa at position 65 is Xaa at position 66 is I Xaa at position 67 is Xaa at position 68 is I Xaa at position 69 is C Xaa at position 70 is i Xaa at position 71 is z Trp, or Asn; Xaa at position 72 is S Xaa at position 73 is A Xaa at position 74 is Xaa at position 75 is G Gin, or Leu; Xaa at position 76 is S 4et, Val or Asn; Met, Arg, Ala, Gly, Glu, Leu, Thr, Asp, is, Phe, Met or Gin Asn, Arg, Met, Pro, Asn, His, Arg, Leu, Leu, Thr, Ala, Gly, Arg, Asp, Ile, Ser, Leu; Arg, Thr, Val, Ser, Pro, Gly, Cys, Ser, Pro, Tyr, Ser, Gly, Glu, Val, Leu, Gin, Asn, Lys, Thr, Ser, Pro, Thr, His, Asn, or Asp; Ser, or His; or Thr; Lys, Ser, or Met; Gin, Asn, or Gly; Glu, Arg, His, he, Asn Leu, Glu Ala, Phe, Asn, Arg, Ala, Val, Lys, Ser, Leu, lIn, Asn, la, ;er, la, Leu, Val or Lys or Gly; Ser, Asp, Arg, Tyr, His, Leu, Gn Ser, Asn, His, Tyr, Asn, Thr, Ile, Ala, Val, Ala, Leu, Met, Glu, Glu, Pro, Glu, Val, Trp, Pro, Pro, Arg, Phe, Trp, Pro, Val, Leu, Met, Asp, Tyr, Pro, Arg, Lys, Ser, His, Val, Val, Ser, Thr, Trp, Pro, Ala, Leu, Gin, Val, or Cys; Pro, or Arg; Asn, or Thr; Lys, Arg, or Ser; Pro, Thr, Asp, or Ile; Ser, His, Pro, or Val; or Lys; Leu, Phe, or Ser; Asn, Glu, or Ser; Gly, Asn, Ile, Pro, or His; Ile, Phe, Thr, or His; Glu, Arg, Trp, Gly, or Leu; Pro, or Ala; Arg, Glu, Thr, Gin, His, Ser, Asn, Arg, or Asp; Gly, Thr, or Arg; Ile, Met, Thr, Pro, Arg, Gly, Ala; lu, Lys, Gly, Asp, Pro, Trp, Arg, Ser, er, Val, Ala, Asn, Trp, Glu, Pro,.Gly, or Asp; WO 97/12985 545 Xaa at position 77 is Ile, Ser, Arg, Thr, or Leu; PCT/US96/15774 Xaa at position 78 is Xaa at position 79 is Xaa at position 80 is Xaa at position 81 is Xaa at position 82 is His, Thr, Ser, Xaa at position 83 is Xaa at position 84 is Xaa at position 85 is Xaa at position 86 is Xaa at position 87 is Xaa at position 88 is Xaa at position 89 is Xaa at position 90 is Xaa at position 91 is Xaa at position 92 is Leu; Xaa at position 93 is Xaa at position 94 is Ala, or Pro; Xaa at position 95 is Lys, Ser, Ala, Xaa at position 96 is Xaa at position 97 is Xaa at position 98 is Glu, Gin, Ser, Xaa at position 99 is Gly, Ser, Phe, Xaa at position 100 i Xaa at position 101 i Tyr, Glu, Asn, Xaa at position 102 i Xaa at position 103 i Xaa at position 104 i Leu, Lys, Asn, Leu, Leu, Ala, Pro, Cys, Leu, Pro, Leu, Ala, Thr, Ala, Ala, Pro, Thr, Arg, His, Trp, Pro, Ile, Ala, Thr, Trp, Gin, Gin, Tyr, Ala, Glu, Asn, Cys, Ser, Lys, Asp, Pro, Pro, Phe, Asp, Ile, Gin, Phe, Lys, Val, Ser, Asn, Val, Gly, Lys, Phe, Thr, Gly, Val, Arg, Trp, Arg, Cys, Ser, Ser, Arg, Ser, Ser, Pro, Ile, Tyr, Lys, Glu, Phe, Gly, or Met, Arg, Ile, G1 Gly, Thr, Leu, G1 Ala, Trp, Arg, Va Trp, Arg, Asp, G1 Ile, Met or Val; Trp, Arg, or Met; Arg, Met, or Val; or Gin; Ala, or Lys; or Gly; Val, or Trp; Leu, Val, Glu, Hi; Thr, Gly, Asp, Il Thr, Phe, Leu, As Ser, Lys, His, Al Arg; y, or Asp; u, or Arg; 1, or Lys; U, Asn, s, e, p, a, Asn, or Ser; or Met; or His; Gly, Ile or or Arg; Lys, His, Asn, Glu, Pro, Leu, Ala, Val, Leu, Gin, Arg, Val, or Tyr; Gly, Ile, Leu, Gly, Thr, Asn, or Thr; Ala, Leu, or Asn; Asp, Ala, Thr, His, Ile, Asn, Phe, Met, Val, Lys, Arg, Tyr or Pro; Ile, Leu, Arg, Asp, Val, Pro, Gin, or His; s Lys, Tyr, Leu, His, Arg, Ile, Ser, Gin, s Asp, Pro, Met, Lys, His, Thr, Val, Ser, Ala, Gly, Ile, Leu, or Gin; s Gly, Leu, Glu, Lys, Ser, Tyr, or Pro; s Asp, or Ser; s Trp, Val, Cys, Tyr, Thr, Met, Pro, Leu, or Pro; WO 97/12985 PCT/US96/15774 Gin, Lys, Ala, Phe, or Gly; Xaa at position 105 is Asn, Pro, Ala, Leu, Lys, Ile, Asp, or His; Xaa at position 106 is Glu, Ser, Ala, Xaa at position 108 is Arg, Lys, Asp, Ala or Pro; Xaa at position 109 is Arg, Thr, Pro, Xaa at position 110 is Lys, Ala, Asn, Ser, or Trp; Xaa at position 111 is Leu, Ile, Arg, Xaa at position 112 is Thr, Val, Gin, Xaa at position 113 is Phe, Ser, Cys, Lys, Leu, Ile, Val or Asn; Xaa at position 114 is Tyr, Cys, His, Xaa at position 115 is Leu, Asn, Val, Trp, or Met; Xaa at position 116 is Lys, Leu, Pro, Phe, Ser, Trp, Gin, Tyr, Lys, Leu, Glu, Thr, Asp, Tyr, His, Ser, Pro, Thr, Ile, Thr, Ile, Tyr, Leu, Leu, Arg, or Met; Glu, His, Gly, Trp, Gly, Gin, Ser, Gin, or Pro; His, Ser, or Gly; His, Glu, Ser, or Phe; Tyr, Asp, or Leu; His, Thr, Trp, Arg, Arg, Ala, Thr, Met, Asp, Val, Glu. Arg, Trp, Ser, Asn, His, Ala, Tyr, Phe, Gin, or Ile; Xaa at position 117 is Thr, Ser, Asn, Ile, Trp, Lys, or Pro; Xaa at position 118 is Leu, Ser, Pro, Ala, Glu, Cys, Asp, or Tyr; Xaa at position 119 is Glu, Ser, Lys, Pro, Leu, Thr, Tyr, or Arg; Xaa at position 120 is Asn, Ala, Pro, Leu, His, Val, or Gin; Xaa at position 121 is Ala, Ser, Ile, Asn, Pro, Lys, Asp, or Gly; Xaa at position 122 is Gin, Ser, Met, Trp, Arg, Phe, Pro, His, Ile, Tyr, or Cys; Xaa at position 123 is Ala, Met, Glu, His, Ser, Pro, Tyr, or Leu; wherein from 1 to 14 amino acids can optionally be deleted from the N-terminus and/or from 1 to 15 amino acids can optionally be deleted from the C-terminus of said modified human interleukin-3 amino acid sequence; and wherein from 0 to 44 of the amino acids designated by Xaa are different from the corresponding amino acids of native (1-133) human interleukin-3; and WO 97/12985 PrCT/ITSA/1577A 547 wherein the N-terminus is joined to the C-terminus directly or through a linker (L2) capable of joining the N-terminus to the C-terminus and having new C- and N-termini at amino acids; 26-27 49-50 83-84 27-28 50-51 84-85 28-29 51-52 85-86 29-30 52-53 86-87 30-31 53-54 87-88 31-32 54-55 88-89 32-33 64-65 89-90 33-34 65-66 90-91 34-35 66-67 91-92 35-36 67-68 92-93 36-37 68-69 97-98 37-38 69-70 98-99 38-39 70-71 99-100 39-40 71-72 100-101 40-41 72-73 101-102 41-42 82-83 102-103 or 103-104 respectively; wherein L1 is a linker capable of linking R 1 to R2; and said hematopoietic protein can optionally be immediately preceded by (methionine- 1 (alanine- 1 or (methionine- 2 alanine- 1 6. A hematopoietic protein comprising; an amino acid sequence of the formula: R1-L1-R2, R2-L1-R1, R1-R2, or R2-R1 wherein R1 is a polypeptide comprising; a modified human G-CSF amino acid sequence of the formula: 1 Xaa Xaa Xaa Gly Pro Ala Ser Ser Leu Pro Gin Ser Xaa WO 97/12985 548 PCT/US96/1577 4 Leu Leu Xaa Xaa Xaa Glu Gin Val Xaa Lys Xaa Gin Gly Xaa Gly Ala Xaa Leu Xaa Glu Xaa Ala Pro Leu Xaa Leu Ser Leu Gin Ala Xaa Thr Leu 120 Gin Gin Met Gin Gly Ala 150 Gly Gly Val Ser Tyr Arg wherein Xaa at posit Xaa at posit Xaa at posit: Xaa at posit: Xaa at posit: Xaa at posit: Xaa at posit: Xaa at posit: Xaa at posit: Xaa at posit: Xaa at posit Xaa at posit Xaa at posit Xaa at positj Xaa at positj Gin Xaa Ser Gin Leu Gin Glu Met Leu Glu Val Ser Leu Glu Xaa Xaa Pro Val Xaa Xaa Xaa His Gly Asp Xaa Ala Ala Leu Xaa Pro Ser Ile 110 Val Gly 140 Phe Ser Xaa Gly Ser Gly Ser Ala Met Ala Xaa Ala His Xaa Leu Pro Asp Ala Ser Leu Thr Ser Ala Phe Glu Phe Pro Ala Gin Tyr Xaa Leu Leu Leu Ala Ala Xaa Xaa Xaa Lys Leu Gly Ile Xaa Leu Tyr Gin 100 Gly Pro Xaa Thr 130 Leu Gin Gin Xaa 160 Phe Leu Xaa Pro Ala Gly Thr Ile Pro Xaa Xaa Xaa Trp Gly Leu Leu Trp Thr Ala Xaa 170 Val ion ion ion ion ion ion ion ion ion ion ion ion ion Lon ion Leu Xaa Xaa Leu Ala Gin Pro (SEQ ID NO:1) 1 is Thr, Ser, Arg, Tyr or Gly; 2 is Pro or Leu; 3 is Leu, Arg, Tyr or Ser; 13 is Phe, Ser, His, Thr or Pro; 16 is Lys, Pro, Ser, Thr or His; 17 is Cys, Ser, Gly, Ala, Ile, Tyr or Arg; 18 is Leu, Thr, Pro, His, Ile or Cys; 22 is Arg, Tyr, Ser, Thr or Ala; 24 is Ile, Pro, Tyr or Leu; 27 is Asp, or Gly; 30 is Ala, Ile, Leu or Gly; 34 is Lys or Ser; 36 is Cys or Ser; 42 is Cys or Ser; 43 is His, Thr, Gly, Val, Lys, Trp, Ala, )r Leu; Arg, Cys, c WO 97/12985 PCTrF/TQo/15 77A 549 Xaa at pos'.-ion 44 is Pro, Gly, Arg, Asp, Val, Ala, His, Trp, Gin, or Thr; 1 xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa position position position position position position position position position position position position position position position position position position position position position posicion position 46 47 49 50 54 64 67 70 74 104 108 115 120 123 144 146 147 156 159 162 163 169 170 is is is is is is is is is is is is is is is is is is is is is is is Glu, Arg, Phe, Arg, Ile or Ala; Leu or Thr; Leu, Phe, Arg or Ser; Leu, Ile, His, Pro or Tyr; Leu or His; Cys or Ser; Gin, Lys, Leu or Cys; Gin, Pro, Leu, Arg or Ser; Cys or Ser; Asp, Gly or Val; Leu, Ala, Val, Arg, Trp, Gin or Gly; Thr, His, Leu or Ala; Gin, Gly, Arg, Lys or His Glu, Arg, Phe or Thr Phe, His, Arg, Pro, Leu, Gin or Glu; Arg or Gin; Arg or Gin; His, Gly or Ser; Ser, Arg, Thr, Tyr, Val or Gly; Glu, Leu, Gly or Trp; Val, Gly, Arg or Ala; Arg, Ser, Leu, Arg or Cys; His, Arg or Ser; wherein optionally 1-11 amino acids from the N-terminus and from the C-terminus can be deleted from said modified human G-CSF amino acid sequence; and wherein the N-terminus is joined to the C-terminus directly or through a linker capable of joining the N-terminus to the C-terminus and having new C- and N-termini at amino acids; 38-39 39-40 40-41 41-42 42-43 43-44 45-46 48-49 49-50 52-53 53-54 54-55 55-56 56-57 62-63 63-64 64-65 65-66 66-67 67-68 68-69 69-70 70-71 71-72 91-92 92-93 93-94 94-95 123-124 124-125 125-126 126-127 128-129 128-129 129-130 130-131 131-132 132-133 133-134 134-135 135-136 136-137 WO 97/12985 550 PCTIUS96/'1577 4 57-58 58-59 59-6O 60-61 61-62 95-96 96-97 97-98 98-99 99 -100 137-13 8 138-13 9 139 -140 140 -141 or -142-143 respectively; and R2 is a Polypeptide comprising; a modified human IL-3 amino acid sequence of the formula: Ala Pro Met Thr Gin Thr Thr Ser Leu Lys Thr Ser Trp Val Asn 1 510 Cys Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 25 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Asn Xaa Xaa Xaa Xaa Xaa Xaa 35 40 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 55 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 100 105 Xaa Phe Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 110 115 120 Xaa Xaa Xaa Gin Gin Thr Thr Leu Ser Leu Ala Ile Phe WO 97/12985 PCT/US96/15774 125 wherein Xaa at position 17 Xaa at position 18 is Asn, Xaa at position 19 is Met, Xaa at position 20 is Ile, Xaa at position 21 is Asp, Thr, Ser or Val; Xaa at position 22 is Glu, 0 Leu, Val or Gly; 130 is Ser, Lys, Gly, Asp, Met, Gin, or Arg; His, Phe, Cys, Phe, Leu, Ile, Gin, Lys, Ile, Arg, Glu, Arg, Phe, Arg, Gly, Ala, Arg, Pro, Ala, Gly, or Gin; or Cys; or Ala; Glu, Gin, Asn, Trp, Pro, Ser, Ala, His, Asp, Asn, Gin, Xaa at position 23 is Ile, Val, Ala, Gly, Trp, Lys, Phe Leu, Ser, Xaa at position Xaa at position Xaa at position Xaa at posit',-n Xaa at position Xaa at position Xaa at position Xaa at position Xaa at position Xaa at position Xaa at position Arg, Ala, Xaa at position Xaa at position Xaa at position Xaa at position Xaa at position Xaa at position Xaa at position Val, Glu, Xaa at position Gin, Arg, Xaa at position or Arg; 24 is I 25 is T 26 is H 27 is L 28 is L 29 is G 30 is P: 31 is P: 32 is L 33 is P: 34 is L< Phe, Il 35 is L 36 is Ai 37 is P1 38 is As 40 is L( 41 is As 42 is G: Phe, Ty] I le, hr, is, eu, ys, In, ro, ro, eu, ro, eu, Gly, His, Thr, Gly, Arg, Asn, His, Asp, Val, Leu, Val, Val, Gly, Phe, Arg, Leu, Leu, Thr, Gly, Arg, Gin, Gly, Arg, Gin, Gly, Thr, Gin, Pro, Gly, Ala, Gin, Ala, Ser, Ser, Arg, Arg, Ser, Gly, Arg, Asp, Arg, Asn, Thr, Lys, Phg, or Leu; Pro, or Ala; Ala, or Trp; or Ala; Pro, Val or Trp; or Val; Gin, Ser, Leu, or Lys; Leu, or Gin; Gly, Ala, or Glu; or Glu; Glu, Gin, Thr, e or Met; eu, Ala, Gly, Asn, Pro, Gin, or Val; sp, he, sn, eU, sn, ly, Leu, or Val; Ser, Pro, Trp, or Ile; or Ala; Trp, or Arg; Cys, Arg, Leu, His, Met, Asp, Ser, Cys, Asn, Lys, or Pro; Thr, Leu, r, Ile, Met or Ala; 43 is Glu, Asn, Tyr, Leu, Phe, Asp, Ala, Cys, Thr, Gly or Ser; 44 is Asp, Ser, Leu, Arg, Lys, Thr, Met, Trp, WO 97/12985 PCT/US96/15774 Glu, Asn, Xaa at position Trp, Asp, Xaa at position Lys, His, Xaa at position Xaa at position Lys, Thr, Xaa at position Xaa at position Ala, Ile, Xaa at position Xaa at position Xaa at position Xaa at position Lys, His, Xaa at position Xaa at position Thr, Ala, Xaa at position Xaa at position 5 Xaa at position E Xaa at position Xaa at position Xaa at position E Xaa at position E Xaa at position 6 Xaa at position 6 Xaa at position 6 Xaa at position 6 Xaa at position 6 Xaa at position 6 Xaa at position 7 Xaa at position 7 Gin, Ala or Pro; 45 is Gin, Pro, Phe, Val, Met, Leu, Thr, Lys, Asn, Arg, Ser, Ala, Ile, Glu or His; 46 is Asp, Ala, Tyr, 47 is Ile, 48 is Leu, Ala, Met, 49 is Met, 50 is Glu, Val, His, 51 is Asn, 52 is Asn, 53 is Leu, 54 is Arg, Phe, Ser, Thr, Cys, Ile, Val or Gly; Gly, Val, Ser, Arg, Ser, Cys, Arg, Ile, Val or Asn; Arg, Ala, Gly, Pro, Leu, Thr, Asp, Tyr, Phe, Met or Gin; Glu, Asn, Gin, Pro, His, Asn, Lys, Thr, Sert, Pro, Thr, or His; Phe, Glu, His, Asn, or Asp; Ser, Arg, His, Thr, Met, Arg, Ala, Pro, Ser, Leu, Gly, Gly, Glu, or His; or Thr; Lys, Ser, Gin, Asn, or Met; Asp, Ile, Ser, Val, Ala or Leu; 55 is Arg, Thr, Val, Ser, Leu, 56 is Pro, Tyr, Phe, Gly, Cys, Ser, Gin, Leu, Val or Lys; or Gly; Glu, Arg, His, Asn or Gly; Leu, Ser, Asp, Arg, Glu Tyr, His, Leu, Ala, Ser, Pro, Tyr, Phe, Asn, Glu, Pro, Asn, His, Val, Arg, Arg, Tyr, Trp, Lys, Ala, Asn, Pro, Ser, Val, Thr, Pro, His, Lys, Ile, Arg, Val, Ser, Ala, Phe, Val, Leu, Val, Trp, Ser, Gin, Ala, Pro, Thr, Asn, Leu, Val, Trp, Ala, Met, Leu, Pro, Gin, Val, or Cys; Pro, or Arg; Asn, or Thr; Lys, Arg, or Ser; Pro, Thr, Asp, or Ser, His, Pro, or or Lys; Leu, Phe, or Ser; Asn, Glu, or Ser; Gly, Asn, Ile, Pro, Ile, Phe, Thr, or I Glu, Arg, Trp, Gly, Pro, or Ala; Arg, Glu, Thr, Gin, Ile; Val; or His; [is; or Leu; Trp, or Asn; WO 97/12985 PCTIUS96/15774 Xaa at position 72 is Ser, Xaa at position 73 is Ala, Xaa at posit-,on 74 is Ile, Xaa at position 75 is Glu, Gin, or Leu; Xaa at position 76 is Ser, Xaa at position 77 is Ile, Xaa at position 78 is Leu, Xaa at position 79 is Lys, Xaa at position 80 is Asn, Xaa at position 81 is Leu, Xaa at position 82 is Leu, His, Thr, Ser, Ala, Xaa at position 83 is Pro, Xaa at position 84 is Cys, Xaa at position 85 is Leu, Xaa at position 86 is Pro, Xaa at position 87 is Leu, Xaa at position 88 is Ala, Xaa at position 89 is Thr, Xaa at position 90 is Ala, Xaa at position 91 is Ala, Xaa at position 92 is Pro, Leu; Xaa at position 93 is Thr, Xaa at position 94 is Arg, Ala, or Pro; Xaa at position 95 is His, Lys, Ser, Ala, Trp, P Xaa at position 96 is Pro, Xaa at position 97 is Ile, Xaa at position 98 is His, Glu, Gin, Ser, Phe, M Xaa at position 99 is Ile, Gly, Ser, Phe, or His Glu Glu Met Lys Val Ser Ala Thr Trp Gin Gin Tyr, Ala Glu Asn Cys Ser, Lys, Asp, Pro, Pro, Phe, Asp, Ile, Gin, 'he, Lys, Val, Ile, Met, ,Asp, ,Thr, SGly, Ala, ,Arg, Ser, Asn, Val, SGly, ,Lys, Phe, Thr, Gly, ,Val, ,Arg, Trp, Arg, Cys, Ser, Ser, Arg, Ser, Ser, Pro, Ile, c Tyr, Lys, Ala, His, Asn, Leu, Ser, Gly, Pro, Arg, Gly, Asp, Pro, Trp, Asn, Trp, Glu, Thr, or Leu; Glu, Phe, Gly, Met, Arg, Ile, Gly, Thr, Leu, Ala, Trp, Arg, Trp, Arg, Asp,. Ile, Met or Val; Trp, Arg, or Me Arg, Met, or Va or Gin; Arg, Thr, Ala; Arg, Asp; Arg; Ser, Pro, Gly, or Asp; or Arg; Gly, or Glu, or Val, or Asp; Arg; Lys; Glu, Asn, Ala, or Lys; or Gly; Val, or Trp; Leu, Val, Glu, Thr, Gly, Asp, Thr, Phe, Leu, Ser, Lys, His, His, Ile, Asp, Ala, Leu, Gin, Asn, or Ser; or Met; or His; Gly, Ile or or Arg; Lys, His, Asn, Glu, Pro, Leu, Ala, Val, Arg, Val, Leu, Gly, Thr, Asn, or Tyr; Gly, Ile, or Thr; Ala, or Asn; Leu, Asp, Ala, Thr, Asn, et, Val, Lys, Arg, Tyr or Pro; Leu, Arg, Asp, Val, Pro, Gin, WO 97/12985 PCT/US96/15774 Xaa at position 100 is Lys, Tyr, Leu, His, Arg, Ile, Ser, Gin, or Pro; Xaa at position 101 is Asp, Pro, Met, Lys, His, Thr, Val, Tyr, Glu, Asn, Ser, Ala, Gly, Ile, Leu, or Gin; Xaa at position 102 is Gly, Leu, Glu, Xaa at position 103 is Asp, or Ser; Xaa at position 104 is Trp, Val, Cys, Gin, Lys, Ala, Phe, or Gly; Xaa at position 105 is Asn, Pro, Ala, Lys, Ser, Tyr, or Pro; Tyr, Thr, Met, Pro, Leu, Phe, Ser, Trp, Gin, Tyr, Leu, Lys, Ile, Asp, or His; Xaa at position 106 is Glu, Ser, Ala, Lys, Thr, Ile, Gly, or Pro; Xaa at position 108 is Arg, Lys, Asp, Leu, Thr, Ile, Gin, His, Ser, Ala or Pro; Xaa at position 109 is Arg, Thr, Pro, Glu, Tyr, Leu, Ser, or Gly; Xaa at position 110 is Lys, Ala, Asn, Thr, Leu, Arg, Gin, His, Glu, Ser, or Trp; Xaa at position 111 is Leu, Ile, Arg, Asp, or Met; Xaa at position 112 is Thr, Val, Gin, Tyr, Glu, His, Ser, or Phe; Xaa at position 113 is Phe, Ser, Cys, His, Gly, Trp, Tyr, Asp, Lys, Leu, Ile, Val or Asn; Xaa at position 114 is Tyr, Cys, His, Ser, Trp, Arg, or Leu; Xaa at position 115 is Leu, Asn, Val, Pro, Arg, Ala, His, Thr, Trp, or Met; Xaa at position 116 is Lys, Leu, Pro, Thr, Met, Asp, Val, Glu, Arg, Trp, Ser, Asn, His, Ala, Tyr, Phe, Gin, or Ile; Xaa at position 117 is Thr, Ser, Asn, Ile, Trp, Lys, or Pro; Xaa at position 118 is Leu, Ser, Pro, Ala, Glu, Cys, Asp, or Tyr; Xaa at position 119 is Glu, Ser, Lys, Pro, Leu, Thr, Tyr, or Arg; Xaa at position 120 is Asn, Ala, Pro, Leu, His, Val, or Gin; Xaa at position 121 is Ala, Ser, Ile, Asn, Pro, Lys, Asp, or Gly; Xaa at position 122 is Gin, Ser, Met, Trp, Arg, Phe, Pro, His, Ile, Tyr, or Cys; Xaa at position 123 is Ala, Met, Glu, His, Ser, Pro, Tyr, or Leu; wherein from 1 to 14 amino acids can optionally be deleted from the N-terminus and/or from 1 to 15 amino acids can WO 97/12985 nn'T,'l T -s T j 55 5 rl/U~UY6/15774 optionally be deleted from the C-terminus; and wherein from 1 to 44 of the amino acids designated by Xaa are different from the corresponding amino acids of native (1-133) human interleukin-3; wherein L 1 is a linker capable of linking R 1 to R2; and additionally said hematopoietic protein can be immediately preceded by (methionine-1), (alanine- 1 or (methionine-2, alanine- 1 7. A hematopoietic protein comprising-; an amino acid sequence of the formula: RI-L1-R2, R2-L1-R1, R1-R2, or R2-R1 wherein R1 is a polypeptide comprising; a modified human G-CSF amino acid sequence of the formula: 1 Xaa Xaa Xaa Gly Pro Ala Ser Ser Leu Pro Gin Ser Xaa Leu Leu Xaa Xaa Xaa Glu Gin Val Xaa Lys Xaa Gin Gly Xaa Gly Ala Xaa Leu Gin Glu Xaa Leu Xaa Ala Thr Tyr Lys Leu Xaa Xaa Xaa Glu Xaa Xaa Val Xaa Xaa Gly His Ser Xaa Gly Ile Pro Trp Ala Pro Leu Ser Ser Xaa Pro Ser Xaa Ala Leu Xaa Leu Ala Gly Xaa Leu Ser Gin Leu His Ser Gly Leu Phe Leu Tyr Gin Gly Leu 100 Leu Gin Ala Leu Glu Gly Ile Ser Pro Glu Leu Gly Pro Thr Leu 110 Xaa Thr Leu Gin Xaa Asp Val Ala Asp Phe Ala Xaa Thr Ile Trp WO 97/12985 PCT/Ui I S/1 CTT77 556 120 130 Gin Gin Met Glu Xaa Xaa Gly Met Ala Pro Ala Leu Gin Pro Thr 140 Gin Gly Ala Met Pro Ala Phe Ala Ser Ala Xaa Gin Xaa Xaa Ala 150 160 Gly Gly Val Leu Val Ala Ser Xaa Leu Gin Xaa Phe Leu Xaa Xaa 170 Ser Tyr Arg Val Leu Xaa Xaa Leu Ala Gin Pro (SEQ ID NO:1) wherein Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa at position 1 is Thr, Ser, Arg, Tyr or Gly; at position 2 is Pro or Leu; at position 3 is Leu, Arg, Tyr or Ser; at position 13 is Phe, Ser, His, Thr or Pro; at position 16 is Lys, Pro, Ser, Thr or His; at position 17 is Cys, Ser, Gly, Ala, Ile, Tyr or Arg; at position 18 is Leu, Thr, Pro, His, Ile or Cys; at position 22 is Arg, Tyr, Ser, Thr or Ala; at position 24 is Ile, Pro, Tyr or Leu; at position 27 is Asp, or Gly; at position 30 is Ala, Ile, Leu or Gly; at position 34 is Lys or Ser; at position 36 is Cys or Ser; at position 42 is Cys or Ser; at position 43 is His, Thr, Gly, Val, Lvs, TrD Ala. Arg, Cys, or Leu; Xaa at position 44 is Pro, Gly, Arg, Asp, Val, Ala, His, Trp, Gin, or Thr; Xaa at position 46 is Glu, Arg, Phe, Arg, Ile or Ala; Xaa at position 47 is Leu or Thr; Xaa at position 49 is Leu, Phe, Arg or Ser; Xaa at position 50 is Leu, Ile, His, Pro or Tyr; Xaa at position 54 is Leu or His; Xaa at position 64 is Cys or Ser; Xaa at position 67 is Gin, Lys, Leu or Cys; Xaa at position 70 is Gin, Pro, Leu, Arg or Ser; Xaa at position 74 is Cys or Ser; Xaa at position 104 is Asp, Gly or Val; Xaa at position 108 is Leu, Ala, Val, Arg, Trp, Gin or G Xaa at position 115 is Thr, His, Leu or Ala; Xaa at position 120 is Gin, Gly, Arg, Lys or His Xaa at position 123 is Glu, Arg, Phe or Thr Xaa at position 144 is Phe, His, Arg, Pro, Leu, Gin or G Xaa at position 146 is Arg or Gin; Xaa at position 147 is Arg or Gin; Xaa at position 156 is His, Gly or Ser; Xaa at position 159 is Ser, Arg, Thr, Tyr, Val or Gly; ly; lu; WO 97/12985 Tirf^T'/TT^l^/- If J 557 r 1/ Uao/ 1//4 Xaa at position 162 is Glu, Leu, Gly or Trp; Xaa at position 163 is Val, Gly, Arg or Ala; Xaa at position 169 is Arg, Ser, Leu, Arg or Cys; Xaa at position 170 is His, Arg or Ser; wherein optionally 1-11 amino acids from the N-terminus and from the C-terminus can be deleted from said modified human G-CSF amino acid sequence; and wherein the N-terminus is joined to the C-terminus directly or through a linker capable of joining the N-terminus to the C-terminus and having new C- and N-termini at amino acids; 38-39 39-40 40-41 41-42 42-43 43-44 45-46 48-49 49-50 52-53 53-54 54-55 55-56 56-57 57-58 58-59 59-60 60-61 61-62 62-63 63-64 64-65 65-66 66-67 67-68 68-69 69-70 70-71 71-72 91-92 92-93 93-94 94-95 95-96 96-97 97-98 98-99 99-100 123-124 1-24-125 125-126 126-127 128-129 128-129 129-130 130-131 131-132 132-133 133-134 134-135 135-136 136-137 137-138 138-139 139-140 140-141 141-142 or 142-143 respectively; and R2 is a polypeptide comprising; a modified human c-mpl ligand amino acid sequence of the formula: SerProAlaProProAlaCysAspLeuArgValLeuSerLysLeuLeuArgAspSer 1 5 10 HisValLeuHisSerArgLeuSerGlnCysProGluValHisProLeuProThrPro 25 30 ValLeuLeuProAlaValAspPheSerLeuGlyGluTrpLysThrGlnMetGluGlu 45 50 WO 97/12985 PCT/US96/15774 558 ThrLysAlaGlnAspIleLeuGlyAlaValThrLeuLeuLeuGluGlyValMetAla 65 70 AlaArgGlyGlnLeuGlyProThrCysLeuSerSerLeuLeuGlyGlnLeuSerGly 85 90 GlnValArgLeuLeuLeuGlyAlaLeuGlnSerLeuLeuGlyThrGInXaaXaaXaa 100 105 110 XaaGlyArgThrThrAlaHisLysAspProAsnAlaIlePheLeuSerPheGlnHis 115 120 125 130 LeuLeuArgGlyLysValArgPheLeuMetLeuValGlyGlySerThrLeuCysVal 135 140 145 150 Arg (SEQ ID NO:256) 153 wherein; Xaa at position 112 is deleted or Leu, Ala, Val, Ile, Pro, Phe, Trp, or Met; Xaa at position 113 is deleted or Pro, Phe, Ala, Val, Leu, Ile, Trp, or Met; Xaa at position 114 is deleted or Pro, Phe, Ala, Val, Leu, Ile, Trp, or Met; Xaa at position 115 is deleted or Gin, Gly, Ser, Thr, Tyr, or Asn; and wherein the N-terminus is joined to the C-terminus directly or through a linker (L2) capable of joining the N-terminus to the C-terminus and having new C- and N-termini at amino acids; 26-27 51-52 108-109 27-28 52-53 109-110 28-29 53-54 110-111 29-30 54-55 111-112 30-31 55-56 112-113 32-33 56-57 113-114 33-34 57-58 114-115 34-35 58-59 115-116 WO 97/12985 WO 9712985PCTIUS96/15774 559 36-37 59-60 116-117 37-38 78-79 117-118 38-39 79-80 118-119 40-41 80-81 119-120 41-42 81-82 120-121 42-43 82-83 121-122 43-44 83-84 122-123 44-45 84-85 123-124 46-47 85-86 124- 125 47-48 86-87 125-126 48-49 87-88 126-127 50-51 88-89 or 127-128; wherein Li is a linker capable of linking R1 to R2; and additionally said hematopoietic protein 'can be immediately preceded by (methionine- 1 (alanine- 1 or (methionine- 2 alanine-'). 8. A hematopoietic protein comprising; an amino acid sequence of the formula: Rl-Ll-R2, R2-LI-Rl, Rl-R2, or R2-Rj wherein R1 is a polypeptide comprising; a modified human c-mpl ligand amino acid sequence of the formula: SerProAlaProProAlaCysAspLeuArgvalLeuS erLysLeuLeuArgAspser 1 5 10 HisValLeuHisSerArgLeuSerGlnCysProGluValHisProLeuProThrPro 20 25 30 ValLeuLeuProAlaValAspPheS erL euGlyGluTrpLy sThrGlnMetGluGlu 45 50 ThrLysAlaGlnAsplleLeuGlyAlaValThrLeuLeuLeucluGlyValMetAla 65 70 AlaArgolyGlnLeuclyProThrCysLeuSerSerLeuLeuGlyGlnLeuSerGly 85 90 G lnValArgLeuLeuLeuGlyAlabeuGins erLeuLeuGlyThrGlnXaaXaaXaa 100 105 110 Xa~yr~rh~ai~ss~os~al~ee~rh~ni WO 97/12985 PCT/US96/15774 115 120 125 130 LeuLeuArgGlyLysValArgPheLeuMetLeuValGlyGlySerThrLeuCysVal 135 140 145 150 Arg (SEQ ID N0:256) 153 wherein; Xaa at position 112 is deleted or Leu, Phe, Trp, or Met; Xaa at position 113 is deleted or Pro, Ile, Trp, or Met; Xaa at position 114 is deleted or Pro, Ile, Trp, or Met; Xaa at position 115 is deleted or Gin, or Asn; and Ala, Val, Ile, Pro, Phe, Ala, Val, Leu, Phe, Ala, Val, Leu, Gly, Ser, Thr, Tyr, wherein the N-terminus is joined to the C-terminus directly or through a linker (L2) capable of joining the N-terminus to the C-terminus and having new C- and N-termini at amino acids; 26-27 27-28 28-29 29-30 30-31 32-33 33-34 34-35 36-37 37-38 38-39 40-41 41-42 42-43 43-44 44-45 46-47 47-48 48-49 51-52 52-53 53-54 54-55 55-56 56-57 57-58 58-59 59-60 78-79 79-80 80-81 81-82 82-83 83-84 84-85 85-86 86-87 87-88 108-109 109-110 110-111 111-112 112-113 113-114 114-115 115-116 116-117 117-118 118-119 119-120 120-121 121-122 122-123 123-124 124-125 125-126 126-127 WO 97/12985 PCT/US96/15774 561 50-51 88-89 or 127-128; wherein R2 is a polypeptide comprising; a modified human IL-3 amino acid sequence of the formula: Ala Pro Met Thr Gin Thr Thr Ser Leu Lys Thr Ser Trp Val Asn Cys Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 25 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Asn Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 100 105 Xaa Phe Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 110 115 120 Xaa Xaa Xaa Gin Gin Thr Thr Leu Ser Leu Ala Ile Phe 125 130 wherein Xaa at position 17 is Ser, Lys, Gly, Asp, Met, Gin, or Arg; Xaa at position 18 is Asn, His, Leu, Ile, Phe, Arg, or Gin; WO 97/12985 PCT/US96/15774 Xaa at position 19 is Met, Xaa at position 20 is Ile, Xaa at position 21 is Asp, Thr, Ser or Val; Xaa at position 22 is Glu, Leu, Val or Gly; Xaa at position 23 is Ile, Leu, Ser, or Arg; Phe, Ile, Cys, Gin, Phe, Lys, Arg, Glu, Arg, Gly, Arg, Ala, Ala, or Cys; Pro, or Ala; Gly, Glu, Gin, Asn, Trp, Pro, Ser, Ala, His, Asp, Asn, Gin, Val, Ala, Gly, Trp, Lys, Phe, Xaa at position 24 is Ile, Gly, Val, Arg, Xaa at position 25 is Thr, His, Gly, Gin, Xaa at position 26 is His, Thr, Phe, Gly, Xaa at position 27 is Leu, Gly, Arg, Thr, Xaa at position 28 is Lys, Arg, Leu, Gin, Xaa at position 29 is Gin, Asn, Leu, Pro, Xaa at position 30 is Pro, His, Thr, Gly, Xaa at position 31 is Pro, Asp, Gly, Ala, Xaa at position 32 is Leu, Val, Arg, Gin, Xaa at position 33 is Pro, Leu, Gin, Ala, Xaa at position 34 is Leu, Val, Gly, Ser, Arg, Ala, Phe, Ile or Met; Xaa at position 35 is Leu, Ala, Gly, Asn, Xaa at position 36 is Asp, Leu, or Val; Xaa at position 37 is Phe, Ser, Pro, Trp, Xaa at position 38 is Asn, or Ala; Xaa at position 40 is Leu, Trp, or Arg; Xaa at position 41 is Asn, Cys, Arg, Leu, Xaa at position 42 is Glv. Aznr, n Ser, Arg, Arg, Ser, Gly, Arg, Asp, Arg, Asn, Thr, Lys, Phe, or Leu; Pro, or Ala; Ala, or Trp; or Ala; Pro, -Val or Trp; or Val; Gin, Ser, Leu, or Lys; Leu, or Gin; Gly, Ala, or Glu; or Glu; Glu, Gin, Thr, Pro, Gin, or Val; or Ile; His, Asn, Met, Lys, or Pro; Thr, Leu, I I I Y S, YL3 Val, Glu, Phe, Tyr, Ile, Met or Ala; Xaa at position 43 is Glu, Asn, Tyr, Leu, Phe, Asp, Ala, Cys, Gln, Arg, Thr, Gly or Ser; Xaa at position 44 is Asp, Ser, Leu, Arg, Lys, Thr, Met, Trp, Glu, Asn, Gin, Ala or Pro; Xaa at position 45 is Gin, Pro, Phe, Val, Met, Leu, Thr, Lys, Trp, Asp, Asn, Arg, Ser, Ala, Ile, Glu or His; Xaa at position 46 is Asp, Phe, Ser, Thr, Cys, Glu, Asn, Gin, WO 97/12985 563 Lys, His, Ala, Tyr, Ile, Val or Gly; PCTIUS96/15774 Xaa at position 47 is Ile, Xaa at position 48 is Leu, Lys, Thr, Ala, Met, Xaa at position 49 is Met, Xaa at position 50 is Glu, Ala, Ile, Val, His, Xaa at position 51 is Asn, Xaa at position 52 is Asn, Xaa at position 53 is Leu, Xaa at position 54 is Arg, Lys, His, Ala or Leu Xaa at posit.on 55 is Arg, Xaa at position 56 is Pro, Thr, Ala, Tyr, Phe, I Xaa at position 57 is Asn c Xaa at position 58 is Leu, Xaa at position 59 is Glu Xaa at position 60 is Ala, Xaa at position 61 is Phe, Xaa at position 62 is Asn, Xaa at position 63 is Arg, Xaa at position 64 is Ala, Xaa at position 65 is Val, Xaa at position 66 is Lys, Xaa at position 67 is Ser, Xaa at position 68 is Leu, Xaa at position 69 is Gin, Xaa at position 70 is Asn, Xaa at position 71 is Ala, Trp, or Asn; Xaa at position 72 is Ser, Xaa at position 73 is Ala, Xaa at position 74 is Ile, XA a- ii-; Gly, Val, Ser, Arg, Ser, Cys, Arg, Ile, Val or Asn; Arg, Ala, Gly, Pro, Leu, Thr, Asp, Tyr, Phe, Met or Gin; Arg, Met, Pro, Ser, His, Arg, Leu, Gly, Thr, Ala, Gly, Glu, Asp, Ile, Ser, Val, Thr, Val, Ser, Leu, Gly, Cys, Ser, Gin, Leu, Val or Lys; or Gly; Pro, or His; His, Phe, Glu, Asn, Lys, Thr, Ser, Pro, Thr, His, or Asp; Asn, Ser, or His; or Thr; Lys, Ser, Gin, Asn, or Met; or Gly; Glu, Arg, His, Ser, Asp, Arg, Fyr, His, Leu, Ser, Asn, His, Tyr, Asn, Thr, Ile, Ala, Val, Ala, Leu, Met, Glu, Glu, Met, Pro, Glu, Val, Trp, Pro, Pro, Arg, Phe, Trp, Pro, Val, Leu, Met, Asp, Thr, Tyr, Pro, Arg, Lys, Ser, His, Val, Val, Ser, Thr, Trp, Pro, Ala, Leu, Pro, Gin, Val, or Cys; Pro, or Arg; Asn, or Thr; Lys, Arg, or Ser; Pro, Thr, Asp, or Ile; Ser, His, Pro, or Val; or Lys; Leu, Phe, or Ser; Asn, Glu, or Ser; Gly, Asn, Ile, Pro, or His; Ile, Phe, Thr, or His; Glu, Arg, Trp, Gly, or Leu; Pro, or Ala; Arg, Glu, Thr, Gin, His, Ser, Arg, Asn, Gly, Gly, Arg, Thr, Ala; or Asp; or Arg; Pro, Arg, Gly, Ala; s OVUn 73 is Glu, Lys, Gly, Asp, Pro, Trp, Arg, Ser, WO 97/12985 PCT/US96/15774 564 Gin, or Leu; Xaa at position 76 Xaa at position 77 Xaa at position 78 Xaa at position 79 Xaa at position 80 Xaa at position 81 Xaa at position 82 His, Thr, Ser Xaa at position 83 Xaa at position 84 Xaa at position 85 Xaa at position 86 Xaa at position 87 Xaa at position 88 Xaa at position 89 Xaa at position 90 Xaa at position 91 Xaa at position 92 is Ser, Val, Ala, Asn, Trp, Glu, Pro, Gly, or Asop is Ile, Ser, is Leu, Ala, is Lys, Thr, is Asn, Trp, is Leu, Gin, is Leu, Gin, Ala, Tyr, is Pro, Ala, is Cys, Glu, is Leu, Asn, is Pro, Cys, is Leu, Ser, is Ala, Lys, is Thr, Asp, is Ala, Pro, is Ala, Pro, is Pro, Phe, I Arg, Ser, Asn, Val, Gly, Lys, Phe, Thr, Gly, Val, Arg, Trp, Arg, Cys, Ser, Ser, Arg, Thr, or Leu; Glu, Phe, Gly, or Met, Arg, Ile, Gly Gly, Thr, Leu, Glu Ala, Trp, Arg, Val Trp, Arg, Asp, Glu Ile, Met or Val; Trp, Arg, or Met; Arg, Met, or Val; or Gin; Ala, or Lys;. or Gly; Val, or Trp; Leu, Val, Glu, His, Thr, Gly, Asp, Ile, Thr, Phe, Leu, Asp, Ser, Lys, His, Ala, Arg; or Asp; Sor Arg; Sor Lys; Asn, Asn, or Ser; or Met; or His; Gly, Ile or zU Leu; Xaa at position 93 is Thr, Asp, Ser, Asn, Pro, Ala, Leu, or Arg; Xaa at position 94 is Arg, Ile, Ser, Glu, Leu, Val, Gin, Lys, His, Ala, or Pro; Xaa at position 95 is His, Gln, Pro, Arg, Val, Leu, Gly, Thr, Asn, Lys, Ser, Ala, Trp, Phe, Ile, or Tyr; Xaa at position 96 is Pro, Lys, Tyr, Gly, Ile, or Thr; Xaa at position 97 is Ile, Val, Lys, Ala, or Asn; Xaa at position 98 is His, Ile, Asn, Leu, Asp, Ala, Thr, Glu, Gin, Ser, Phe, Met, Val, Lys, Arg, Tyr or Pro; Xaa at position 99 is Ile, Leu, Arg, Asp, Val, Pro, Gin, Gly, Ser, Phe, or His; Xaa at position 100 is Lys, Tyr, Leu, His, Arg, Ile, Ser, Gin, or Pro; Xaa at position 101 is Asp, Pro, Met, Lys, His, Thr, Val, Tyr, Glu, Asn, Ser, Ala, Gly, Ile, Leu, or Gin; Xaa at position 102 is Gly, Leu, Glu, Lys, Ser, Tyr, or Pro; WO 97/12985 565 Xaa at position 103 is Asp, or Ser; Xaa at position 104 is Trp, Val, Cys, Gin, Lys, Ala, Phe, or Gly; Xaa at position 105 is Asn, Pro, Ala, Leu, Lys, Ile, Asp, or His; PCT/US96/15774 Tyr, Thr, Met, Pro, Leu, Phe, Ser, Trp, Gin, Tyr, Xaa at position 106 is Glu, Ser, Xaa at position 108 is Arg, Lys, Ala or Pro; Xaa at position 109 is Arg, Thr, Xaa at position 110 is Lys, Ala, Ser, or Trp; Xaa at position 111 is Leu, Ile, Xaa at position 112 is Thr, Val, Xaa at position 113 is Phe, Ser, Lys, Le.I, Ile, Val or Asn; Xaa at position 114 is Tyr, Cys, Xaa at position 115 is Leu, Asn, Trp, or Met; Ala, Asp, Pro, Asn, Arg, Gin, Cys, His, Val, Lys, Leu, Glu, Thr, Asp, Tyr, His, Ser, Pro, Thr, Thr, Tyr, Leu, Ile, Ile, Leu, Arg, Gly, Gin, Ser, Gin, Ser, Tyr, or Pro; His, Ser, or Gly; His, Glu, or Phe; Asp, or Met; Glu, His; Gly, Trp, Trp, Arg, Arg, Ala, or Leu; His, Thr, Xaa at position Arg, Trp, Xaa at position Xaa at position Xaa at position Xaa at position Xaa at position Xaa at position Ile, Tyr, Xaa at position 116 is Lys, Leu, Pro, Thr, Met, Asp, Val, Glu, Ser, Asn, His, Ala, Tyr, Phe, Gin, or Ile; 117 is Thr, Ser, Asn, Ile, Trp, Lys, or Pro; 118 is Leu, Ser, Pro, Ala, Glu, Cys, Asp, or Tyr; 119 is Glu, Ser, Lys, Pro, Leu, Thr, Tyr, or Arg; 120 is Asn, Ala, Pro, Leu, His, Val, or Gin; 121 is Ala, Ser, Ile, Asn, Pro, Lys, Asp, or Gly; 122 is Gin, Ser, Met, Trp, Arg, Phe, Pro, His, or Cys; 123 is Ala, Met, Glu, His, Ser, Pro, Tyr, or Leu; wherein from 1 to 14 amino acids can optionally be deleted from the N-terminus and/or from 1 to 15 amino acids can optionally be deleted from the C-terminus of said modified human interleukin-3 amino acid sequence; and wherein from 1 to 44 of the amino acids designated by Xaa are different WO 97/12985 1D.'R/l'nk 1- 566 r S *u96/157l74 from the corresponding amino acids of native (1-133) human interleukin-3; wherein L 1 is a linker capable of linking R 1 to R2; and said hematopoietic protein can optionally be immediately preceded by (methionine-l), (alanine-1) or (methionine- 2 alanine- 1 9. The hematopoeitic protein of claim 6 or 8 wherein R2 is selected from the group consisting of; Ala Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg Pro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Ala Glu Asp Val Asp Ile Leu Met Glu Arg Asn Leu Arg Leu Pro Asn Leu Glu Ser Phe Val Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly Ile Glu Ala Ile Leu Arg Asn Leu Gin Pro Cys Leu Pro Ser Ala Thr Ala Ala Pro Ser Arg His Pro Ile Ile Ile Lys Ala Gly Asp Trp Gin Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu Gin Ala Gin Glu Gin Gin (SEQ ID NO:225); Ala Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg Pro Pro Asn Pro Leu Leu Asp Pro Asn Asn Leu Asn Ser Glu S Asp Met Asp Ile Leu Met Glu Arg Asn Leu Arg Thr Pro Asn Leu Leu Ala Phe Val Arg Ala Val Lys His Leu Glu Asn Ala Ser Gly Ile Glu Ala Ile Leu Arg Asn Leu Gin Pro Cys Leu Pro Ser Ala Thr Ala Ala Pro Ser Arg His Pro Ile Ile Ile Lys Ala Gly Asp Trp Gin Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu Gin Ala Gin Glu Gin Gin (SEQ ID NO:226); Ala Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Val Pro Pro Ala Pro Leu Leu Asp Ser Asn Asn Leu Asn Ser Glu WO 97/12985 Prr/TTcnc III C 567 7I~ Asp Met Asp Ile Leu Met Giu Arg Asn Leu Arg Leu Pro Asn Leu Leu Ala Phe Vil Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly Ile Glu Ala Ile Leu Arg Asn Leu Gin Pro Cys Leu Pro Ser Ala Thr Ala Ala Pro Ser Arg His Pro Ile le Ile Lys Ala Gly Asp Trp Gin Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Giu Gin Ala Gin Giu Gin Gin (SEQ ID NO:227); and Asn Cys Ser Ile Met Ile Asp Giu Ile Ile His His Leu Lys Arg Pro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Giu Asp Val Ser Ile Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Giu Ser Phe Val Arg Ala Val Lys Asn Leu Giu Asn Ala Ser Gly Ile Giu Ala Ile Leu Arg Asn Leu Gin Pro Cys Leu Pro Ser Ala Thr Ala Ala Pro Ser Arg His Pro Ile Ile Ile Lys Ala Gly Asp Trp Gin Giu Phe Arg Giu Lys Leu Thr Phe Tyr Leu Val Thr Leu Giu Gin Ala Gin Glu Gin Gin (SEQ ID NO:228). A hematopojetic protein comprising; an amino acid sequence of the formula: R1-L1-R2, R2-L1-R1, R1-R2, or R2-Rl wherein R1 is a polypeptide comprising; a modified human c-mpl ligand amino acid sequence of the formula: S erProAlaProProAlaCysAspLeuArgValLeuS erLysLeuLeuArgAspSer 1 5 10 Hi~le~se~ge~rl~sr~ua~sr~ur~rr 20 25 30 ValLeuLeuProAlaVaAspPheSerLellUc~ypLyTrly eGlulGlu 45 50 ThrLysAlaGinAsp~le~euGlyAlaValThreLeuLeu~luGlVlMetAla 65 70 AlaArgGlyG lnLeuGlyProThrCysLeuSerS erLeuLeuGlyGlnLeuSerGly 85 -90 WO 97/12985 T rf~«T'fTTn 68 ri uY /15774 GlnValArgLeuLeuLeuGlyAlaLeuGlnSerLeuLeuGlyThrGlnXaaXaaXaa 100 105 110 XaaGlyArgThrThrAlaHisLysAspProAsnAlaIlePheLeuSerPheGlnHis 115 120 125 130 LeuLeuArgGlyLysValArgPheLeuMetLeuValGlyGlySerThrLeuCysVal 10135 140 145 150 Arg (SEQ ID N0:256) 153 wherein; Xaa at position 112 is deleted or Leu, Ala,-Val, Ile, Pro, Phe, Trp, or Met; Xaa at position 113 is deleted or Pro, Phe, Ala, Val, Leu, Ile, Trp, or Met; Xaa at position 114 is deleted or Pro, Phe, Ala, Val, Leu, Ile, Trp, or Met; Xaa at position 115 is deleted or Gin, Gly, Ser, Thr, Tyr, or Asn; and wherein the N-terminus is joined to the C-terminus directly or through a linker (L2) capable of joining the N-terminus to the C-terminus and having new C- and N-termini at amino acids; 26-27 51-52 108-109 27-28 52-53 109-110 28-29 53-54 110-111 29-30 54-55 111-112 30-31 55-56 112-113 32-33 56-57 113-114 33-34 57-58 114-115 34-35 58-59 115-116 36-37 59-60 116-117 37-38 78-79 117-118 38-39 79-80 118-119 40-41 80-81 119-120 41-42 81-82 120-121 42-43 82-83 121-122 WO 97/12985 PCTIUS04/I AZ-I'7A 569 43-44 83-84 122-123 44-45 84-85 123-124 46-47 85-86 124-125 47-48 86-87 125-126 48-49 87-88 126-127 50-51 88-89 or 127-128 respectively; wherein R2 is G-CSF or G-CSF Ser 17 i wherein Li is a linker capable of linking R1 to R2; and said hematopoietic protein can optionally be immediately preceded by (methionine-1), (alanine- 1 or (methionine- 2 alanine- 1 11. The hematopoietic protein as recited in claim 1, 2, 3, 4, 5, 6, 7, 8, or 10 wherein said linker (L2) is selected from the group consisting of; GlyGl_/-:lySer (SEQ ID NO: 12) GlyGlyGlySerGlyGlyGlySer (SEQ ID NO:242); GlyGlyGlySerGlyGlyGlySerGlyGlyGlySer (SEQ ID NO:243); SerGlyGlySerGlyclySer (SEQ ID NO:244); GluPheGlyAs-IJetAla (SEQ ID NO:245); GluPheGlyGlyAsnMetAla (SEQ ID NO:246); GluPheGlyGlyAsnGlyGlyAs~etAla (SEQ ID NO:247); and GlyGlySerAspMetAlaGly (SEQ ID NO:248). 12. The hematopoietic protein as recited in claim 9 wherein said linker (L2) is selected from the group consisting of; GilyGlyGlySer (SEQ ID NO:12); GlyGlyGlySerGlyGlyclySer (SEQ ID NO:242); GlyGlyGlySerGlyGlyGlySerGlyGlyGlySer (SEQ ID NO:243); SerGlNy('lySerGlyGlyser (SEQ ID NO:244); GluPheGlyAsn~etAla (SEQ ID NO:245); WO 97/12985 Pd-lrfucn rrrc 570 GluPheGlyGlyAsnMetAia (SEQ ID NQ:246); GluPheGlyGlyAsnGlyGyAsnMetAia (SEQ ID NO:247); and GiyGlySerAspMetAiaGiy (SEQ ID NO:248). 13. The hematopoietic protein as recited in claim 1 wherein said protein is selected from the group consisting of; Asn Pro Vai Ser Glu Ala Gin Gin Gly His Trp Gly Leu Leu Trp Thr Ala Val Ser Arg Ala Asn Pro Val Ser Glu Ala Gin Gin Gly Ser His Trp Gly Leu Leu Trp Thr Cys Pro Ser Phe Ala Ala Glu Ala Gly Pro Ala Cys Leu Asp Gin Gin Gly Ser Gly Lys Thr Cys Pro Ser Phe Ala Ala Glu Ala Glu Lys Pro Ala Cys Leu Asp Gin Gin Ser Ile Ala Pro Ile Leu Val Arg ile Leu Pro Ser Phe Arg Gin Glu Gly Ser Glu Glu Pro Leu Leu Ser Gin Ala Thr Leu Gin Met Gly Ala Gly Val Tyr Arg Gly Ser Ile Gin (SEQ ID Met Ile Asp Leu Leu Asp Met Asp Arg Ala Val Lys Arg Asn Leu Arg His Pro Glu Lys Leu Gin Gin Tyr Gly Gly Gly Leu Val Leu Ser Ser Cys Gin Leu His Leu Giu Gly Gin Leu Asp Glu Giu Leu Met Pro Ala Leu Val Ala Val Leu Arg Gin Ser Phe Gly Asp Gly NO:166); Glu Ile Pro Asn Asn Leu Asn Leu Gin Pro Ile Ile Thr Phe Val Glu Ser Asn Leu Gly Pro Ser Ser Gly Ile Ser Vai Ala Gly Met Phe Ala Ser His His Leu Leu Leu Ala Ala Ile Asn Arg Glu Cys Ile Tyr Gly Met His Gin Leu Pro Asp Ala Ser Leu Ala Lys Leu His His Leu Asn Leu Pro Asn Ala Leu Pro Lys Ala Leu Val Gly Gly Ala Tyr Ser Leu Ala Leu Phe Leu Glu Leu Phe Ala Pro Ala Ala Phe Gin Ser Gin Pro Ser Leu Gin Glu Leu Asp Asn Ser Ser Gly Thr Gly Lys Gly Gin Tyr Gly Thr Leu Gin Phe Ser Glu Lys Lys Glu Leu Gly Ala Asp Leu Ser Leu Ile Leu Gin Pro Thr Gin Arg Leu Gly Gin Leu Arg Asp Glu Ile Thr Trp Glu Pro Cys Pro Ala Gly Thr Ile Pro Arg Glu Gly Val Cys Ser Ala Ile Val Ile Pro Phe Gin Pro Glu Glu Pro Leu Gin Thr Gin Gly Ile Pro Leu Arg Leu Ser Arg Glu Ser Ser Glu Leu Ser Ala Leu Met Ala Met Ile Asp Leu Leu Asp Met Asp Arg Ala Val Lys Arg Asn Leu Arg His Pro Glu Lys Leu Gin Gin Tyr Gly Pro Ile His Lys Ser Leu Val Leu Ser Ser Cys Gin Leu His Leu Giu Gly Gin Leu Asp Glu Giu Leu Met Pro Ala Glu Ile Pro Asn Asn Leu Asn Leu Gin Pro Ile Ile Thr Phe Val Glu Ser Thr Pro Asn Leu Gly Pro Ser Ser Gly Ile Ser Val Ala Gly Met Phe Ala Ile Asn Arg Glu Cys Ile Tyr Gly Ile Met His Gin Leu Pro Asp Ala Ser His Leu Leu Asn Leu Lys Leu Gly Asn Ala Ser Ala Phe Glu Phe Pro Ala His Asn Pro Ala Pro Ala Val Gly Pro Tyr Leu Leu Leu Leu Ala Ala Phe Leu Asp Asn Ser Ser Gly Thr Gly Ser Lys Gly Gin Tyr Gly Thr Leu Gin Lys Glu Leu Gly Ala Asp Leu Ser Pro Leu Ile Leu Gin Pro Thr Gln Arg Arg Asp Glu Ile Thr Trp Glu Pro Pro Cys Pro Ala Gly Thr Ile Pro Arg WO 97/12985 PCT/US96/15774 Ala Gly Val Ser Ser Gly Arg Lys Ala Thr Gly Val Leu Val Ala Ser Tyr Arg Val Leu Arg His Gly Ser Gin Ser Phe Leu Ile Gin Gly Asp Gly Ala (SEQ ID NO:167); His Leu Leu Ala Leu Ala Lys Leu Gin Ser Gin Pro Ser Leu Gin Glu Phe Leu Glu Ser Gly Gly Glu Gin Val Lys Leu Cys Asn Cys Ser Ile Met Ile Pro Pro Ala Pro Leu Leu Val Ser Ile Leu Met Asp Ser Phe Val Arg Ala Val Glu Ala Ile Leu Arg Asn Ala Ala Pro Ser Arg His Gin Glu Phe Arg Glu Lys Gin Ala Gin Glu Gin Gin Gly Gly Gly Ser Gly Gly Pro Thr Leu Asp Thr Leu Thr Ile Trp Gin Gin Met Gin Pro Thr Gin Gly Ala Arg Arg Ala Gly Gly Val Leu Glu Val Ser Tyr Arg Gly Gly Ser Gly Gly Ser Gin Val Arg Lys Ile Gin Leu Cys Ala Thr Tyr Lys Leu Gly His Ser Leu Gly Pro Ser Gin Ala Leu Gin Ser Gly Leu Phe Leu Tyr Ile Ser (SEQ ID NO:168); Asp Glu Asp Pro Arg Asn Lys Asn Leu Gin Pro Ile Leu Thr Tyr Val Gly Ser Gin Leu Glu Glu Met Pro Leu Val Val Leu Gin Ser Gly Asp Leu Cys Ile Pro Leu Ala Gin Gly Ile Asn Leu Leu Pro Ile Phe Glu Asn Asp Leu Ala Ala Arg Phe Gly His Trp Gly Leu Ile Asn Arg Glu Cys Ile Tyr Gly Met Val Gly Phe Ser His Leu Ala Pro Ala Cys Leu His His Leu Asn Leu Pro Asn Ala Leu Pro Lys Ala Leu Val Gly Gly Ala Pro Ala Asp Met Ala Ala Ser His Leu Leu Ala Leu Lys Ala Leu Glu Glu Pro Leu Leu Ser Gin Ala Leu Asp Asn Ser Ser Gly Thr Gly Glu Phe Pro Ala Gin Gin Ser Gin Leu Ser Gin Leu Lys Glu Leu Gly Ala Asp Leu Ser Leu Ala Ala Phe Ser Pro Leu Glu Val Ser Leu Glu Arg Asp Glu Ile Thr Trp Glu Pro Gly Thr Leu Gin Phe Ser Glu Lys Leu Cys His Gly Asn Pro Val Ser Glu Ala Gin Gin Gly Ser Pro Thr Gin Arg Leu Gly Gin Leu Leu Pro Ser Ile Cys Pro Ser Phe Ala Ala Glu Ala Glu Lys Thr Ile Pro Arg Glu Gly Val Cys Gly Ser Gly Ser Sei Ile Met Ile Asp Ala Pro Leu Leu Asp Ile Leu Met Asp Arg Val Arg Ala Val Lys Ile Leu Arg Asn Leu Pro Ser Arg His Pro Phe Arg Glu Lys Leu Gin Glu Gin Gin Tyr Pro Ser Gly Pro Ile Glu Ser His Lys Ser Leu Asp Thr Leu Gin Trp Gin Gin Met Glu Thr Gin Gly Ala Met Ala Gly Gly Val Leu Val Ser Tyr Arg Val Ser Gly Gly Ser Gin Arg Lys Ile Gin Gly Ala Thr Tyr Lys Leu His Ser Leu Gly Ile Gin Ala Leu Gin Leu Leu Phe Leu Tyr Gin (SEQ ID NO:169); Glu Pro Asn Asn Gin Ile Thr Val Ser Pro Leu Glu Pro Val Leu Ser Asp Cys Pro Ala Gly Ile Asn Leu Leu Pro Ile Phe Glu Thr Asn Asp Leu Ala Ala Arg Phe Gly His Trp Gly Leu Ile Asn Arg Glu Cys Ile Tyr Gly Ile Met Val Gly Phe Ser His Leu Ala Pro Ala Cys Leu His His Leu Asn Leu Pro Asn Ala Leu Pro Lys Ala Leu Val Gly Gly Asn Pro Ala Pro Ala Asp Met Ala Ala Ser His Leu Leu Ala Leu Lys Ala Leu Glu Glu Pro Leu Leu Ser Gin Ala Leu Asp Asn Ser Ser Gly Thr Gly Ser Glu Phe Pro Ala Gin Gin Ser Gin Leu Ser Gin Leu Lys Arg Glu Asp Leu Glu Gly Ile Ala Thr Asp Trp Leu Glu Ser Pro Pro Pro Leu Gly Ala Thr Ala Leu Phe Gin Ser Phe Pro Ser Leu Glu Glu Lys Val Leu Ser Cys Leu His Glu Gly WO 97/12985 PCT/US96/15 7 7 4 Asn Pro Val Ser Glu Ala Gin Gin Gly Leu Gin Phe Ser Giu Lys Leu Cys His G ly Asp Leu Cys Pro Ser Phe Ala Ala Glu Ala Gly Gin Arg Leu Gly Gin Leu Leu Pro Ser Ile Val Gly Ser Ile Ala Pro Ile Leu Val Arg Ile Leu Pro Ser Phe Arg Gin Glu Gly Ser Pro Thr Arg Ala Glu Val Gly Ser Val Arg Cys Ala Gly His Ser Gin Gly Leu Sej- Pro Ala Asp (SEQ ID Met Ile Leu Leu Met Asp Ala Val Arg Asn Arg His Giu Lys Gin Gin Gly Gly Gin Gly Gly Gly Ser Tyr Gly Gly Lys Ile Thr Tyr Ser Leu Ala Leu Phe Leu Glu Leu Phe Ala NO: 17 0) Asp Asp Arg Lys Leu Pro L eu Tyr Gly Ala Val Arg Ser Gin Lys Gly Gin Tyr G ly Thr Giu Ile Pro Asn Asn Leu Asn Leu Gin Pro Ile Ile Thr Phe Val Giu Ser Asn Met Pro Leu Val Val Leu Gin Ser Gly Asp Leu Cys Ile Pro Leu Ala Gin Gly Pro Thr Thr Ile Ile Asn Arg Glu Cys Ile Tyr Gly Met Ala Ala Arg Phe Gly His Trp Gly Leu Leu Trp His is Leu Asn Leu Pro Asn Ala Leu Pro Lys Ala Leu Val Gly Gly Ala Met Phe Ala Ser His His Leu Leu Leu Ala Ala Pro Glu Ala Pro Cys -L-eu Leu Gin Asp Thr Gin Gin Leu Asp Asn Ser Ser Gly -Thr Gly Ala Ser Leu Ala Lys Leu Giu Leu Ser Ala Leu Met Lys Giu Leu Gly Ala Asp Leu S er Pro Ala Gin Gin Ser Gin Leu Ser Gin Leu Gin Glu Arg Asp Glu Ilie Thr Trp Giu Pro Ala Phe Ser Pro Leu Giu Val Ser Leu Giu L eu Glu Asn Pro Val Ser Glu Ala Gin Gln Gly Ser Leu Gin Phe Ser Giu Lys Leu Cys His Gly Asp Leu Asn Pro Val Cys Ser Ile Pro Ala Pro Ser Ile Leu Phe Val Arg Ala Ile Leu Ala Pro Ser Giu Phe Arg Ala Gin Giu Giu Pro Ser Lys Glu Ser Gin Pro Thr Arg Arg Ala Leu Giu Val Gly Gly Ser Gin Val Arg Leu Cys Ala Leu Gly His Pro Ser Gin Ser Gly Leu Ile Ser Pro Val Ala Asp Gly (SEQ ID Met Ile Asp Leu Leu Asp Met Asp Arg Ala Val Lys Arg Asn Leu Arg His Pro Glu Lys Leu Gin Gin Tyr Gly Pro Ile His Lys Ser Gin Giy Ala Gly Gly Val Ser Tyr Arg Gly Gly Ser Lys Ile Gin Thr Tyr Lys Ser Leu Gly Ala Leu Gin Phe Leu Tyr Giu Leu Gly Phe Ala Thr NO:171); Gu Ile Ile Pro Asn Asn Asn Leu Arg Asn Leu Giu Gin Pro Cys Ile Ile Ile Thr Phe Tyr Val Giu Gly Ser Thr Ile Pro Asn Met Met Pro Ala Leu Vai Ala Val Leu Arg Gin Ser Phe Gly Asp Gly Leu Cys His Ile Pro Trp Leu Ala Gly Gin Gly Leu Pro Thr Leu Thr Ile Trp His L eu L eu Asn L eu Lys L eu Gly Asn Ala Phe Ser His Leu Ala Pro Ala Cys Leu Asp Gin His Leu Asn Asp Pro Asn Ala Ser Pro Ser Ala Gly Val Thr Gly Gly Pro Ser Met Ala Ala Ser His Leu Leu Ala Leu Lys Ala Leu Giu Glu Pro Leu Leu Ser Gin Ala Thr 'Leu Gin Met Lys Glu L eu Gly Ala Asp L eu Ser Pro Pro Ala Gin Gin Ser Gin L eu Ser Gin Leu Gin Glu Arg Asp Giu Ile Thr Trp Glu Pro Pro Ala Phe Ser Pro Leu G iu Val Ser Leu Giu Leu Glu Cys Ser Ile Met Ie Asp Giu Ile Ile His His Leu LYS Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Ser Ie Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Arg Asp Giu WO 97/12985 PCT/US96/15774 Ser Glu Ala Gin Gin Gly Met Leu Val Gin Gly Leu Ile Leu Gin Pro Thr Gin Phe Val Arg Ala lie Leu Ala Pro Ser Glu Phe Arg Ala Gin Glu Gly Gly Ser Pro Ala Phe Val Ala Ser Leu Arg His Ser Phe Leu Asp Gi:- Ala Cys His Pro Pro Trp Ala Ala Gly Cys Gly Leu Leu Thr Leu Asp Ile Trp Gin Pro (SEQ ID Ala Val Arg Asn Arg His Glu Lys Gin Gin Gly Gly Ala Ser His Leu Leu Ala Leu Lys Ala Leu Glu Glu Pro Leu Leu Ser Gin Ala Thr Leu Gin Met NO:172); Lys Leu Pro Leu Tyr Gly Ala Gin Gin Ser Gin Leu Ser Gin Leu Gin Glu Asn Gin Ile Thr Val Ser Phe Ser Pro Leu Glu Val Ser Leu Glu Leu Glu Leu Glu Pro Cys Ile Ile Phe Tyr Glu Gly Asn Met Gin Arg Phe Leu Ser Gly Glu Gin Lys Leu Leu Leu Cys Pro His Ser Gly Ile Asp Val Leu Gly Asn Ala Leu Pro Lys Ala Leu Val Gly Gly Ala Thr Arg Ala Glu Val Gly Ser Val Arg Cys Ala Gly His Ser Gin Gly Leu Ser Pro Ala Asp Met Ala Ser Gly Ser Ala Gly Asp Thr Leu Gly Ser Gin Gly Gly Gly Ser Tyr Gly Gly Lys Ile Thr Tyr Ser Leu Ala Leu Phe Leu Glu Leu Phe Ala Pro Ala Ile Thr Trp Glu Pro Ala Val Arg Ser Gin Lys Gly Gin Tyr Gly Thr Leu Asn Pro Val Ser Glu Ala Gin Gin Gly Ser Met Leu Val Gin Gly Leu Ile Leu Gin Pro Thr Gin Asn Pro Val Ser Glu Ala Gin Gin Cys Pro Ser Phe Ala Ala Glu Ala Glu Lys Pro Val Leu Ser Asp Cys Pro Ala Gly Thr Ile Pro Ser Ile Ala Pro Ile Leu Val Arg Ile Leu Pro Ser Phe Arg Gin Glu Pro Ser Glu Ser Ala Phe Ala Ser Arg His Phe Leu Gly Ala His Pro Trp Ala Gly Cys Leu Leu Leu Asp Trp Gin (SEQ ID Met Leu Met Ala Arg Arg Glu Gin Gly His Ala His Leu Leu Ala Glu Pro Leu Gin Thr Gin Ile Leu Asp Val Asn His Lys Gin Pro Lys Ser Leu Ala Lys Leu Glu Leu Ser Ala Leu Met Asp Glu Asp Pro Arg Asn Lys Asn Leu Gin Pro Ile Leu Thr Tyr Val Ile Ser Ser Pro Ala Phe Gin Ser Gin Pro Ser Leu Gin Glu Leu Val Ser Ser Gin Leu Leu Glu Gin Leu Glu Glu Ile Asn Leu Leu Pro Ile Phe Glu Thr Asn Gin Phe Ser Glu Lys Leu Cys His Gly Asp Leu lie His His Asn Leu Asn Arg Leu Pro Glu Asn Ala Cys Leu Pro Ile Lys Ala Tyr Leu Val Gly Gly Gly Ile Asn Pro Met Ala Thr Arg Arg Ala Leu Glu Val Gly Gly Ser Gin Val Arg Leu Cys Ala Leu Gly His Pro Ser Gin Ser Gly Leu Ile Ser Pro Val Ala Asp Gly Met Ala Leu Asp Asn Ser Ser Gly Thr Gly Ser Gin Gly Ser Gly Lys Thr Ser Ala Phe Glu Phe Pro Leu Asp Asn Ser Ser Gly Thr Gly Lys Arg Glu Asp Leu Glu Gly Ile Ala Thr Asp Trp Leu Glu Ser Pro Pro Pro Gly Ala Gly Val Tyr Arg Gly Ser Ile Gin Tyr Lys Leu Gly Leu Gin Leu Tyr Leu Gly Ala Thr Ala Leu NO:173); Cys Ser Pro Ala Ser Ile Phe Val Ala Ile Ala Pro Glu Phe Ala Gin Ile Met Pro Leu Leu Met Arg Ala Leu Arg Ser Arg Arg Glu Glu Gin Ile Asp Glu Leu Asp Pro Asp Arg Asn Val Lys Asn Asn Leu Gin His Pro Ile Lys Leu Thr Gin Tyr Val Ile Ile Asn Asn Leu Arg Leu Glu Pro Cys Ile Ile Phe Tyr Glu Gly His His Leu Asn Leu Pro Asn Ala Leu Pro Lys Ala Leu Val Gly. Gly i l Lys Arg Glu Asp Leu Glu Gly Ile Ala Thr Asp Trp Leu Glu Ser Pro WO 97/12985 PCT[US96/1577 4 Gly Arg Leu Gly Gin Leu L eu Pro Ser Ile Val Gly Phe Gly Arg Giu Gly Val Cys Gly S er Giy Ser Ala Met Ala Gly Ser Aid Gly Val Ser Ser Giy Arg Lys Ala Thr His Ser Gin Ala Leu Phe Pro Glu Asp Phe Aia Pro (SEQ ID Gly Gly Giy Gly Val Leu Tyr Arg Val Gly Ser Gin Ile Gin Gly Tyr Lys Leu Leu Giy Ile Leu Gin Leu Leu Tyr Gin Leu Giy Pro Ala Thr Thr Ala Leu Gin NO: 177) Ser Val L eu Ser Asp Cys Pro Ala Gly Thr Ile Pro Asn Ala Arg Phe Gly His Trp Gly Leu Leu Trp Thr Met Ser His Leu Ala Pro Ala Cys Leu Asp Gin Gin Ala Ser His Leu Leu Ala Leu Lys Ala Leu Giu Giu Pro Leu Leu Ser Gin Ala Thr Leu Gin Met Giy Ala Ala Gin Gin Ser Gin Leu Ser Gin -Leu Gin Giu Met Phe Ser Pro Leu Giu Val Ser Leu Giu Leu Glu Pro Gin Phe Ser Giu Lys Leu Cys His Gly Asp Leu Ala Asn Pro Val Ser Glu Ala Gin Gin Gly Ser Arg Leu Giy Gin Leu L eu Pro Ser Ile Val Gly Phe Asn Pro Val Ser Giu Ala Gin Gin Gly His Trp Giy Leu Cys Pro Ser Phe Ala Ala Giu Ala Giu Lys Arg Glu Gly Val Cys G ly Ser Gly Ser Ala Met Ala Cys Pro Ser Phe Ala Ala Giu Ala Gly Pro Ala Cys Leu Ser Ile Ala Pro Ile Leu Val Arg Ile Leu Pro Ser Phe Arg Gin Giu Pro Ser Giu Ser Ala Giy Val Ser Ser Gly Arg Lys Ala Thr His Ser Gin Ala Leu Phe Pro Glu Asp Phe Ala Pro (SEQ ID Ser Ile Ala Pro Ile Leu Val Arg Ile Leu Pro Ser Phe Arg Gin Giu Gly Ser Giu Glu Pro Leu Leu Ser Gin Ala Met Ile Asp Leu Leu Asp Met Asp Arg Ala Val Lys Arg Asn Leu Arg His Pro Giu Lys Leu Gin Gin Tyr Gly Pro Ile His Lys Ser Gly Val Leu Tyr Arg Val Gly Ser Gin Ile Gin Gly Tyr Lys Leu Leu Gly Ile Leu Gin Leu Leu Tyr Gin Leu Gly Pro Ala Thr Thr Ala Leu Gin NO: 175); Giu Pro Asn Asn Gin Ile Thr Val Ser Pro Val Leu Ser Asp Cys Pro Ala Giy Thr Ile Pro Ile Asn Leu Leu Pro Ile Phe Giu Thr Asn Ala Arg Phe G ly His Trp Gly L eu Leu Trp Thr Ile Asn Arg Giu Cys Ile Tyr Gly Ile Met Ser His Leu Ala Pro Ala Cys Leu Asp Gin Gin His His Leu Leu Asn Asp Leu Pro Asn Asn-A-ia Ser Leu Pro Ser Lys Ala Gly Leu Val Thr Gly Gly Gly Asn Pro Ser Ala Ser Ala His Leu Gin Leu Ala Gin Leu Lys Ser Ala Leu Gin Giu Glu Leu Pro Leu Ser Leu Ser Gin Gin Ala Leu Thr Leu Gin Gin Met Giu Gly Ala Met Lys Glu Leu Gly Ala Asp L eu Ser Pro Phe S er Pro L eu G lu Val S er Leu Giu L eu Giu Pro Arg Asp Giu Ile Thr Trp Giu Pro Pro Gin Phe Ser Giu Lys Leu Cys His Gly Asp Leu Ala Met Ile Leu Leu Met Asp Ala Val Arg Asn Arg His Glu Lys Gin Gin Gly Gly Leu Val Ser Ser Gin Leu Leu Giu Asp Asp Arg Lys Leu Pro Leu Tyr Gly Leu Cys His Gly Glu Pro Asn Asn Gin Ile Thr Val Ser Leu Pro Ser Ile Ile Asn Leu Leu Pro Ile Phe Giu Asn Gly Ser Gly Ser Ile Asn Arg Giu Cys Ile Tyr Gly Met His Gin Leu Pro His Leu L eu Asn L eu Lys Leu Gly Ala Ser Ala Phe Glu His Asn Pro Ala Pro Ala Val Gly Tyr Leu Leu Leu Leu Leu Asp Asn Ser Ser Oly Thr Gly Lys Gly Gin Tyr Gly Lys Arg Giu Asp Leu Glu Gly Ile Ala Thr Asp Trp Leu Glu Ser Pro Leu Cys Ile Pro Leu Ala Gin Gly Pro Thr WO 97/12985 PCT/US96/15774 Leu Trp Thr Ala Val Gly Glu Lys Asp Gin Gin Gly Ser Pro Gin Leu Thr Leu Gin Met Gly Ala Gly Val Tyr Arg Ala Ser Val Arg Cys Ala Gin Glu Met Leu Val Ser Lys Thr Leu Asp Glu Leu Pro Ala Val Ala Leu Arg Leu Pro Ile Gin (SEQ ID Val Ala Asp Gly Met Ala Phe Ala Ser Ser His Leu His Leu Ala Gin Ser Phe Gly Asp Gly NO:176); Phe Pro Ala Gin Gin Leu Ala Ala Ala Phe Ser Pro Leu Ala Thr Leu Gin Phe Thr Lys Leu Thr Ile Gin Pro Arg Arg Leu Glu Pro Leu Ser Leu Gin Glu Asn Pro Val Ser Glu Ala Gin Gin Gly Ser His Trp Gly Leu Leu Trp Thr Ala Val Gly Glu Lys Asn Pro Val Ser Glu Ala Gin Gin Gly Ser Pro Thr Gin Arg Leu Pro Ser Gin Cys Pro Ser Phe Ala Ala Glu Ala Glu Lys Pro Ala Cys Leu Asp Gin Gin Gly Ser Pro Gin Leu Ser Ile Ala Pro Ile Leu Va- Arg Ile Leu Pro Ser Phe Arg Gin Glu Pro Ser Glu Ser Glu Glu Pro Leu Leu Ser Gin Ala Thr Leu Gin Met Gly Ala Gly Val Tyr Arg Ala Ser Val Arg Cys Ala Met Ile Asp Leu Leu Asp Met Asp Arg Ala Val Lys Arg Asn Leu Arg His Pro Glu Lys Leu Gin Gin Tyr Gly Pro Ile His Lys Ser Leu Val Leu Ser Ser Cys Gin Leu His Leu Glu Gly Gin Leu Asp Glu Glu Leu Met Pro Ala Leu Val Ala Val Leu Arg Ser Leu Pro Lys Ile Gin Thr (SEQ ID Glu Pro Asn Asn Gin Ile Thr Val Ser Pro Leu Pro Ser Ile Val Gly Phe Ser His Gin Gly NO:1 Ile Asn Leu Leu Pro Ile Phe Glu Thr Asn Gly Ser Gly Ser Ala Met Ala His Leu Ser Asp .77); Ile Asn Arg Glu Cys Ile Tyr Gly Ile Met His Gin Leu Pro Asp Ala Ser Leu Ala Phe Gly His His Leu Asn Leu Pro Asn Ala Leu Pro Lys Ala Leu Val Gly Gly Asn Pro Ala Tyr Ser Leu Ala Leu Phe Leu Glu Leu Phe Ala Pro Ala Ala Phe Gin Ser Gin Pro Leu Leu Ala Ala Leu Asp Asn Ser Ser Gly Thr Gly Ser Lys Gly Gin Tyr Gly Thr Leu Gin Phe Thr Lys Leu Lys Glu Leu Gly Ala Asp Leu Ser Pro Leu Ile Leu Gin Pro Thr Gin Arg Leu Pro Ser Gin Arg Asp Glu Ile Thr Trp Glu Pro Pro Cys Pro Ala Gly Thr Ile Pro Arg Glu Leu Leu Glu Cys Pro Ser Phe Ala Ala Glu Ala Glu Lys Thr Ile Pro Arg Glu Leu Leu Glu Ser Ala Ile Val Ile Pro Phe Gin Pro Glu Leu Trp Thr Ala Val Gly Glu Lys Ile Met Ile Pro Leu Leu Leu Met Asp Arg Ala Val Leu Arg Asn Ser Arg His Arg Glu Lys Glu Gln Gin Ser Gly Pro Ser His Lys Asp Thr Leu Gin Gin Met Gin Gly Ala Gly Gly Val Ser Tyr Arg Pro Ala Ser Gin Val Arg Leu Cys Ala Asp Asp Arg Lys Leu Pro Leu Tyr Ile Ser Gin Glu Met Leu Val Ser Lys Thr Glu Ile Pro Asn Asn Leu Asn Leu Gin Pro Ile Ile Thr Phe Val Glu Ser Thr Pro Asn Leu Asp Glu Leu Pro Ala Val Ala Leu Arg Leu Pro Ile Gin Tyr Lys Ile His His Asn Leu Asn Arg Leu Pro Glu Asn Ala Cys Leu Pro Ile Lys Ala Tyr Leu Val Gly Gly Gly Ile Asn Pro Met Ala Pro Val Ala Asp Gly Met Ala Phe Ala Ser Ser His Leu His Leu Ala Gin Ser Phe Gly Asp Gly Leu Cys His Leu Asp Asn Ser Ser Gly Thr Gly Ser Glu Phe Pro Ala Gin Gin Leu Ala Pro Lys Glu Leu Gly Ala Asp Leu Ser Pro Leu Ala Ala Phe Ser Pro Leu Ala Glu Arg Asp Glu Ile Thr Trp Glu Pro Pro Gly Thr Leu Gin Phe Thr Lys Leu Glu WO 97/12985 PCT/US96/15774 Leu Ser Gin Leu Val Ser Leu Glu Leu Leu Cys Pro His Ser Gly Ile Gly His Ser Ser Gin Ala Gly Leu Phe Ser (SEQ ID Leu Gly Ile Leu Gin Leu Leu Tyr Gin NO:179); Pro Trp Ala Gly Gly Leu Ala Cys Leu Pro Leu Gin Leu Ser Ala Asn Cys Ser Pro Pro Ala Val Ser Ile Ser Phe Val Glu Ala Ile Ala Ala Pro Gin Glu Phe Gin Ala Gin Gly Glu Pro Ser Lys Glu Leu Gin Pro Gin Arg Arg Phe Leu Glu Thr Pro Leu Lys Ser Leu Leu Gin Glu Glu Leu Va. Leu Ser Ser Ser Gin Leu Ala Leu Glu Leu Gin Leu Met Glu Glu Ile Met Ile Asp Pro Leu Leu Asp Leu Met Asp Arg Arg Ala Val Lys Leu Arg Asn Leu Ser Arg His Pro Arg Glu Lys Leu Glu Gin Gin Tyr Ser Gly Pro Ile Ser His Lys Ser Thr Gin Gly Ala Ala Gly Gly Val Val Ser Tyr Arg Gly Pro Ala Ser Glu Gin Val Arg Lys Leu Cys Ala Leu Leu Gly His Cys Pro Ser Gin His Ser Gly Leu Gly Ile Ser Pro Asp Val Ala Asp Leu Gly (SEQ ID Glu Ile Ile Pro Asn Asn Asn Leu Arg Asn Leu Glu Gin Pro Cys Ile Ile Ile Thr Phe Tyr Val Glu Gly Ser Thr Ile Pro Asn Met Met Pro Ala Leu Val Ala Val Leu Arg Ser Leu Pro Lys Ile Gin Thr Tyr Lys Ser Leu Gly Ala Leu Gin Phe Leu Tyr Glu Leu Gly Phe Ala Thr NO:181); His Leu Leu Asn Leu Lys Leu Gly Asn Ala Phe Ser His Gin Gly Leu Ile Leu Gin Pro Thr His Leu Asn Asp Pro Asn Ala Ser Pro Ser Ala Gly Val Thr Gly Gly Pro Ser Met Ala Ala Ser His Leu -Leu Ala Ser Phe Asp Gly Cys His Pro Trp Ala Gly Gly Leu Thr Leu Ile Trp Lys Glu Leu Gly Ala Asp Leu Ser Pro Pro Ala Gin Gin Leu Ala Pro Ala Cys Leu Asp Gin Arg Asp Glu Ile Thr Trp Glu Pro Pro Ala Phe Ser Pro Leu Ala Glu Pro Leu Gin Thr Gin Asn Cys Pro Pro Val Ser Ser Phe Glu Ala Ala Ala Gin Glu Gin Ala Gly Gly Met Pro Leu Val Val Leu Ser Leu Lys Ile Thr Tyr Ser Leu Ala Leu Phe Leu Glu Leu Phe Ala Pro Ala Ser Ala Ile Val Ile Pro Phe Gin Gly Ala Ala Arg Pro Gin Lyri Gly Gin Tyr Gly Thr Leu Ile Pro Leu Arg Leu Ser Arg Glu Ser Phe Ser His Gin Gly Leu Ile Leu Gin Pro Thr Gin Met Leu Met Ala Arg Arg Glu Gin Gly Ala His Leu Ser Asp Cys Pro Ala Gly Thr Ile Pro Ile Asp Leu Asp Asp Arg Val Lys Asn Leu His Pro Lys Leu Gin Tyr Gly Gly Ser Ala Leu Gin Ala Gin Phe Leu Gly Ala His Pro Trp Ala Gly Cys Leu Leu Leu Asp Trp Gin (SEQ ID Glu Ile Ile Pro Asn Asn Asn Leu Arg Asn Leu Glu Gin Pro Cys Ile Ile Ile Thr Phe Tyr Val Glu Gly Ser Asn Met Phe Gin Arg Ser Phe Leu Pro Thr Pro Leu Lys Ser Ala Leu Gin Glu Glu Leu Pro Leu Ser Leu Ser Gin Gin Ala Leu Thr Leu Gin Gin Met Glu NO:182); His Leu Leu Asn Leu Lys Leu Gly Ala Arg Glu Leu Leu Glu Val Ser Leu Glu Leu Glu His Asn Pro Ala Pro Ala Val Gly Thr Ala Val Gly Glu Lys Leu Cys His Gly Asp Leu Leu Lys Asp Glu Asn Leu Ser Gly Ser Ala Gly Asp Thr Leu Gly Ser Gin Gly Gly Gly Ser Tyr Pro Ala Gin Val Leu Cys Leu Gly Pro Ser Ser Gly Ile Ser Arg Asp Glu Ile Thr Trp Glu Pro Ala Val Arg Ser Arg Ala His Gin Leu Pro Val Ala Asp Gly Met Ala WO 97/12985 PCTIUS96/'15774 Asn Pro Val Ser Glu Ala Gin Gin Gly Ser Met Leu Val Ser Lys Thr Ser Ala Phe Glu Phe Pro Cys Pro Ser Phe Ala Ala Glu Ala Glu Lys Pro Val Leu Leu Ile Tyr Leu Leu Leu Leu Ala Ala Ser Ala Ile Val Ile Pro Ph e Gi Pro Glu Ala Ala Arg Pro Gin Lys Gly Gin Tyr Gly Thr Leu Ile Pro Leu Arg Leu Ser Arg Glu Ser Ser Phe Ser His Gin Gly Leu Ile L eu Gin Pro Thr Gin Met Ile Asp Leu Leu Asp Met Asp Arg Ala Val Lys Arg Asn Leu Arg His Pro Giu Lys Leu Gin Gin Tyr Gly Pro Ile His Lys Ser Ala Ser Ala His Leu Gin Leu Ala Gin Ser Phe Leu Asp Gly Ala Cys His Pro Pro Trp Ala Ala Gly Cys Gly Leu Leu Thr Leu Asp Ile Trp Gin Pro (SEQ ID Giu Ile Pro Asn Asn Leu Asn Leu Gin Pro Ile TIe Thr Phe Val Glu Ser Thr Pro Asn Phe Gin Ser Phe Pro Thr Leu Lys Ala Leu Giu Giu Pro Leu Leu Ser Gin Ala Thr Leu Gin Met NO: 183) Ile Asn Arg Giu Cys Ile Tyr Giy Ile Met Arg Leu Pro Ser Gin Leu Ser Gin Leu Gin Giu His L eu Leu Asn L eu Lys Leu Gly Asn Ala Arg G iu Leu L eu Giu Val S er L eu Giu L eu Giu His Asn Pro Ala Pro Ala Val Gly Pro Thr Ala Val Gly Glu Lys Leu Cys Gly Asp L eu Leu Asp Asn Ser Ser Gly Thr Gl1y Ser Gin Gly Ser Pro Gin Leu Leu Pro Ser Ile Val Gly Lys Giu Leu Gly Ala Asp Leu Ser Pro Gly Gly Tyr Ala Val Cys Giy Ser Gly Ser Ala Met Arg Asp Glu Ile Thr Trp, Glu Pro Pro Ala Val Arg Ser Arg Ala His Gin Leu Pro Asp Ala Asn Pro Val Ser Glu Ala Gin Gin Gly Arg Leu Pro Ser Gin Leu Ser Gin Leu Gin Giu Met Cys Pro Ser Phe Ala Ala Glu Ala Gly Arg Giu Leu L eu Giu Vai Ser L eu Giu Leu Giu Pro Ser Ile Ala Pro Ile Leu Val Arg Ile Leu Pro; Ser Phe Arg Gin Giu Gly Ser Ala Gly Val Ser Gly Pro Giu Gin Lys Leu Leu Leu Cys Pro His Ser Gly Ile Asp Val Leu Gly Ala Phe Met Ile Asp Leu Leu Asp Met Asp Arg Ala Val Lys Arg Asn Leu Arg His Pro Glu Lys Leu Gin Gin Tyr Gly Giy Gly Gly Val Leu Tyr Arg Val Ala Ser Ser Val Arg Lys Cys Ala Thr Giy His Ser Ser Gin Ala Gly Leu Phe Ser Pro Giu Ala Asp Phe Met Ala Pro Ala (SEQ ID Giu Pro Asn Asn Gin Ile Thr Val Ser Val Leu Leu Ile Tyr Leu Leu Leu Leu Ala Ala NO: -J Ile Asn Leu L eu Pro Ile Phe Giu Asn Ala Arg Pro Gin Lys Gly Gin Tyr Gly Thr Leu Ile Asn Arg Giu Cys Ile Tyr Gly Met Ser His Gin C ly Leu Ile Leu Gin Pro Thr Gin His L eu L eu Asn Leu Lys L eu G iy Ala His Leu Ser Asp Cys Pro Ala G ly Thr Ile Pro His Asn Pro Ala Pro Ala Val Gly Ser Leu Ala Phe C ly His Trp Gly Leu Leu Trp Thr Leu Asp Asn Ser Ser Gly Thr Giy Ala Gin Gin Leu Ala Pro Ala Cys Leu Asp Gin 'Gin Lys Glu L eu C ly Ala Asp Leu Ser Phe S er Pro Leu Ala C iu Pro Leu Gin Thr Gin Gly Arg Asp Glu Ile Thr Trp Glu Pro Gin Phe Thr Lys Leu Giu Leu Ser Ala Leu Met Ala MetAiaAsnCysSerl leMet IleAspGluleleHi sHisLeuLysArgProProAla ProLeuLeuAspProAsn~snLeuAsnAspGluAspValSerIleLeuetAspArgAsn LeuArgLeuProAsnLeu~l~rheajg~aa 5 ~neul~n~ae Glyl leGluAlaT ~urgs~u~nr~y~uroe aThrAiaAlaPro WO 97/12985 PI-Tfrrcnc 578 i/ 1 SerArgHisProIle~l~ey~al s~pi~uh~r~uy~uh PheTyrLeuValThrLeuGluGln~laGlnGluGlnGln~rValGluGlyGlyGlyGly SerProc~lyG luProS erGlyProI leS erThrleAsnProSerProProSerLysGlu SerHisLysS erProAsniMetAlaTyrLysLeuCysHisProGluGluLeValeu GlyHisSerLeuGlyleProTrpAlproLeuSerSerCr Srlnleun LeuAlaGlyCysLeuS erGlnLeuHisS erGlyLeuPheLeu~yrGlnGlyLeuLeuGln AlaLeuGuGlyIleSerProGluLeuGlyProThrLAhrhulnespa AlaAspPheAlaThrThrIeTrpGnG1etlGluLGly LAlaProAlaLeu GlnProThrG inGlyAlaMet ProAlaPheAlaS erAlaPheGlnArg~rgA1 aG lyGly ValLeuVaAaSerisLeuGnSerPheLeuGal~al~rAVal~e~gi LeuAlaGlnProGy~yGlyoeryspeAptlaThr~oe~rL~la re ProGlnSerPheLeuLeuLyser~luGln lna lLlln~ys~y AlaLeuGlnGluLysLeuCysAlaThr (SEQ ID NO:194); MetAlaAsnCysSerIleMetIleAspGluIleIleHisHisLeuLysArgPPola ProLeuLeuAspProAsnAsnL euAsrAspGluAspValSerIleLeuetAspArgAsn SerArgHisProIle~l~ey~ai s~pl~uh~r~uy~uh PheTyrLeuValThrLeuGuGnAaGnGuGlnGl~yV ll~yl~y SerProGlyGluProSerGlyProleS erThrleAsnProSerProProSerLysGlu SerHisLysS erProAsniletAlaProGluLeuGlyProThrLeuAspThLGlne AspValAlaAspPheAaTThrIep rGnGlueGleGly tlar GlyAlaAlaLeuGlnGluLysLeuCysAaThrTyrLysLCysHi 1~ol~ue ValLeuLeuGlyHisSerLeuGlyIleProTrpAlaPrLeuSSCysr~rl AlaLeuGlnLeuAlaGlyCysLeuSerGnLeu~isSGlLhe~uy~n LeuLeuGlnAlaLeucluGlyIleSer (SEQ ID NO: 195); MetAlaAsnCysSerIleMetIleAspGluIleIleHsHisLeuy~gr~o ProLeuLeuAspProAsnAsnLeuAsnAspGluAspValSerIieLeuetAspArgAsn erPheValArgAl aValLysAsnLeuGluAsn~laSer Gl~el~al~ur~ne~n~oy~ur~rl~rl~ar Se~gi~ol~el~sl~y~pr~nl~er~uy~uh PheTyrLeuVdThrLeuGlnG1laGnl~ nGlnGyr~ln~luGlyl~yl SerProGlyGluProS erGlyProlleSerThrleAsnProSerProProSerLysGlu Se~sy~rr~ne~ae~a~el~gr~al~ya~ua Al~ri~ul~rh~ul~l~ry~ga~ur~se~ai ProGlyGlyG lySerAspMetAlaThrProLeuGlyProAlaS erSerLeuProGinS er Ph~ue~se~ul~na~g~sl~nl~pl~al~ul GluLysLeuCysAlaThrTyrLysLeuCys~isProGluGluLeuVaeiu~Yi SerLeuGlyl leProTrpAlaProLeuSerSerCysProSerGlnAlaLeuGlnLeuAla GlyCysLeuSerGnLeuHisSerGeuhLeuT'r~yLeurG Gl~laLe GluGlyIleS erProGluLeuGlyProThrLeuAspThrLeuGlnLeuAspValAlaAsp PheAaThrThrIeTrpGletGl~e uGulyeuG1MAl~Uln r ThrGlnGlyAlaMetProAlaPheAla (SEQ ID NO: 196); WO 97/12985 IDd"rr /Y To ProLeuLeuAspProAsnAsnLeuAsnAspGiuAspVaiSerleLeuMetAspArgAsn Le~ge~os~ul~rh~l~gl~ly~ne~us~ae Gl~el~al~ur~ne~n~oy~ur~rl~rl~ar SerArgHi sProIl eleley al~s~pl~uh~r~uy~u PheTyrLeuV.;iThrLeuGuGnAaGnGuGnGnyrVaGuGyGyGiyGi SerProGiyG.LuProSerGiyProleS erThrleAsnProSerProProSerLy sGiu SerHisLysSerProAsnMetAaMetAaProAaLeuGlnProThrGlGiAiae Pr~ah~ae~ah~nr~g~al~ya~ua~ae~se GinSerPheLeuciuValSerTyrArgVaiLeuArgHisLeuAiaGlnPro~lyQly~ly SerAspMetAiaThrProLeuGyProAaSerSerLeuProGnSerPheLLLy Se~ul~na~gy~el~y~pl~al~ul~uy~uy AiaThrTyrLysLeuCysHisProGiuGluLeuValLeuLeuGlyHisSerLeuGlle ProTrpAiaProLeuSerSerCysProSerGnAaLeuGnLeuAaGyCysLSe GinLeuHi sS erGiyLeuPheLeuTyrGinGiyLeuLeuGin~iaLeuGluGiyI ieSer ProG iuLeuGlyproThrL euASpThrLeuGinLeuAspVaiAiaAspPheAiaThrThr IieTrpGinGliMetGiuGiuLeuGiy (SEQ ID NO:i97); MetAiaAsnCysSerleMetleAspGiulelleHisHisLeu~ysArgProProAia ProLeuLeuAspProAsnAsnLeuAsnAspGluAspVa1SerIle~euetAspArgAsn Le~ge~os~ul~rh~l~gl~ly~ne~us~ae Gl~el~al~ur~ne~n~oy~ur~rl~rl~ar Se~gi~ol~el~sl~y~pr~nl~er~uy~uh Ph~re~a ie~l~nl~ nGiuGinGinTyrVaiGiuGiyoiyGiyGly SerProGlyGiuProSerolyproI leS erThrleAsnProSerProProSerLysGiu SerHisLysSerProAsniMetAiaThrGinGiyAiaMetProAiaPheAiaSerAiaPhe G inArgArgAiaGiyGiyVaiLeuVaiAlaSer~j sLeuGinS erPheLeuGiuVaiS er Ty~ga~ur~se~al~o~yl~ye~pe~ah~oe GiyProAiaSerSerLeuProGinSerPheLeuLeuLysSerLeuGiuGinValArgLys IieGlnGiyAspGiyAlaAlaLeuGinGiuLysLeuCysAiaThr~yrLysLeuCysHis ProGiuGiuLeuValLeuLeuGiyHisS erLeuGiylieProTrpAiaproLeuSerSer CysProSerGlnAiabeuGinbeuAiaGiyCysLeuSerGinLeuHi sSerGiyLeuPhe LeuTyrGinciyLeuLeuclnAiaLeuGiuGlyleSerProGiuLeuGiyProThrLeu AspThrLeuGinLeuAspVaiAiaAspPheAlaThrThrIleTrpGinGinetGiuGiu LeuGiyMetAiaProAiaLeuGinPro (SEQ ID NO:198); Ala Asn Cys Arg Pro Pro Asp Val Ser Glu Ser Phe Ile Giu Ala Thr Ala Ala Trp Gin Giu Glu Gin Ala Gly Glu Pro Ser Lys Glu Ser Ser Leu Gly Ala Leu Ser Ile Met Ile Ala Pro Leu Leu Ile Leu met Asp Val Arg Ala Val Ile Leu Arg Asn Pro Ser Arg His Phe Arg Giu Lys Gin Glu Gin Gin Ser Gly Pro Ile Ser His Lys Ser Leu Giy Gin Leu Gin Ser Leu Leu Asp Gu Ile Ile Asp Pro Asn Asn Arg Asn Leu Arg Lys Asn Leu Giu Leu Gin Pro Cys Pro Ile Ile Ile Leu Thr Phe Tyr Tyr Val Giu Giy Ser Thr Ile Asn Pro Asn Met Gly Ser Gly Gin Val Giy Thr Gin Leu His His Leu Lys Leu Asn Asp Giu Leu Pro Asn Leu Asn Ala Ser Gly Leu Pro Ser Ala Lys 'Ala Gly Asp Leu Val Thr Leu Giy Giy Ser Pro Pro Ser Pro Pro Pro Thr Cys Leu Arg Leu Leu Leu Pro Pro Gin Gly WO 97/12985 PCTIUS96/15774 Arg Gin Gly Pro Arg Val S er Asp Ala Thr His Ser Ala Asp His Leu Ile Arg Thr Leu Thr Pro Ser Pro Gly Leu Gly Ala Leu Leu Pro His Leu Glu Gly Gin His Arg Cys Ala Val Pro Trp Ala Leu Lys Asp Pro Asn Ala Gly Lys Val Arg Phe Val Arg Giu Phe Gly Cys Asp Leu Arg Val Leu His Ser Arg Leu Thr Pro Val Leu Leu Lys Thr Gin Met Giu Val Thr Leu Leu Leu (SEQ ID NO:209); Ile L eu G ly Leu Ser Pro Giu Glu Phe Met Asn Ser Gin Ala Thr Gly Leu Leu Met Ly s Cys Val Lys Val Ser Val Ala Leu Pro Asp Ala Met Phe Gly Ser Leu Giu Phe Gin Ala Ala Arg Asp Giu Ile Thr Trp Giu Gly Ser Pro L eu Leu Met Lys Cys Val Lys Val Leu L eu Asn Pro Val Ser Giu Aia Gin Gin Giu Lys Gin Ser Val Ala Leu Pro Asp Ala Met Leu Gin Cys Pro Ser Phe Ala Ala Glu Ala Pro Giu Gly Phe Gly Ser Leu Giu Phe Gin Ala Gly Ser Ser Ala Ile Val Ile Pro Phe Gin Ser Ser Arg Gin Gly Pro Arg Vai Ser Asp Ala Gin Leu Ile Pro L eu Arg Leu Ser Arg Giu G ly His Thr His S er Ala Asp His Leu Ile Arg Leu Leu Met Ile Leu Leu Met Asp Ala Val Arg Asn Arg His Giu Lys Gin Gin Pro Ile Lys Ser Thr Ala Leu Leu Thr Leu Pro Pro Ser His Pro Leu Gly Giu Leu Gly Giy Gin Ser Gly (SEQ ID Asp Giu Ile Asp Pro Asn Arg Asn Leu Lys Asn Leu Leu Gin Pro Pro Ile Ile Leu Thr Phe Tyr Val Giu Ser Thr Ile Pro Asn Met His Lys Asp Arg Gly Lys Cys Val Arg Ala Cys Asp Val Leu His Pro Thr Pro Trp Lys Thr Ala Val Thr Leu Gly Pro Gin Val Arg NO:210); Ile His Asn Leu Arg Leu Glu Asn Cys Leu Ile Lys Tyr Leu Gly -Gly Asn Pro Gly Thr Pro Asn Vai Arg Giu Phe Leu Arg Ser Arg Val Leu Gin met Leu Leu Thr Cys Leu Leu His Asn Pro Ala Pro Ala Val Giy Ser Gin Ala Phe Gly Val Leu Leu Glu Leu Leu Leu Leu Asp Asn Ser Ser Giy Thr Ser Pro Leu Ile Leu Giy Leu Ser Pro Giu Giu Ser Gly Lys Glu Leu Gly Ala Asp L eu Pro Pro Pro Phe Met Asn Ser Gin Ala Thr Giy Ser Ala Ala Arg Asp Giu Ile Thr Trp Giu Giy Ser His Arg Cys Aia Val Pro Trp, Ala Asn Pro Val Ser Giu Ala Gin Gin Giu Lys Lys Gly Val Cys Leu Thr Lys Val Cys Pro Ser Phe Ala Ala Giu Ala Pro Giu Asp Lys Arg Asp His Pro Thr Thr Ser Ala Ile Val Ile Pro Phe Gin Ser Ser Pro Val Giu Leu Ser Val Gin Leu Ile Met Ile Pro Leu Leu Leu Met Asp Arg Ala Val Leu Arg Asn Ser Arg His Arg Giu Lys Giu Gin Gin Gly Pro Ile His Lys Ser Asn Ala Ile Arg Phe Leu Phe Gly Gly Arg Val Leu Arg Leu Ser Leu Leu Pro Met Giu Giu Leu Leu Giu Asp Giu Ile Asp Pro Asn Arg Asn Leu Lys Asn Leu Leu Gin Pro Pro Ile Ile Leu Thr Phe Tyr Val Giu Ser Thr Ile Pro Asn Met Phe Leu Ser Met Leu Val Asn Met Ala Ser Lys Leu Gin Cys Pro Ala Val Asp Thr Lys Ala Gly Val Met Ile Asn Arg Giu Cys Ile Tyr Gly Asn G ly Phe Giy Ser Leu G iu Phe Gin Ala His Leu Leu Asn Leu Lys Leu Gly Pro Arg Gin Gly Pro Arg Val Ser Asp Ala His Asn Pro Ala Pro Ala Val Gly Ser Thr His Ser Ala Asp His Leu le Arg Leu Asp Asn Ser Ser Gly Thr Ser Pro Thr Leu Thr Pro S er Pro Gly Leu Gly Lys Giu Leu Giy Ala Asp Leu Pro Pro Ala L eu Leu Pro His Leu Giu Gly Gin WO 97/12985 PCT/US96/15774 Leu Gin Gin Ala Arg Asp Glu Ile Thr Trp Glu Gly Ser Asn Arg Phe Arg Arg Leu Met Leu Cys Leu Gin Leu Asp Val Asn His Lys Gin His Gly Pro Thr Ala Val Ser Arg Ala His Gin Leu Pro Asp Ala Gly Val Leu Asn Pro Val Ser Glu Ala Gin Gin Glu Lys Ala Phe Gly Val Leu Leu Glu Leu Leu Leu Gly Asp Arg Lys Leu Pro Leu Gly His Gly Ser Gin Gly Ser Gly Lys Thr Ser Ala Phe Glu Phe Pro Pro Arg Pro Cy Pro Ser Phe Ala Ala Glu Ala Pro Glu Ile Leu Gly Leu Ser Pro Glu Glu Ser Gly Arg Pro Asn Asn Gin lie Thr Gly Leu Ser Pro Gly Gly Tyr Gly Ile Tyr Leu Leu Leu Leu Ala Ala Thr Leu Pro Ser Ala Ile Val Ile Pro Phe Gin Ser Ser Phe Met Asn Ser Gin Ala Thr Gly Ser Ala Thr Asn Leu Leu Pro Ile Phe Gly Lys Pro Pro Ala Val Arg Ser Gin Lys Gly Gin Tyr Gly Thr Leu Cys Leu Gin Ile Pro Leu Arg Leu Ser Arg Glu Gly His Leu Leu Met Lys Cys Val Lys Val Leu Leu Thr Leu Ser Leu Gly (SEQ ID Met Ile Leu Leu Met Asp Ala Val Arg Asn Arg His Glu Lys Gin Gin Pro Ile Lys Ser Ser Phe Val Gly Ala Ser Leu Leu Pro Glu Asp Phe Ala Gin Met Ala Leu Gly Gin Ser (SEQ ID Ser Leu Leu Gly Gin Leu Ala Leu Gin Ser Leu Leu NO:211); Asp Glu Ile Ile His His Asp Pro Asn Asn Leu Asn Arg Asn Leu Arg Leu Pro Lys Asn Leu Glu Asn Ala Leu Gin Pro Cys Leu Pro Pro Ile Ile Ile Lys Ala Leu Thr Phe Tyr Leu Val Tyr Val Glu Gly Gly Gly Ser Thr Ile Asn Pro Ser Pro Asn Met Ala His Lys Gin His Leu Leu Arg Gly Gly Ser Thr Leu Cys Val Pro Ala Pro Pro Ala Cys Arg Asp Ser His Val Leu Val His Pro Leu Pro Thr Ser Leu Gly Glu Trp Lys Asp Ile Leu Gly Ala Val Ala Arg Gly Gin Leu Gly Gin Leu Ser Gly Gin Val Leu Leu Gly Thr Gin Leu NO:212); Ser Gly Gly Thr Leu Lys Asp Glu Asn Leu Ser Gly Ser Ala Gly Asp Thr Leu Ser Pro Pro Pro Asp Pro Lys Val Arg Glu Asp Leu His Ser Pro Val Thr Gin Thr Leu Pro Thr Arg Leu Pro Pro Asn Leu Arg Leu Glu Asn Cys Leu Ile Lys Tyr Leu Ser Asn Arg Pro Gly Glu Ser Lys Met Pro Leu Val Val Leu Gin Ser Gly Asp Leu Cys Ile Pro Leu Ala Gin Gly Pro Thr Thr Ile Gin Pro Asn Asp Pro Asn Ala Ser Pro Ser Ala Gly Val Thr Cys Ser Pro Ala Pro Ser Glu Ser Ala Phe Ala Ser Arg His Phe Leu Gly Ala His Pro Trp Ala Gly Cys Leu Leu Leu Asp Trp Gin (SEQ ID Glu Asp Val Leu Glu Ser Gly Ile Glu Ala Thr Ala Asp Trp Gin Leu Glu Gin Ile Met Ile Pro Leu Tyr Gly Pro Ile His Lys Ser Ala Ser Ala His Leu Gin Leu Ala Gin Leu Lys Ser Ala Leu Gin Glu Glu Leu Pro Leu Ser Leu Ser Gin Gin Ala Leu Thr Leu Gin Gin Met Glu NO:186); Ser Phe Ala Ala Glu Ala Asp Val Ser Pro Phe Ser Pro Leu Glu Val Ser Leu Glu Leu Glu Ile Leu Met Val Arg Ala Ile Leu Arg Pro Ser Arg Phe Arg Glu Gin Glu Gin Glu Ile Ile Glu Gly Gly Thr Ile Asn Asn Met Ala Gin Arg Arg Phe Leu Glu Ser Gly Gly Glu Gin Val Lys Leu Cys Leu Leu Gly Cys Pro Ser His Ser Gly Gly Ile Ser Asp Val Ala Leu Gly Met WO 97/12985 PCT/US96/1 5774 Asn Leu Lys Leu Asn Pro Val Ser ely Pro Thr Ala Val Ser Arg Ala His Gin Leu Pro Asp Ala Ala Ser Pro Ser Ala Gly Val Thr Cys Ser Pro Ala Ser Ile Phe Val Gly Ser Ser Pro Gin Gly Gly Gly Ser Tyr Gly Gly Lys Ile Thr Tyr Ser Leu Ala Leu Phe Leu Glu Leu Phe Ala Pro Ala Gly Ala Asp Leu Ile Pro Leu Arg Pro Pro Ala Val Arg Ser Gin Lys Gly Gin Tyr Gly Thr Leu Ile Thr Trp Glu Met Leu Met Ala Gly Ser Met Leu Val Gin Gly Leu Ile Leu Gin Pro Thr Gin Glu Ala Gin Gin Ile Leu Asp Val Glu Lys Pro Val Leu Ser Asp Cys Pro Ala Gly Thr Ile Pro Ala Ile Ala Pro Glu Phe Ala Gin Asp Glu Asp Pro Arg Asn Lys Asn Pro Ser Glu Ser Ala Phe Ala Ser Arg His Phe Leu Gly Ala His Pro Trp Ala Gly Cys Leu Leu Leu Asp Trp Gin (SEQ ID Leu Arg Ser Arg Arg Glu Glu Gin Ile Ile Asn Asn Leu Arg Leu Glu Gly Pro His Lys Ala Ser His Leu Leu Ala Leu Lys Ala Leu Glu Glu Pro Leu Leu Ser Gin Ala Thr Leu Gin Met NO: 187) Asn His Lys Gin His Leu Leu Tyr Ile Ser Ala Gin Gin Ser Gin Leu Ser Gin Leu Gin Glu Leu Pro Leu Gly His Asn Pro Val Ser Pro Phe Ser Pro Leu Glu Val Ser Leu ?lu Leu Glu Gin Ile Thr Gly Leu Asp Asn Glu -Thr Asn Gin Phe Ser Glu Lys Leu Cys His Gly Asp Leu Pro Cys Ile Ile Phe Tyr Gly Ser Lys Arg Glu Asp Leu Glu Gly Gly Ile Asn Met Ala Arg Arg Leu Glu Gly Gly Gin Val Leu Cys Leu Gly Pro Ser Ser Gly Ile Ser Val Ala Gly Met Ala Glu Ala Asp Asp Arg Lys Leu Gly Pro Thr Ala Val Ser Arg Ala His Gin Leu Pro Asp Ala Leu Asp Vai Asn Pro Phe Gin Glu Pro Asn Asn Gin Gly Ser Gin Gly Ser Gly Lys Thr Ser Ala Phe Glu Phe Pro Ser Arg Glu Ile Asn Leu Leu Pro Ser Pro Gly Gly Tyr Gly Ile Tyr Leu Leu Leu Leu Ala Ala Arg Glu Gin Ile Asn Arg Glu Cys Pro Pro Ala Val Arg Ser Gin Lys Gly Gin Tyr Gly Thr Leu His Lys Gin His Leu Leu Asn Leu Gly Ser Met Leu Val Gin Gly Leu Ile Leu Gin Pro Thr Gin Asn Arg Glu Cys Pro Leu Gly His Asn Pro Ala Pro Glu Lys Pro Val Leu Ser Asp Cys Pro Ala Gly Thr Ile Pro Ile Ile Ile Lys Ala Thr Phe Tyr Leu Val Gly Gly Ser Asn Cys Leu Lys Arg Pro Pro Asp Giu Asp Val Ser Asn Leu Giu Ser Phe Ser Gly Ile Glu Ala Ser Ala Thr Ala Tyr Pro Ser Gly Pro Ile Glu Ser His Lys Ser Ala Phe Ala Ser Ala Ala Ser His Leu Gin Arg His Leu Ala Gin Phe Leu Leu Lys Ser ely Ala Ala Leu Gin His Pro Giu Giu Leu Trp Ala Pro Leu Ser ely Cys Leu Ser Gin Leu Leu Gin Ala Leu Leu Asp Thr Leu Gin Trp Gin Gin Met Glu (SEQ ID NO:189); Gly Thr Ser Ala Ile Vai Ile Val Ser Pro Phe Ser Pro Leu Glu Vai Ser Leu Glu Leu Glu Asp Leu Ile Pro Leu Arg Leu Glu Thr Asn Gin Phe Ser Glu Lys Leu Cys His Gly Asp Leu Trp Gin Glu Gin Met Ile Leu Leu Met Asp Ala Val Arg Asn Gly Gly Ile Asn Met Ala Arg Arg Leu Glu Gly Gly Gin Val Leu Cys Leu Gly Pro Ser Ser Gly Ile Ser Val Ala Gly Met Asp Pro Asn Arg Asn Leu Lys Asn Leu Leu Gin Pro Leu Asn Lew Pro Asn Ala Leu Pro Asp Giu Asp Val Asn Leu Giu Ser Ser Gly Ile Glu Ser Ala Thr Ala Ser Phe Ala Ala Ile Leu Met Val Arg Ala Ile Leu Arg Pro Ser Arg WO 97/12985 PCTIUS96/15774 His Pro Ile Lys Leu Thr Gin Gly Gi; Ser TIe Met Ala Pro Leu Ser Gly Pro Ser His Lys Phe Ala Ser Ser His Leu His Leu Ala Leu Leu Lys Ala Ala Leu Pro Giu Giu Ala Pro Leu Cys Leu Ser Leu Gin Ala Asp Thr Leu Gin Gin Met ID NO:190); Ile Phe Gly Ile Tyr Ile Ser Ala Gin Gin Ser Gin Leu Ser Gin Leu Gin Glu Asn Ala Ser Gly Leu Pro Ser Ala Lys Ala Gly Asp Leu Val Thr Leu Gly Gly Glyt Ser Giu Ile Ile His Pro Asn Asn Leu Asn Leu Arg Leu Asn Leu Giu Tyr Ser Gly Pro Ile Ser His Lys Ser Phe Ala Ser Ala Ser His Leu Gin His Leu Ala Gin Leu Leu Lys Ser Ala Ala Leu Gin Pro Giu Glu Leu Ala Pro Leu Ser Cys Leu Ser Gin Leu Gin Ala Leu Asp Thr Leu Gin Gin Gin Met Giu (SEQ ID NO:i91) Ile Tyr Ser Asp Val S er Pro Phe Ser Pro Leu Giu Val Ser Leu Glu Leu Giu Ile Thr Trp Giu G ly His Asn Pro Val S er Pro Phe Ser Pro Leu Giu Val Ser Leu Giu Leu Glu Lys Leu Gly Giu Giu Thr Asn Gin Phe Ser Glu Lys Leu Cys His Gly Asp Leu Giu Ala Gin Gin Gly Leu Asp Asn Glu Thr Asn Gin Phe Ser Glu L-ys Leu Cys His Gly Asp Leu Ala Val G ly Ile G ly Ile Met Arg Leu Gly Gin L eu Leu Pro Ser Ile Val Gly Ala Ala Giu Ala Gly Lys Giu Leu G ly Ile Met Arg Leu Gly Gin Leu Leu Pro Ser Ile Val Gly Giy Thr Gly Ile Gly Asn Ala Arg Giu Gly Val Cy s Gly Ser Gly Ser Ala Met Ile Pro Phe Gin Ser Arg Asp Giu G ly Asn Ala Arg Giu Gly Val Cys Gly Ser Gly Ser Ala Met Asp L eu S er His Gly Pro Thr Ala Val Ser Arg Ala His Gin Leu Pro Asp Ala Leu Ser Arg Giu Asn Pro Val Ser Gly Pro Thr Ala Val Ser Arg Ala His Gin Leu Pro Asp Ala Trp Giu Gly His Gly Ser Gin Gly Ser Gly Lys Thr Ser Ala Phe Giu Phe Pro Arg Arg Giu Gin Cys Pro Ser Phe Gly Ser Gin Gly Ser Gly Lys Thr Ser Ala Phe Giu Phe Pro Gin Gin Gly Leu Ser Pro Gly G ly Tyr Gly Ile Tyr Leu Leu L eu Leu Ala Ala Asn His Lys Gin S er Ala Ile Val S er Pro Gly Gly Tyr Gly Ile Tyr L eu L eu Leu Leu Ala Ala Glu Phe Ala Gin Gly Ser Lys Arg Pro Gly Pro Ser Ala Met Vai Leu Arg w3a1 Ser Gin Gin Gly Lys Leu Gly Ile Gin Leu Tyr Gin Gly Pro Thr Thr Leu Gin Leu Pro Leu G ly Ile Pro Leu Arg Pro Pro Ala Val Arg Ser Gin Lys Gly Gin Tyr Gly Thr Leu Gin Ile Thr Gly Met Leu Met Ala Gly Ser Met Leu Val Gin Gly L eu Ile Leu Gin Pro Thr Gin Arg Giu Giu Gin Asn Cys Pro Pro Giu Pro Lys Giu Pro Ala Val Ala Leu Arg Ser Phe Asp Gly Cys His Pro Trp Ala Gly Giy Leu Thr Leu Ile Trp Pro (SEQ Pro Cys Ile Ile Phe Tyr Gly Ser Ile Asp Leu Asp Asp Arg Val Lys Giu Pro Lys Glu Pro Ala Val Ala Leu Arg Ser Phe Asp Gly Cys His Pro Trp, Ala Gly Gly Leu Thr Leu Ile Trp Pro; Metla~n~y~ers~e~lesp~u~l~lehr~SLeuLysGinProProLeu ProLeuLeuAspPheAsnAsnL euAsnG iyGiuAspGinAspIl1eLeuMetAspAsnAsn LeuArgArgProAsnL euGluAlaPheAsnArgAlaVaiLys SerLeuGinAsnAlaSer AialleGiuSerleLeuLysAsnLeuLeuProCysLeuPro~euAlaThrAlaAlaPro Th~gi~ol~sl~ss~y~pr~nl~er~gy~uh Ph~re~sh~ul~nl~n~al~ny~ll~yl~yl WO 97/12985 Df-rlyT 584 YU,J1f/ SerProGlyGluProSerGlyPro~leSerThrIleAsnProSerProPrSeysl SerHisLysS erProAsnMetAlaThrGinGlyAlaetProAlaPheAlaS erAlaPhe Gl~gr~a~yl leua~ae~ sLeuGinSerPheLeuGluValSer LysLeuCysAlaThrTyrLysLeuCysHisProGluluLeuValLeLGl.se LeuGlyl leProTrpAlaProLeuSerSerCysProSerG n~laLeuGlnLeuAlaGl CysLeuSerGlnLeuHisSerGlyLeuPheLeuyrGlnGlyLeuLeuGlnla~u Glyl leSerProGluLeuGlyProThrLeuAspThrLeuGlnLeuAspValAlAphe AlaThrThrIleTrpGlnGlnMetGluGluLeuGlyMetAaProAlLGln~ (SEQ ID NO:199) MetAlaAsnCysSerAsriet IleAspGlulleIl eThrHi sLeuLysGlnProProLeu ProLeuLeuAspPheAsnAsnLeuAsnGyGuAspGnAspIleLu~tGluns Le~gr~os~ul~ah~n gl~ly~re~ns~aer Alal eGluS er leLeuLysAsnLeuLeuProCysLeuProLeuAlaThrAlaAlaPr Th~gi~ol~el~gs~y~pr~nl~er~gy~uh PheTyrLeuLysThrLeucluAsnAlac lnAlaGlnGlnTyrVdl1oluGlyGlyG lyG ly SerProGlyGluProSerGlyProIleSer nIleAsnProSerProPLslu SerHisLysS erProAsnxetAlaThrGlnGlyAlaetProAlaPheAlaSerAlaPhe Gi~gr~al~ya~ua~a~ri~ul~rh~ul~le TyrArgValLeuArgHi sLeuAlaGlnProThrP'roLeuGlyProAl aS erS erLeupro GlnSerPheLeuLeuLysSerLeuGuGnVaArgLyIelnlysly~la~ia LeuGlnGluLysLeuCysAlaThrTyrLysLeuCysHisProGlu~LuVlLLe GlyHi sSerLeuGlyl leProTrpAlaProLeuSerSerysProSerG1n~laLeuGln LeuAlaGlyCysLeuSerGlnLeuHisSerGlyLeuPheLeuTyrGl LeLuln AlaLeuGluGlyleSerProGuLeuGlyProThrLeup pr~hrlLeulAVal AlaAspPheAlaThrThrIleTrpGlnGl1ietGluGluLeuGlyMe tAlaProAlaLeu GlnPro (SEQ ID NO:200); MetAlaAsnCysSerAsnetIleAspGluTleIleThrHi sLeuLysclnProProLeu ProLeuL euAspPheAsn snLeuAsnGlyGuAspGlInjsp~ 1eLeuMetGluAsnAsn Le~gr~os~ul~ah~n~gl~ly~re~ns~ae AlaIleGluSerIleLeuLysAsnLeuLeuProCysLeuProLeuAaThAllaPr Th~gi~ol~el~gs~y~pr~nl~er~gy~uh PheTyrLeuLysThrLeuGuAsnAaGnAaGnGnyrVaGuGlGlGlyGl SerProGlyGluProSerGlyProleSerThleAsnoeProeProSLGlu Se~sy~rr~r~tl~rl~yl~tr~ah~ae~ah GlnArgArgAlaGlyGlyVa1LeuValA1l5~erj sLeuGlnSerPheLeuGluValSer Ty~ga~ur~se~al~o~rl~ye~yl~rl~rh Le~uy~re~ul~lr~s~el~ys~yl~ae~nl LysLeuCysAlaThrTyrLysLeuCysHi sProGluGluLeuValLeuLeuGlyHi sSer LeuGlyIleProTrpAaProLeuSerSerysProSerGnAaLeuGnLAlaGly CysLeuSerGlnLeuHisSerGyLeuPheLeurGnGyLeuLeuGAlLGl Glyl leSerProGluLeuGlyProThrLeuAspThrLeuGlnLeuAspValAlaASPPhe Al~rh~er~nl~tl~u~ul~tl~ol~ul~o (SEQ ID NO:201) MetAlaAsnCysSerAsri4etIleAspGluIleIleThrHisLeuLysGlnProProLeu WO 97/12985 WO 9712985PCTIUS96I1 5774 585 ProLeuLeuAspPheAsnAsnLeuAsnGlyGluAspGlnAspI leLeuMet.AspAsnAsn LeuArgArgP-oAsnLeuGluAlaPheAsnArgAlaValLy sSerLeuGlnAsn1aS er Alal leGluSerlleLeuLysAsnLeuLeuProCysLeuProLeUAlaThrAlaAlaPro Th~gi~ol~sl~ss~y~pr~nl~er~gy~uh PheTyrLeuLysThrLeuGluAsnAlaGlnAlaGlnGlnTyrValGluGlyGlyGlyGly SerProGlyGluProSerGlyProlleSerThrlleAsnProSerProProSerLysclu SerHisLysS erProAsnmetAlaThrGlnGlyAlaMetProAlaPheAlaSerAlaPhe Gl~gr~al~ya~ua~a~ri~ul~rh~ul~le Ty~ga~ur~se~al~o~rr~ul~olgre~ur GlnSerPheLeuLeuLysSerLeuGluGlnvalArgLysIleGlnGlyAspGlyAlaAla Le~nl~se~sl~ry~s~uy~sr~ul~ua~ue Gl~se~ul~er~pl~o~ue~ry~oe~nl~ul LeuAlaGlyCysLeuSerGlnLeuHi sS erGlyLeuPheLeuTyrGlnGlyLeuLeuGln AlaLeuGluGlyIleSerProGluLeuGlyProThrLeuAspThrLeuGlnLeuAspVal AlaAspPheAlaThrThrIleTrpGlnGlniMetGluGluLeuclyMetAlaProAlaLeu GinPro (SEQ ID NO:202); AlaAsnCysSer~leYetIleAspGluIleIleHi sHisLeuLybArgProProAlaPro LeuLeuAspProAsnAsnLeuAsnAspGluAspValSerlleLeuMetAspArgAsnLeu ArgLeuProAsnLeuG luSerPheValArgAlaValLysAsnLeuGluAsnAlaserGly ArgHisProllellelleLysAlaGlyAspTrpGlnGluPheArgcluLysLeuThrPhe TyrLeuValThrLeuGluGlnAlaGlnGluGlnGlnTyrVal~luGlyGlyGlyGlySer ProGlyGluP. oSerGlyProlleSerThrlleAsnProSerProProSerLysGluSer Hi sLysSerProAsniMetGlyProThrCysLeuSerSerLeuLeuGlyGlnLeuSerGly GlnValArgLeuLeuLeuGlyAlaLeuGlnS erLeuLeuGlyThrGlnLeuProProGln GlyArgThrThrAlaHisLysAspProAsnAlal ePheLeuSerPheGinHi sLeuLeu ArgG lyLysValArgPheLeuMetLeuValGlyGlySerThrLeuCysValArgGluPhe GlyAsfMetAlaSerProAlaProProAlaCysAspLeuArgValLeuSerLysLeuLeu ArgAspSerHisValLeuflisSerArgLeuSerGlnCysProGluValHisProLeuPro ThrProValLeuLeuProAlaValAspPheSerLeuGlyGluTrpLysThrGl1etclu GluThrLysAlaGlnAsp~leLeuGlyAlaValThrLeuLeuLeuGluGlyValMetAla AlaArgGlyGlnLeu (SEQ ID NO:221); AlaAsnCysSerIleMetIleAspGluIleIleHis-isLeuLysArgProProAlaPro LeuLeuAspProAsnAsnLeuAsnAspGluAspValSerlleLeuyetAspArgAsnLeu ArgL euProAsnLeuGluSerPheValArgAlaValLysAsnLeuGluAsnAl aSerGly IleGluAlalleLeuArgAsnLeuGlnProCysLeuProSerAlaThrAlaAlaProSer ArgHisProllellelleLysAlaGlyAspTrpGlnGluPheArgoluLysLeuThrPhe TyrLeuValThrLeuGluGlnAlaGlnGluGlnGlnTyrValGluGlyGlyGlyGlySer ProGlyGluProSerGlyProI leSerThrl leAsnProSerProProSer~ysGluSer HisLysSerProAsriMetGlyThrclnLeuProProGlnGlyArgThrThrAlaHisLys AspProAsnAlallePheLeuSerPheGlnHisLeuLeuArgGlyLysValArgPheLeu MetLeuValGlyGlySerThrLeuCysValArgGluPheGlyAsnetAlaSerProAla ProProAlaCysAspLeuArgValLeuS erLysLeuLeuArgAspserHisValLeuHis SerArgLeuS erGlnCysProGluValHisProLeuProThrProValbeuLeuProAla ValAspPheSerLeuGlyGluTrpLysThrGliMtetGluGluThrLysAlaGlnAspIle LeuGlyAlaValThrLeuLeuLeuGluGlyValMetAlaAlaArgclyGlnbeuGlyPro ThrCysLeuSerSerLeuLeuelyGlnLeuSerGlyclnValArgLeuLeuLeuGlyAla LeuGlnSerLeuLeu (SEQ ID NQ:222); WO 97/12985 ]DO-'r luaYU1131., /4 586 Al~ny~rl~tl~pl~e~ei~se~sr~or~ar LeuLeuAspProAsnAsnLeuAsnAspG luAspVa iSerI leLeuMetASpArgAsnLeu~ Ar~ur~ne~ue~ea~g~aa~ss~ul~nl~rl I leG luAlale ur~ne~n~oy~ur~rlah~al~o ArgHisProllel ey~al~pr~n~uh~gl~se~rh TyrLeuValThrLeuGluGn~laGlnGluGlnGlnTyrVaGlulyGlGlyly ProGlyGluProSerGlyproI leSerThrlleAsnProSerProPrGSerLYS~luSer HisLysSerP-oAsMetGyProThrCysLeuSerSerLeuLeuG ylLe Srly GlnValArgL euLeuLeuGlyAlaLeuolnS erLeuLeuGlyThrolnLeuProProGln Gl~gh~rl~sy~pr~n~al~ee~rh~ni~ue Ar-go ~sa~ghee~te~llyl~rh~uy~~lr~u GlyGlyAsnO lyGlyAsniMetAlaserProAlaProProAlaCysAspLeuArgValLe Se~se~ur~pe~sa~u~se~ge~rl~sr~ua Hi sProLeuProThrProValL euLeuProAlaVa lAspPheSerLeuGlyGluTrpLys ThrGlnI~etlGluG~ThrLysAaGnAspIeLeuGyAaValThrLeuLeuGlu GlyValMetAlaAlaArgolyolnLeu (SEQ ID NO:223; Al~ny~rl~tl~pl~e~ei~se~sr~or~ar LeuLeuAspProAsnAsnLeuAsnAspGluAspValSerI leLeuMetAspArgAsnLeu ArgLeuProAsnLeu~ luS erPheValArgAlaValLysAsnLeuoluAsnAarQly Il~ul~ee~gs~ul~o~se~oe~ah~al~oe Ar~sr~el~ey~al~p~pl~uh~gl~se~rh TyrLeuValThr~euG luGiriAl aGlnGluGlnGlnTyrValGluGlyGlyGlyGlySer ProGlyGluProSerGlyProI leSerThrlleAsnProSerProProSerLysGluSer Hi~se~os e~l~rl~ur olnl~gh~rl~ s~ As~os~al~ee~rh~nise~ur',yy~lr~ee Me~ua~yl~rh~uy~lr~uh~yl~nl~ysie AlaS erProAlaProProAlaCysAspLeuArgVaLeuSerLysLeuLurg~pr Hi~le~se~ge~rl~s~ol~li~oe~oh~oa LeuLeuProAi-'aValAspPheS erLeuGlyGluTrpLysThrGlnI~etGluGluThrLys AlaGlnAspllebeuolyAlaValThrLeuLeuLeuoluolyValMetAlaAlaArgoly GlnLeuolyProThrCysLeuserSerLeuLeuolyolnLeuSerolyolnValArgLeu LeuLeuGlyAlaLeuGlnSerLeuLeu (SEQ ID NO:234); AlaAsnCysSerIileMetlleAspGlul lelleHisHisLeuLysArgProProAlaPro Le~us~osns~us p~us~le~ eLeuMetAspArgAsnLeu erPheVa lArgAlaValLysAsnLeuojuAslAl aS erGly Il~ul~ee~gs~ul~o~se~oe~ah~al~oe ArgHisProIleIle~ lebysAlaGlyAspTrpGlnoluPheArgGluLysLeuThrPhe TyrL euValThrLeuG luGlnAlaGlnG luGlnGlnTyrValGluGlyOlyGlyolyS er ProGlyGluProSerGlyProIleSerThrIleAsnProSerProProSerLysGluSer HisLysSerProAsnj~etolyArgThrThrAlaHi sLysAspProAsnAlaIlePheLeu Se~el~se~ur~yy~l~gh~ue~ua~yl~rh SerGlnCysProGluValHisProLeuProThrProValLeuLeuProAlaValAspPhe SerLeuGlyGluTrpLysThrGl1etoluGluThrLysAlaGlnAspIleLeuGlyAla Va~re~ue~ul~le~a~ar~yl~ul~oh~se WO 97/12985 PCTIUSQA/Ir.'7'7A 587 SerS erLeuLeuclyG LeuLeuGlyThrGlnLeuProProGln (SEQ ID NO:235); Al~ny~rl~tl~pl~e~ei~se~sr~or~ar LeuLeuAspProAsnAsnLeuAsnAspGluAspValSerl eLeuMetAspArgAsnLeu Ar~ur~ne~ue~ea~g~aa~ss~ul~nl~rl IleGluAlale ur~ne~n~oy~ur~rlah~al~o ArgHisProIleIleIley al~prpl~uh~gluLse~rh TyrLeuValThrLeuGluGlnAlaGlnGluGlnGlnTyrValcluGlyGlyolyGlySer ProGlyGluProSerGlyProl leSerThrlleAsnProSerProProSerLysGluSer HisLysSerProAsniyetAaHisLysAspProAsnAla~1 ePheLeuSerpheGinHis LeuLeuArgG lyLysValArgPheLeuMetLeuVa iGlyGlyS erThrLeuCy sValArg G luPheGlyG lyAsnGlyGlyAsnlmetAlaSerProAlaProProAlaCysAspLeuArg ValLeuSerLysLeuLeuArgAspSerHisVa1LeuHisSerArgLeuSercjn 0 ysPro GluVaiHi sProLeuProThrProValLeubeuProAlaValAspPheSerLeuGlyGlu TrpLysThrG lriMetG luGluThrLysAlaGlnAspIl1eLeuGlyAl aValThrLeuLeu Le~ul~!e~al~gl~n~ul~oh~se~re~ue GlyGlnLeuSerGlyclnValArgLeuLeuLeuclyAlaLeuGfn~erLeuLeuGlyThr GilnLeuProProGlnGlyArgThrThr (SEQ ID NO:236); AlaAsnCysSerlleMetlleAspGluleIleji sHisLeuLysArgProProAlaPro LeuLeuAspProAsnAsnLeuAsnAspGluAspValSerleLeul~etAspArgAsnLeu ArgLeuProAsnLeuGluSerPheValArgAlaVal~ysAsnLeuGluAsn~laSerGly Ilel al~ur~n~ul~oy~ur~e~ah~al~oe ArgHisProIleIleIleLysAlaGlyAspTrpGlnGluPheArgGluLysLeuThrPhe TyrLeuValThrLeuGluGlnAlaGlnGluGlnGlnTyrValGluclyelyGlyGlySer ProGlyGluProSerGlyProIl1eSerThrlleAsnProSerProProSerLyscluSer HisLysSerProAsnMetAspProAsnAlallePheLeuSerPheGlnHisLeuLeuArg GlyLy sValArgPheLeu'e tLeuValG lyGlyS erThrLeuCysValArgGluPheGly GlyAsnGlyG lyAsrMetAlaSerProAlaProProAlaCysAspLeuArgValLeuSer LysLeuLeuArgAspSerHisValLeuHisSerArgLeuSerGlnCysProGluValHis ProLeuProThrProValLeuLeuProAlaValAspPheS erLeuGlyGluTrpLysThr GlrMetGluGluThrLysAlaGlnAspIleLeuGlyAlaValThrmeuLeuLeuGluGly ValMetAlaAlaArgGlyGlnLeuGlyProThrCysLeuS erS erLeuLeuGlyGlnLeu S erG lyG lnValArgLeuLeuLeuG lyAlabeuGlnSerLeuLeuGlyThrGlnLeuPro ProGlnGlyArgThrThrAlaHisLys (SEQ ID NO: 237); AlaAsnCysSerlleMetl leAspGluI leIleHi sHisLeuLysArgProProAlaPro LeuLeuAspProAsnAsnLeuAsnAspGluAspValSerl eLeuMetAspArgAsnLeu ArgLeuProAsnLeuG luSerPheValArgAlaVa lLysAsnLeuGluAsnAl aSerGly IleGluAlaIleLeuArgAsnLeuGlnProCysLeuProSerAlaThr~laAlaProSer Ar~sr~el~ey~al~p~pl~uh~gl~se~rh TyrLeuValThrLeuGluGlnAlaGlnGluGlnGlnTyrValGluGlyGlyGlyGlySer ProGlyGluProSerG lyProl leSerThrl leAsnProSerProProSerLysGluSer HisbysSerProAsrMetAlallePheLeuSerPheGlnHisLeuLeuArgGlyLysVal ArgPheLeul~etLeuValG lyG lyS erThrLeuCy sValArgGluPheGlyGlyAsnGly GlyAsnMetAlaSerProAlaProProAlaCysAspbeuArgValLeuSerLysLeubeu ArgAspSerHisValLeuHiss erArgLeuSerGlnCysProGluValHis ProLeuPro ThrProValLeuL-euProAlaValAspPheSerLeuGlyGluTrpLysThrGlnyetGlu WO 97/12985 PCT/US96/15-77A 588PCtJQ/ '7 GluThrLysAlaGln~spIleLeuGlyAlaValThrLeuLeULeuGlGlVletl AlaArgGlyc lnLeuGlyProThrCysLeuSerSerLeuLeuGlyGlnLeuSerGlyGln ValArgLeuLeuLeuclyAlaL euGinS erLeuLeuGlyThrGlnLeuProProGlnGly ArgThrThrAlaHisLysAspPrAfl (SEQ ID NO:238); and AlaAsnCysS erlle~etlleAspGlul lel leHi sHisLeuLysArgProPro~laPro ArgHisProle el~sl~y~pr~nl~ergl~se~r TyrLeuValThrLeuGluGlnAlaGlnluGlnGlnTyrValGluGlGllGl~e ProGlyGluProSerclyProI leSerThrlleAsnProSerProProSerLysGluSer Hi sLysSerProAsniMetAspProAsnAlallePheLeuSerPheGlnHisLeuLeuArg Gl~sa~gh~ue~ua~y~ye~re~sa~gl~el Gl~ne~ae~ol~or~a~ss~ur~le~ry~ue ArgAspSerHi sValLeuHisS erArgLeuS erGlnCysProGluValHi sProLeuPro ThrProValLeuLeuProAlaVaAspPheSerLeuGlyGluTr;LThrGln~t GluThrLysAlaGlnAspleLeuGlyAlaValThrLeuLeuLeGlGlVletl Al~gl~ne~yr~ry~u~re~ue~yl~ue~yl ~ue~y~ri~yrgh~rl HisLys (SEQ ID NO:239). 14. The hematopoietic protein of claim 1, 2, 3, 4, 5, 6, 7, 8, 10 or 11 wherein said colony stimulating factor is selected from the group consisting of GM-CSE, G-CSF, G-CSF Ser 17 c-mpl ligand (TPO), M-CSF, erythropoietin (EPO), IL-i, IL-4, IL-2, IL-3, IL 6, IL-7, IL-8, IL-9, IL-10, IL-li, IL-12, IL-13, IL-iS, LIF, flt3/flk2 ligand, human growth hormone, B-cell growth factor, B-cell differentiation factor, eosinophil differentiation factor and stem cell factor (SCE). The hematopoietic protein of claim 14 wherein said colony stimulating factor is selected from the group consisting of G-CSF, G-CSF Ser 17 and c-mpl ligand (TPO). 16. A nucleic acid molecule encoding said-hematopoietic protein of claim 1. 17. A nucleic acid molecule encoding said hematopoietic protein of claim 2. WO 97/12985 PCT/IS6/15 774 589 18. A nucleic acid molecule encoding said hematopoietic protein of claim 3. 19. A nucleic acid molecule encoding said hematopoietic protein of claim 4. A nucleic acid molecule encoding said hematopoietic protein of claim 21. A nucleic acid molecule encoding said hematopoietic protein of claim 6. 22. A nucleic acid molecule encoding s'aid hematopoietic protein of claim 7. 23. A nucleic acid molecule encoding said hematopoietic protein of claim 8. 24. A nucleic acid molecule encoding said hematopoietic protein of claim 9. A nucleic acid molecule encoding said hematopoietic protein of claim 26. A nucleic acid molecule encoding said hematopoietic protein of claim 11. 27. A nucleic acid molecule encoding said hematopoietic protein of claim 12. 28. A nucleic acid molecule encoding said hematopoietic protein of claim 13. 29. A nucleic acid molecule encoding said hematopoietic protein of claim 14. WO 97/12985 PCT/US96/15774 590 A nucleic acid molecule encoding said hematopoietic protein of claim 31. The nucleic acid molecule according to claim 27 selected from group consisting of; 1 51 101 151 201 251 301 351 401 451 501 551 601 651 701 751 801 851 901 1 51 101 151 1 251 3'01 351 401 451 501 551 601 651 701 751 801 851 901 951 ATGGCTAACT ACCACCTGCA CTATC CTGAT AGGGCTGTCA TAATC TCCAA CAATCATCAT TTCTATCTGG CGGTGGAGGC ACAAGCTGTG ATCCCCTGGG AGGCTGCTTG TGCAGGCCCT CTGCAGCTGG AGAACTGGGA CCTTCGCCTC CATCTGCAGA GCAGCCCTCT TAGAGCAAGT CTGTGTGCCA ATGGC TAACT ACCACCTGCA CTATCCTGAT AGGGCTGTCA TAATC TCCAA CAATCATCAT TTCTATCTGG CGGTGGAGGC CGTCTCCTCC CTGTGCCACC CTGGGCTCCC GCTTGAGCCA GCCCTGGAAG CTGGACCT C TGGGAATGGC GCCTCTGCTT GCAGAGCTTC CCTCTGGCCG CAAGT CAGAA TGCCAC CTAA GCTCTATAAT CCTTTGCTGG GGACCGAAAC AGAACTTAGA CCATGTCTGC CAAGGCAGGT TTACCCTTGA TCCCCGGGTG CCACCC CGAG C TCC C CTGAG AGCCAACTCC GGAAGGGATA ACGTCGCCGA ATGGCCCCTG TGCTTTCCAG GCTTCCTGGA GGCGGCTCTG GAGAAAGATC GATCGATGAA ACCCGAACAA CTTCGACTTC AAATGCATCA C CTC TGCC AC GACTGGCAAG GCAAGCGCAG GTGGTTCTGG GAGCTGGTC CTCCTGCCCC ATAGCGGCCT TCCCCCGAGT CTTTGCCACC CCCTGCAGCC CGCCGGGCAG GGTGTCGTAC GCGGCTCTCA CAGGGCGATG ATTATACATC CCTCAATGAC CAAACCTGGA GGTATTGAGG GGCCGCACCC AATTCCGGGA GAACAACAGT CGGCGGCTCC TGCTCGGACA AGCCAGGCCC TTTCCTCTAC TGGGTCCCAC ACCATCTGGC CACCCAGGGT GAGGGGTCCT CGCGTTCTAC GAGCTTCCTG GC GCAGCGCT ACTTAAAGAG GAAGACGTCT GAGCTTCGTA CAATTCTTCG TCTC GACATC AAAACTGACG ACGTAGAGG AACATGGCTT CTCTCTGGCC TGCAGCTGGC CAGGGGCTCC CTTGGACACA AGCAGATGGA GCCATGCCGG GGTTGCTAGC GCCACCTTGC CTCAAGTCTT CCAGGAGAAG CCTAATAA (SEQ ID NO:94); GCTCTATAAT CCTTTGCTGG GGACCGAAAC AGAACTTAGA CCATGTCTGC CAAGGCAGGT TTACCCTTGA TCCCCGGGTG GTCTAAAGAA CCGAGGAGCT CTGAGCTCCT ACTCCATAGC GGATATCCCC GCCGACTTTG CCCTGCCCTG TCC AGCGCCG CTGGAGGTGT CTCTGGCGGC AGATCCAGGG GATCGATGAA ACCCGAACAA CTTCGACTTC AAATGCATCA CCTCTGCCAC GACTGGCAAG GCAAGCGCAG AACCGTCTGG TCTCATAAAT GGTGCTGCTC GCCCCAGCCA GCCTTTTCC CGAGTTGGGT C CACCAC CAT CAGCCCACCC GGCAGGAGGG CGTACCGCGT TCTCAGAGCT CGATGGCGCA ATTATACATC CCTCAATGAC CAAACCTGGA GGTATTGAGG GGCCGCACCC AATTCCGGGA GAACAACAGT TCCAATCTCT CTCCAAACAT GGACACTCTC GGCCCTGCAG TCTACCAGGG CC CAC CTTG G CTGGCAGCAG AGGGTGCCAT GTCCTGGTTG TCTACGCCAC TCCTGCTCAA GCGCTCCAGG ACTTAAAGAG GAAGACGTCT GAGCTTCGTA CAATTCTTCG TCTCGACATC AAAACTGACG ACGTAGAGGG ACTATCAACC GGCTTACAAG TGGGCATCCC CTGGCAGGCT GCTCCTGCAG ACACACTGCA ATGGAAGAAC GCCGGCCTTC CTAGCCATCT CTTGCGCAGC GTCTTTAGAG AGAAGCTGTG TAA (SEQ ID WO 97/12985 WO 9712985PCTJUS96/1 5774 1 51 101 151 201 251 301 351 401 451 501 551 601 651 701 751 801 851 901 1 51 101 151 201 251 301 351 401 451 501 551 601 651 701 751 801 851 901 951 1 51 101 151 201 251 301 351 ATGGCTAACT ACCAC CTGCA CTATCCTGAT AGGGCTGTCA TAATCTCCAA CAATCATCAT TTCTATCTGG CGGTGGAGGC CCGAGTTGGG OCCAC CACCA GCAGCCCACC GGGCAGGAGG TCGTACCGCG CTCTCAGAGC GCGATGGCGC CACCCCGAGG TCCCCTGAGC GCCAAVITCCA GAAGGGATAT ATGGCTAACT ACCACCTGCA CTATC CTGAT AGGGCTGTCA TAATCTCCAA CAATCATCAT TTCTATCTGG CGGTGGAGGC CGTCTCCTCC TTGGGTCCCA CACCATCTGG CCACCCAGGG GGAGGGGTCC CCGCGTTCTA AGAGCTTCCT GGCGCAGCGC CGAGGAGCTG TGAGCTCCTG CTCCATAGCG GATATCCTAA ATGGCTAACT ACCACCTGCA CTATCCTGAT AGGGCTGTCA TAATCTCCAA CAATCATCAT TTCTATCTGG CGGTGGAGGC GCTCTATAAT CCTTTGCTGG GGACCGAAAC AGAACTTAGA CCATGT CTGC CAACCCAGGT TTACCCTTGA TCCCCGGGTG TCCCACCTTG TCTGGCAGCA CAGGGTGCCA GGTCCTGGTT TTCTACGCCA TTCCTGCTCA AG CGCT CCAG AGCTGGTGCT TCCTGCCCCA TAGCGGCCTT GATCGATGAA ACCCGAACAA CTTCGACTTC AAATGCATCA CCTCTGCCAC GACTGGCAAG GCAAGCGCAG GTGGTTCTGG GACACACTGC GATGGAAGAA TGCCGGCCTT GCTAGCCATC C CTT GC GCAG AGTCTTTAGA GAGAAGCTGT GCTCGGACAC GCCAGGCCCT TTCCTCTACC ATTATACATC CCTCAATGAC CAAACCTGGA GGTATTGAGG GGC CGC ACC C AATTCCGGGA GAACAACAGT CGGCGGCTCe AGCTGGACGT CTGGGAATGG CGCCTCTGCT TGCAGAGCTT CCCTCTGGCG GCAAGTGAGA GTGCCACCTA TCTCTGGGCA GCAGCTG GCA AGGGGCfTCC T ACTTAAAGAG GAAGACGTCT GAGCTTCGTA CAATTCTTCG TCTCGACATC AAAACTGACG ACGTAGAGGG AACATGGCTC CGCCGACTTT CCCCTGCCCT TTCCAGCGCC CCTGGAGGTG GCTCTGGCGG AAGATCCAGG CAAGCTGTGC TCCCCTGGGC GGCTGCTTGA G CAGG C CC TG CCTAATAA (SEQ ID NO:96); GCTCTATAAT CCTTTGCTGG GGACCGAAAC AGAACTTAGA CC AT GTCT GC CAAGGCAGGT TTACCCTTGA TCCCCGGGTG GTCTAAAGAA CCTTGGACAC CAGCAGATGG TGCCATGCCG TGGTTGCTAG CGCCACCTTG GCTCAAGTCT TCCAGGAGAA GTGCTGCTCG CCCCAGCCAG GCCTTTTCCT GATCGATGAA ACCCGAACAA CTTCGACTTC AAATGCATCA CCTCTGCCAC GACTGGCAAG GCAAGCGCAG AACCGTCTGG TCTCATAAAT ACTGCAGCTG AAGAACTGGG GCCTTCGCCT CCATCTGCAG CGCAGCCCTC TTAGAGCAAG GCTGTGTGCC GACACTCTCT GCCCTGCAGC CTACCAGGGG ATTATACATC CCTCAATGAC CAAACCTGGA GGTATTGAGG GGCCGCACCC AATTCCGGGA GAACAACAGT TCCAATCTCT CTCCAAACAT GACGTCGCCG AATGGCCCCT CTGCTTTCCA AGCTTCCTGG TGGCGGCTCT TGAGAAAGAT AC CTACAAGC GGGCATCCC C TGGCAGGCTG C TC CTGC AG G ACTTAAAGAG GAAGACGTCT GAGCTTCGTA CAATTCTTCG TCTCGACATC AAAACTGACG ACGTAGAGGG ACTATCAACC GGCTCCCGAG ACTTTGCCAC GCCCTGCAGC GCGCCGGGCA AGGTGTCGTA GGCGGCTCTC CCAGGGCGAT TGTGCCACCC TGGGCTCCCC CTTGAGCCAA CCCTGGAAGG TAA (SEQ ID NO:97); GCTCTATAAT CCTTTGCTGG GGACCGAAAC AGAACTTAGA CCATGTCTGC CAAGGCAGGT TTACCC TTGA TCCCCGGGTG GATCGATGAA ACCCGAACAA CTTCGACTTC AAATGCATCA C CTC TGCC AC GACTGGCAAG GCAAGCGCAG GTGGTTCTGG ATTATACATC CCTCAATGAC CAAACCTGGA GGTATTGAGG GGCCGCACCC AATTCCGGGA GAACAACAGT CGGCGGCTCC ACTTA-AAGAG GAAGACGTCT GAGCTTCGTA CAATTCTTCG TCTCGACATC AAAACTGACG ACGTAGAGGG AACATGGCTA I WO 97/12985 WO 9712985PCT/US96/1 5774 401 451 501 551 601 651 701 751 801 851 901 1 51 101 151 201 251 301 351 401 451 501 551 601 651 701 751 801 851 901 951 1 51 101 151 201 251 301 351 401 451 501 551 601 651 701 751 801 TGGCCCCTGC GCTTTCCAGC CTTCCTGGAG GCGGCTCTGG AGAAAGATCC CTACAAGCTG GCATCCCCTG GCAGGCTGCT CCTGCAGGCC CACTGCAGCT GAZAGAACTGG ATGGCTAACT AC CAC CTGCA CTATCCTGAT AGGGC TGTCA TAATCTCCAA CAATCATCAT TTCTATCTGG CGGTGGAGGC CGTCTCCTCC CCTGCCCTGC CCAGCGCCGG TGGAGGTGTC TCTGGCGGCT GATCCAGGGC AGCTG ,.OCPCCA CCCTGGGCTC CTGCTTGAGC AGGCCCTGGA CAGCTGGACG ACTGGGATAA ATGGCTAACT ACCACCTGCA CTATCCTGAT AGGGCTGTCA TAATCTCCAA CAATCATCAT TTCTATCTGG CGGTGGAGGC CCCAGGGTGC GGGGTCCTGG CGTTCTACGC GCTTCCTGCT GCAGCGCTCC GGAGCTGGTG GCTCCTGCCC CATAGCGGCC ATCCC C CGAG CCTGCAGCCC CCGGG CAGG GTGTCGTACC C GGC TC TC AG AGGGCGATGG TGC CAC CC C GGCTCCCCTG TGAGCCAACT CTGGAAGGGA GGACGTCGCC ACCCAGGGTG AGGGGTCCTG GCGTTCTACG AGCTTCCTGC CGCAGCGC TC AGGAGCTGGT AGCTCCTGCC CCATAGCGGC TATCCCCCGA GACTTTGCCA CCATGCCGGC GTTGCTAGC C CCACCTTGCG TCAAGTCTTT CAGGAGAAGC GCTGCTCGGA CCAGCCAGGC CTTTTCCTCT GTTGGGTCCC CCACCATCTG CTTCGCCTCT ATC TCAGAG CACC C TCTC AGACCAAGTG TGTGTGCCAC CACTCTCTGC CCTCCACCTG ACCAGCCCCT ACCTTCCACA GCAGCACATC GATAATAA (SEQ ID NO:98); GCTCTATAAT CCTTTCCTCG GGACCGAAAC AGAACTTAGA CCATCTCTGC CAAGCCAGGT TTACCCTTGA TCCCCGGCTC GTCTAAAGAA ACCCCACCCA GCAGGAGGGG C TACCC GTT CTCAGAGCTT CATGGCGCAG CCCCGAGGAG CCCTGAGCTC CAACTC CATA AGGGATATCC TCGCCGACTT CATC CATGAA ACCCGAACAA CTTCCACTTC AAATGCATCA C CTC TCCAC CACTCGCAAG GCAAGCGCAC AACCGTCTGC TCTCATAAAT GGGTGCCATG TCCTGGTTGC CTACGCCACC CCTGCTCAAG CGCTCCAGGA CTGGTGCTGC CTGCCCCAGC GCGGCCTTTT CCCGAGTTGG TGCCACCACC ATTATACATC CCTCAATGAC CAAACCTGGA GGTATTGAGG GCCGCACCC AATTCCGGGA GAACAACAGT TCCAATCTCT CTCCAAACAT CCGGCCTTCG TAGCCATCTG TTGCGCAGC C TCTTTAGAGC GAAGCTGTGT TCGGACACTC CAGGCCCTGC CCTCTACCAG CTCCCACCTT ATCTGGCAGC ACTTAAAGAG GAACACGTCT GAGCTTCCTA CAATTCTTCC TCTCGACATC AAAACTGACC ACGTACAGGG ACTATCAACC GGCTATGGCC CCTCTCCTTT CAGAGCTTCC CTCTGCCGGC AAGTGAGAAA GCCACCTACA TCTGGGCATC AGCTGCCAGG GGGCTCCTC GGACACACTG AGATGGAAGA TAA (SEQ ID NO:99); GCTCTATA.AT CCTTTGCTGG GGACCGAAAC AGAACTTAGA CCATGTCTC CAAGGCAGGT TTACCCTTGA TCCCCGGGTG CATGCCGGCC TTGCTAGCCA CACCTTGCGC CAAGTCTTTA AGGAGAAGCT CtGCTCGGAC CAGCCAGGCC TTTTCCTCTA TTGGGTCCCA GATCGATGAA ACCCGAACAA CTTCGACTTC AAATGCATCA CCTCTGCCAC GACTGGCAAG C CAAGCCAG GTGCTTCTGC TTCGCCTCTG TCTGCAGAGC ACCCCTCTGG GAGCAAGTGA GTGTGCCACC ACTCTCTGGG CTGCAGCTGC CCACGGGCTC CCTTGGACAC ATTArAC AT C CCTCAATGAC CAAACCTGGA GCTATTGAGG GGCCGCACCC AATTCCGGGA GAACAACAGT CGGCGCTCC CTTTCCAGCG TTCCTGGAGG CGGCTCTGC GAAAGATCCA TACAAGCTGT CAT CCCCTGG CAGGCTGCTT CTGCAGGCCC ACTGCAGCTG ACTTAAAGAG GAAGACGTCT GAGCTTCGTA CAATTCTTCG TCTCGACATC AAAACTGACG ACGTAGAGGG AACATGGCTA CCGGGCAGGA TGTCGTACCG GGCTCTCAGA GGGCGATGC CCCACCCCGA GCTCCCCTGA GAGCCAACTC TCGAAGGGAT GACGTCGCCG WO 97/12985 PCTIUS96/15774 593 851 ACTTTGCCAC CACCATCTGG CAGCAGATGG AAGAACTGGG 901 GCCCTGCAGC CGTAATAA (SEQ ID NO:100); AAT G GeC CT 1 51 101 151 201 251 301 351 401 451 501 551 601 651 701 751 801 851 901 951 1 51 101 151 201 251 301 351 401 451 501 551 601 651 701 751 801 851 901 ATGGCTAACT AC CAC CTGCA CTATC CTGAT AGGGCTGTCA TAATCTCCAA CAATCATCAT TTCTATCTGG CCCT GGAGC CGTCTCCTCC GGTGCCATGC CCTCCTTGCT TAGCC ACC T CTGCTCAAGT GGTCCAGGAG TGGTCCTGGT TGCCCCAGCC CGGCCTTTTG GCGAGTTG CCCAAGCA GCAGCCCTAA ATGGGTAAGT AC GAGCTGCA GTATGCTGAT AGGGCTGTGA TAATGTGGAA GAATCATCAT TTCTATCGC CGTGAGC CTGGTTTCCA AGCTTCCTGG TGCGGCTGT TGAGAAAGAT ACCTAGAAGG GGGCATGCGG TGGCAGCTG GTCGTGCAGG GAGAGTGGAG TGGAAGAAGT CCGGCCTTCG GCTCTATAAT CGTTTGCTG GGACGGAAAC AGAACTTAGA CCATGTGTGG CAAGCAGGT TTACGGTTGA TCGGCGGGTG GTGTAAAGAA CGGGGTTG AGCGATCTGC TGGCGGCC CTTTACAGCA AAGCTGTGTG GGGAGAGTCT AGGCTCA GTCTAGCAG TGGGAGGTTG TCTGGACA GATGATGAA ACGGGAAGAA GTTGACTTC AAATGGATCA GCTGTGCCAC GCTGGGAAC GC AAG CCAG AACGCTGG TCTCATAAAT GTGTGCTTTC AGAGCTTGGT TCTGGCGCT AGTGAGAAAG CGAGCT AGAA CTGGGGATCC GGTGGGAGGG GGCTCCTGCA GACACAGTGC GATGGAAGAA ATTATACATG CGTGAATGAG CAAACCGGA GCTATTGAGG GGCCCAGGQ- AATTGGGGGA GAAGAACGT TCGAATCTGT GTGGAAAGAT C AGC GGCCG GGAGGGTCG CGCGCGGCTG ATGGAGGGCG CTGTGCGAG CCTGGGCTCG TCTTCACG GCCGGAA AGCTGGACCT GTGGGAATGG ACTTAAAGAG GAAGAGTCT GACTTGTA GAATTGTTCG TCTC GAGAT C AAAACTGACG AGGTAGACGC ACTATCAAGC GGGTACCCAG GAGGAGGCOT TACGGCGTTC TCGAGCTTG ATGGCGGAGG CGGGAC C CT GAGCTGC AAGTGGATAG GGGATATGCCC CGGCGAGTTT CCCGCGT TAA (SEQ ID NO:101); CTCTATAAT GGTTTGCTGG GGAGGGAAAG AGAAGTTAGA GCATGTCTGC GAAGCAGGT TTACCCTTGA TGCCCGGGTC GGGCCGGGCA AGGTGTGTA GGCGGCTCTC GCAGGCCAT TGTGCCACGC TGGGCTCCGG CTTGAGGGAA CCC TGCAAGG CTGGACGTCG GGGAATGCC GATGGATGAA AGCCGAAGAA GTTGGAGTTC AAATGCATCA GCCTGCCAC GACTGGAAG GGAAGGGCAC GTGGTTCTGG GGAGGTCG CCGGTTGTA AGAGGTTGCT GGCCCAGCGG CGACCAGCTG TCAGCTCGTG GTCCATAGCG GATATCCC CCGACTTTC GCTGCGCTGC ATTATAGATC CCTGAATGAC CAAACCGGA GGTATTGAGC GGCCGGAGGG AATTCCGGGA GAACAACAGT CGGGGGTC TCGTTCCTAG CGCAGCTTC GGTGAAGTCT TGGAGGAGAA CTCCTGCTGG CCGCAGCCAC GCCTTTTCCT GAGTTGGGTC GAG GAGCAT C AGCCCACCCA AGTTAAAGAG CAAGACGTGT GAGCTTCGTA GAATTCTTCG TCTGGAGATG AAAACTGCG ACGTAGAG AAGATGCGTT CCATCGCAG GCACGTC TTAGAGGAAG GGTGTGTGCC GACACTCTGT GCGCGCAGG CTAGCACGG CCACCTTCGA TGGGAGCAGA GGGTGGCATG CCTAATAA (SEQ ID NO:102); PMON25191 1 ATGGGTAAGT 51 AGGACCTGCA 101 GTATCCTGAT GGTGTATAAT GATGGATGAA ATTATACATC CGTTTGCTGG ACCCGAAGAA CGTGAATGAC GGACGGAAAC CTTCGAGTTC CAAAGGTCCA ACTTAAAGAG GAAGACGTCT GAGGTTCGTA WO 97/12985 PCT/US96/1 5774 151 201 251 301 351 401 451 501 551 601 651 701 751 801 851 901 951 1 51 101 151 201 251 301 351 401 451 501 551 601 651 701 751 801 -851 901 951 1 51 101 151 201 251 301 351 401 451 501 AGGGCTGTCA TAATC TCCAA CAATCATCAT TTCTATCTGG CGGTGGAGGC CGTCTCCTCC TTGGGTCCCA CACCATCTGG CCACCCAGGG GGAGGGGTCC CCGCGTTCTA CCCTGCCCCA CAGGGCGATG GTGCCACCCC GGGCTCCCCT TTGAGCCAAC CCTGGAAGGG ATGGCTAACT ACCACCTGCA CTATCCTGAT AGGGCTGTCA TAATCTCCAA CAATCATCAT TTCTAmCTGG CGGTGGAGGC CGTCTCCTCC TTCCAGCGCC CCTGGAGGTG GCTCTGGCGG AAGATCCAGG CAAGCTGTGC TCCCCTGGGC GGCTGCTTGA GCAGGCCCTG TGCAGCTGGA GAACTGGGAA CTTCGCCTAA AGAACTTAGA C CATGT CT GC CAAGGCAGGT TTACCCTTGA TCCCCGGGTG GTCTAAAGAA CCTTGGACAC CAGCAGATGG TGCCATGCCG TGGTTGCTAG CGCCACCTTG GAGCTTCCTG GCGCAGCGCT GAGGAGCTGG GAGCTCCTGC TCCATAGCGG ATATCCTAAT GCTCTATAAT CCTTTGCTGG GGACCGAAAC AGAACTTAGA CCATGTCTGC CAAGGCAGGT TTACCCTTGA TCCCCGGGTG GTCTAAAGAA GGGCAGGAGG TCGTACCGCG CTCTCAGAGC GCGATGGCGC CACCCCGAGG TCCCCTGAGC GCCAACTCCA GAAGGGATAT CGTCGCCGAC TGGCCCCTGC AAATGCATCA CCTCTGCCAC GACTGGCAAG GCAAGCGCAG AACCGTCTGG TCTCATAAAT ACTGCAGCTG AAGAACTGGG GCCTTCGCCT CCATCTGCAG CGCAGCCCAC CTCAAGTCTT CCAGGAGAAG TGCTGCTCGG CCCAGCCAGG CCTTTTCCTC AA (SEQ ID GATCGATGAA ACCCGAACAA CTTCGACTTC AAATGCATCA CCTCTGCCAC GACTGGCAAG GCAAGCGCAG AACCGTCTGG TCTCATAAAT GGTCCTGGTT TTCTACGCCA TTCCTGCTCA AGCGCTCCAG AGCTGGTGCT TCCTGCCCCA TAGCGGCCTT CCCCCGAGTT TTTGCCACCA C CTGCAGCC C GGTATTGAGG G GC CGCACC C AATTCCGGGA GAACAACAGT TCCAATCTCT CTCCAAACAT GAC CTCCC C AATCGCCCCT CTGCTTTCCA AGCTTCCTGG ACCATTCGC TAGAGCAACT CTGTCTGCCA ACACTCTCTG CCCTGCAGCT TACCACGGC NO:107); ATTATACATC CCTCAATGAC CAAACCTGGA GGTATTGAGG GCCCGCAC CC AATTCCGGGA GAACAACAGT TCCAATCTCT CTCCAAACAT GCTACCCATC CCTTGCGCAG ACTCTTTAGA GAGAAGCTGT GCTCGGACAC GCCAGGCCC T TTCCTCTACC GGGTCCCACC CCATCTGGCA ACCCAGGGTG CAATTCTTCC AAAACTCACG ACCTAGAGGG ACTATCAACC CCCTCCCGAC ACTTTGCCAC GCCCTGCAC GCGCCGCGCA AGGTCTCGTA C CTGC CA C T GAGAAACATC CCTACAAGCT GGCATCCCCT GGCAGGCTC TCCTGCAGCC ACTTAAAGAG GAAGACGTCT GAGCTTCGTA CAATTCTTCG TCTCCACATC AAAACTGACG ACCTAGACGGG ACTATCAACC GCCTTCTGCT TGCACAGCTT CCCTCTCGCG GCAAGTGAGA CTGCCACCTA TCTCTCGGCA GCAGCTGGCA AGGGGCTCCT TTGGACACAC GCAGATGGAA CCATGCCGGC TAA (SEQ ID NO:103); ATGGCTAACT ACCACCTGCA CTATCCTGAT AGGGCTCTCA TAATCTCCAA CAATCATCAT TTCTATCTGG CGGTGCAGGC ACAAGCTGTG ATCCCCTGGC AGGCTGCTTG GCTCTATAAT CCTTTGCTGG CGACCGAAAC ACAACTTAGA COAT GT CTG C CAAGCCAGGT TTACCCTTGA TCCCCGGGTC CCAC CC CGAG CTCCCCTGAG AGCCAACTCC GATCGATGAA ACCCGAACAA CTTCGACTTC AAATGCATCA CCTCTGCCAC GACTGGCAAG GCAAGCGCAG CTGGTTCTGG GAG CTGGT GC CTCCTGCCCC ATAGCGGCCT ATTATACATC CCTCAATGAC CAAACCTGGA GGTATTGAGG GGCCGCACCC AATTCCGGGA GAACAACAGT CGGCGGCTCC TGCTCGGACA AGCCAGGCCC TTTCCTCTAC ACTTAAAGAG GAAGACGTCT GAGO TTCGTA CAATTCTTCG TCTCGACATC AAAACTGAC G ACGTAGAGGG AACATGGCTT CTCTCTGGC TGCAGCTGGC CAGGGGCTCC WO 97/12985 WO 9712985PCTIUS96/1 5774 551 601 651 701 751 801 851 901 1 51 101 151 201 251 301 351 401 451 501 551 601 651 701 751 801 851 901 951 1 51 101 151 201 251 301 351 401 451 501 551 601 651 701 751 801 851 901 951 TGCAGGCCOT CTGCAGCTGG AGAAOTGGGA CCTTCGOCTO CATCTGCAGA GO AGOCCCAC A TOAAGTCTTT OAGGAGAAGC ATGGOTAACT ACCAOOTGCA .CTATOOTGAT AGGGOTGTCA TAATC TOOAA CAATOATOAT TTCTATCTGG CGGTGGAGGO OGTCTCCTCC OTGTGCCAC CTGGGCTCCC GCTTGAGC CA GOCCTGGAAG GCTGGACGTC TGGGAATGGC GCCTOTGCTT GCAGAGCTTC OOACACCATT TOTTTAGAGC GAAGCTGTGT ATGGOTAAOT AOOACCTGOA CTATOCTGAT AGGGCTGTCA TAATCTCCAA CAATO AT CAT TTCTATCTGG CGGTGGAGGC CGTOTCCTOC COTGCCOTGC CCAGCGCCGG TGGAGGTGTC GGCOTGCCA AGTGAGAAAG OOACCTACAA OTGGGCATCC GCTGGOAGGC GGCTCCTGCA GACAOACTGC GATGGAAGAA GGAAGGGATA AC GTOG C CGA ATOGOCCTO TOOT TTCC AG GOTTOCTGGA CCATTGGGC C AGAGCAAGTG TGTGTGCCAC GCTCTATAAT CCTTTGCTGG GGAOCGAAAC AGAACTTAGA OCATGTCTGC CAAGGCAGGT TTACCC TTGA TCOOOGGGTG GTCTAAAGAA COGAGGAGOT CT GAGO TOOT ACTOCATAGO GGATATCCCC GOOGACTTTG CCCTGCCCTG TOCAGOGOOG OTGGAGGTGT GGOOCTGCO AAGTGAGAAA GCOACCTAAT GCTCTATAAT OCTTTGCTGG GGAOOGAAAO AGAACTTAGA CCATGTCTGC CAAGGCAGGT TTAOOCTTGA TCCCOGGGTG GTCTAAAGAA AGOCCACCCA GCAGGAGGOG GTACCGOGTT GCTCOTGCO ATCCAGGGCG GOTGTGCCAC CCTGGGCTCC TGCTTGAGCO GGCCCTGGAA AGCTGGACGT CTGGGATAAT TCCCCCGAGT TGGGTCCCAC CTTGGACACA CTTTGCCACC ACCATOTGGC AGOAGATGGA CCTGCAGOC CACCCAGGGT GCCATGCCGG CGOCGGGCAG GAGGGGTCCT GGTTGCTAGC GGTGTCGTAC CGCGTTCTAC GCOACCTTGC OTGCOAGCTC CCTGOCOCAG AGCTTCCTGC AGAAAGATCC AGGGCGATGG OGOAGOGOTO CTAATAA (SEQ ID NO:104); GATCGATGAA ACCOGAAOAA OTTCGACTTC AAATGCATOA CCTCTGOCAC GACTGGCAAG GCAAGOGCAG AACCGTOTGG TCTCATAAAT GGTGCTGCTC GCOCCAGOCA GGCCTTTTCC CGAGTTGGGT C CAC CAC CAT CAGCOACC GGCAGGAGGG CGTACCGCGT AGOTOOCTOC GATCOAGGGC AA (SEQ ID GATCGATGAA ACCCGAACAA OTTCGACTTC AAATGCATCA CCTOTGCCAC GACTGGCAAG GCAAGCGOAG AAOCGTOTGG TCTCATAAAT GGGTGOCATG TCCTGGTTGC OTACGCCACO O CAGAGCTTO ATGGCGCAGO COOGAGGAGO OOTGAGCTCO AAOTCCATAG GGGATATCCC OGCOGAOTTT AA (SEQ ID ATTATACATO CCTCAATGAC CAAACCTGGA GGTATTGAGG GGOACC AATTCCGGGA GAACAACAGT TCOAATCTOT CTCCAAACAT GGACACTCTC GGOCCTGOAG TCTACCAGOG O 00AC CTTGG OTGGCAGOAG AGGGTGCCAT GTCCTGGTTG TOTACOCCAC CCC AGAGCTT GATGGCGCAG NO:105); ATTATACATO COT CAATGAC OAAACOTGGA GGTATTGAGG GGCCGCACCC AATTCOGGGA GAACAACAGT TOCAATCTCT CTCCAAAAT CCGGCCTTCG TAGCCATCTG TTGCGCAGCC CTGCTOAAGT GOTCCAGGAG TGGTGCTGCT TGCCOAGC OGGCCTTTTC CCGAGTTGGG GOO AC CAC CA NO:109) ACTTAAAGAG GAAGACGTCT GAGOTTCTA CAATTCTTCG TOTOGACATO AAAAOTGAOG ACGTAGAGGG ACTATOAACC GGCTTACAAG TGGGCATCCC OTGOAGGOT GCTCCTGCAG AC AC ACTGCA ATGGAAGAAO GOOGGOOTTO OTAGOCATCT OTTGCGOAGO CCTGOTCAAG OGOTCCAGGA AOTTAAAGAG GAAGACGTCT GAGCTTOGTA OAATTCTTCG TCTOGACATC AAAACTGAOG AOGTAGAGGG ACTATOAACC GGCTATGGC CCTOTGCTTT CAGAGCTTC CACACCATTG CTTTAGAGOA AAGOTGTGTG OGGACACTOT AGGCCCTGCA OTCTACCAGG TCCOACOTTG TCTGGCAGCA WO 97/1 2985 PCT/US96/15774 596 1 51 101 151 201 251 301 351 401 451 501 551 601 651 701 751 801 851 901 1 51 101 151 201 251 301 351 401 451 501 551 601 651 701 751 801 851 901 951 1 51 101 151 201 251 301 ATGGCTAACT ACCACCTGCA CTATCCTGAT AGGGOTGTCA TAATCTCCAA CAATCATCAT TTOTATCTGG CGGTGGAGGC CCCAGGGTGC GGGGTCCTGG CGTTCTACGC TGCCCCAGAG GGCGATGGCG CCACCCCGAG CTCCCCTGAG AGCCAACTCC GGAAGGGATA AOGTCGCCGA ATGGCCCCTG GCTCTATAAT CCTTTGCTGG GGACCGAAAC AGAACTTAGA CCATGTCTGC CAAGGCAGGT TTACOCTTGA TCCCCGGGTG CAT GO GGC TTGCTAGCCA CACCTTGCGC CTTCCTGCTC 0 AGO G CTCCA GAGCTGGTGC OTCOTGCCCC ATAGOGGCoT TCCOCCGAGT CTTTGCCAOO CCCTGCAGCC GATCGATGAA ACCCGAACA-A CTTCGACTTO AAATGCATCA OOTOTGOCAC GAO TGGC AAG GCAAGCGCAG GTGGTTCTGG TTCGCCTCTG TCTGCAGAGC AGCCOACACC AAGTCTTTAG GGAGAAGCTG TGCTOGGACA AGOCAGGCC TTTCCTCTAC TGGGTCCCAC ACCATCTGGO ATTATACATO CO TCAATGAC CAAACCTGGA GGTATTGAGG GGCOGCACCC AATTOCGGGA GAACAACAGT CGGCGGCTCC C TTT CCAGC G TTCCTGGAGG ATTGG GOCCCT AGCAAGTGAG TGTGCOACCT CTCTCTGGGC TGCAGCTGGC CAGGGGCTC CTTGGACACA AOTTAAAGAG, GAAGACGTOT GAG CTTO GT A CAATTCTTCG TOTOGACATC AAAACTGACG AOGTAGAGGG AAOATGGCTA OCGGGCAGGA TGTCGTACOG GCCAGOTCO AAAGATCOAG ACAAGCTGTG ATCCCCTGGG AGGCTGCTTG TGOAGGCCCT OTGCAGOTGG AGAACTGGGA OTAATAA (SEQ ID NO:110); ATGGOTAACT AC CA COTGCA CTATC CTGAT AGGGCTGTOA TAATCTOCAA OAATCATCAT TTOTATCTGG OGGTGGAGGC OGTOTCOTCC GGTGCCATGC CCTGGTTGCT TACGOOAOCT CAGAGOTTC TGGOAGOG COGAGGAGOT CTGAGCTOOT ACTOCATAGc GGATATCCCO GOOGACTTTG OCCTGCCCTG ATGGCTAAOT AOOAOCTGOA CTATCCTGAT AGGGCTGTCA TAATCTOCAA CAATCATCAT TTCTATCTGG GCTCTATAAT OCTTTGOTGG GGAOCGAAAC AGAAOTTAGA CCATGTCTGC OAAGGCAGGT TTACOOTTGA TCCCCGGGTG GTCTAAAGAA OGGOOTTOGO AGO CATO TGC TGCGCAGCCC TGOTCAAGTC OTOCAGGAGA GGTGCTGCTC GCOCAGOCA GGCCTTTTCC OGAGTTGGGT CCACCACCAT CAGCCOTAAT GCTOTATAAT CCTTTGCTGG GGACC GAAAC AG3AACTTAGA C CATG TOTG C OAAGGCAGGT TTACCCTTGA GATCGATGAA ACCCGAACAA CTTCGACTTO AAATGCATCA CCTCTGCOAC GACTGGOAAG GCAAGOGCAG AAOCGTOTGG TCTCATAAAT CTCTGCTTTC AGAGCTTOCT ACACOATTGG TTTAGAGOAA AGOTGTGTGO GGAOACTOTC GGCCCTGCAG TCTACCAGGG OCCACCTTGG CTGGCAGCAG AA (SEQ ID GATCGATGAA AC C GAACAA CTTOGACTTC AAATGCATCA CCTCTGCCAC GACTGGCAAG GCAAGCGCAG ATTATACATO CCTOAATGAC CAAACOTGGA GGTATTGAGG GGCCGOACCO AATTCCGGGA GAAOAACAGT TCCAATCTCT CTCCAAAOAT CAGCGOOGOG GGAGGTGTCG GCCCTGCCAG GTGAGAAAGA OACCTACAAG TGGGCATCCC CTGGOAGGCT GCTOOTGCAG ACAOACTGCA ATGGAAGAAO NO:111); ATTATACATO OCTCAATGAO CAAACCTGGA GGTATTGAGG GGCCGCACOO AATTCCGGGA GAACAACAGT AOTTAAAGAG GAAGACGTCT GAGOTTCGTA CAATTCTTCG TOTOGACATO AAAAOTGACG ACGTAGAGGG ACTATCAACC GGOTACOAG CAGGAGGGGT TACCGCGTTO OTOOOTGCCC TOOAGGGOGA CTGTGCCAC C CTGGGCTCCC GCTTGAGOCA GOCCTGGA.AG GCTGGACGTO TGGGAATGGC ACTTAAAGAG GAAGAOGTOT GAGOTTCTA OAATTCTTOG TO TOGAO AT C AAAACTGACG AOGTAGAGGG WO 97/12985 WO 9712985PCTIUS96/1 5774 351 401 451 501 551 601 651 701 751 801 851 901 CGGTGGAGGC TCCCCCGGTG CTGCTTTCCA GCGCCGGGCA AGCTTCCTGG AGGTGTCGTA ACCATTGGGC CCTGCCAGCT TAGAGCAAGT GAGAAAGATC CTCTGTGCCA CCTACAAGCT ACACTCTCTG GGCATCCCCT CCCTGCAGCT GGCAGGCTGC TACCAGGGGC TCCTGCAGGC CACCTTGGAC ACACTGCAGC GGCAGCACAT GGAAGAACTG GGTGqCATGC CGGCCTTCGC GTGCTTCTGG CGGCGGCTCC AACATGCCTT GGAGGGGTCC TGGTTGCTAG CCATCTGCAG CCGCGTTCTA CGCCACCTTG CGCAGCCCAC CCCTGCCCCA GACCTTCCTG CTCAAGTCTT CAGGGCGATG GCGCAGCGCT CCAGGAGAAG GTGCCACCCC GAGGAGCTCG TGCTCCTCGG GGGCTCCCCT GAGCTCCTGC CCCAGCCAGG TTGAGCCAAC TCCATAGCGG CCTTTTCCTC CCTGGAAGGG ATATCCCC.CG AGTTGGGTCC TCGACGTCGC CGACTTTGCC ACCACCATCT GGAATGGCCC CTGCCCTGCA GCCCACCCAC CTAATAA (SEQ ID NO:112); 1 ATGGCTAAC'r GCTCTATAAT 51 ACCACCTGcA CCTTTGCTGG 101 CTATCCTGAT GGATCGAAAC 151 AGGGCTGTCA AGAACTTAGA 201 TAATCTCCAA CCATGTCTGC 251 CAATCATCAT CAAGGCAGGT 301 TTCTATCTGG TTACCCTTGA 351 CGGTGGAGGC TCCCCGGGTG 401 CGTCTCCTCC GTCTAAAGAA 451 CTGTGCCACC CCGAGGAGCT 501 CTCGGCTCCC CTGAGCTCCT 551 GCTTGAGCCA ACTCCATAGC 601 GCCCTGGAAG GGATATCCCC 651 GCTGGACGTC GCCGACTTTG 701 TGGGAATGGC CCCTGCCCTG 751 GCCTCTGCTT TCCAGCGCCG 801 GCAGAGCTTC CTGGAGGTGT 851 CCGGCGGCGG CTCTGACATG 901 CCCCAGAGCT TCCTGCTCAA 951 CGATGGCGCA GCGCTCCAGG NO:155); GATCGATGAA ATTATACATC ACCCGAACAA CCTCAATGAC CTTCGACTTC CAAACCTGGA AAATGCATCA GGTATTGAGG CCTCTGCCAC GGCCGtACCC GACTGGCAAG AATTCCGGGA GCAAGCGCAG GAACAACAGT AACCGTCTCG TCCAATCTCT TCTCATAAAT CTCCAAACAT GGTGCTGCTC GGACACTCTC GCCCCAGCCA GGCCCTGCAG GGCCTTTTCC TCTACCAGGG CGAGTTGGGT CCCACCTTGG COACCACCAT CTGGCAGCAG CAGCCCACCC AGGGTGCCAT GGCAGGAGGG GTCCTGGTTG CGTACCGCGT TCTACGCCAC GCTACACCAT TAGGCCCTGC GTCTTTAGAG CAAQTGAGGA AGAAGCTGTG TGCCACCTAA ACTTAAAGAG GAAGACGTCT GAGCTTCGTA CAATTCTTCG TCTCGACATC AAAACTGACG ACGTAGAGGG ACTATCAACC GTCTTACAAG T GGGCAT CC C CTGGCAGGCT GCTCCTGCAG ACACACTGCA ATGGAAGAAC GC CGGCCTTC CTAGCCATCT CTTGCGCAGC CAGCTCCCTG AGATCCAGGG TAA (SEQ ID 1 51 101 151 201 251 301 351 401 451 501 551 601 651 701 ATGGCTAACT GCTCTATAAT ACCACCTGCA CCTTTGCTGG CTATCCTGAT GGATCGAAAC AGGGCTGTCA AGAACTTAGA TAATCTCCAA CCATGTCTGC CAATCATCAT CAAGGCAGGT TTCTATCTCG TTACCCTTGA CGGTGGAGGC TCCCCGGGTG CGTCTCCTCC GTCTAAAGAA TTGGGTCCCA CCTTGGACAC CACCATCTGG CAGCAGATGG CCACCCAGGG TGCCATGCCG GGAGGGGTCC TGGTTGCTAG CCGCGTTCTA CGCCACCTTG CACCATTAGG CCCTGCCAGC GATCGATGAA ATTATACATC ACCCGAACAA CCTCAATGAC CTTCGACTTC CAAACCTGGA AAATGCATCA GGTATTGAGG CCTCTGCCAC GGCCGCACCC GACTGGCAAG AATTCCGGGA GCAAGCGCAG GAACAACAG T AACCGTCTGG TCCAATCTCT TCTCATAAAT CTCCAAACAT ACTGCAGCTG GACGTCGCCG AAGAACTGGG AATGGCCCCT GCCTTCGCCT CTGCTTTCCA CCATCTGCAG AGCTTCCTGG CGCAGCCCGG CGGCGGCTCT TCCCTGCCCC AGAGCTTCCT ACTTAAAGAG GAAGACGTCT GAGCTTCGTA CAATTCTTCG TCTCGACATC AAAACTGACG ACGTAGAGGG ACTATCAACC GTCTCCCGAG ACTTTGCCAC GCCCTGCAGC GCGCCGGGCA AGGTGTCGTA GACATGGCTA GCTCAAGTCT WO 97/1 2985 PCTUS96/'15774 598 751 TTAGAGCAAG TGAGGAAGAT 801 GCTGTGTGCC ACCTACAAGC 851 GAOACTCTCT GGGCATCCCC 901 GCCCTGCAGC TGGCAGGOTG 951 CTACCAGGGG CTCCTGCAGG NO:156) CCAGGGCGAT GGCGCAGOGC TGTGCCACCC CGAGGAGCTG TGGGCTCCCC TGAGCTCCTG CTTGAGCCAA CTCCATAGCG CCCTGGAAGG GATATCCTAA GATCGATGAA ATTATACATO ACOGAACAA CCTCAATGAC 1 51 101 151 ATGGCTAAOT GCTCTATAAT ACOACCTGCA CCTTTGCTGG CTATCCTGAT GGATCGAAAC AGGGCTGTCA AGAACTTAGA 201 TAATOTOCAA 251 CAATCATCAT 301 TTCTATCTGG 351 CGGTGGAGGC 401 CGTCTCCTCC 451 TTCCAGCGCC 501 CCTGGAGGTG 551 GCTOTGACAT 601 TTCCTC.CTCA 651 AGCGCr2&CCAG 701 AGCTGGTGCT 751 TOCTGCCCCA 801 TAGCGGCCTT 851 CCCCOGAGTT 901 TTTGCCACCA 951 CCTGCAGCCC ID NO:157) 1 ATGGCTAACT 51 ACCACCTGCA 101 CTATCCTGAT 151 AGGGCTGTCA 201 TAATCTCCAA 251 CAATCATCAT 301 TTCTATCTGG 351 CGGTGGAGGC 401 CGTCTCCTCO 451 OCTGCCOTGC 501 CCAGCGCCGG 551 TGGAGGTGTC 601 TCTGACATGG 651 CCTGCTCAAG 701 CGCTCCAGGA 751 CTGGTGCTGC 801 CTGCOCAGC 851 GCGGCCTTTT 901 CCCGAGTTGG 951 TGCCACCAC ID NO:158) CCATGTCTGC CAAGGCAGGT TTACCCTTGA TCCCCGGGTG GTCTAAAGAA GGGCAGGAGG TCGTACCGCG GGCTACACOA AGTCTTTAGA GAGAAGCTGT GCTCGGACAC GC CAGGC CC T TTCCTCTACC GGGTCCCACC CCATCTGGCA ACCCAGGGTG CTTCGACTTC AAATGCATCA C C TOTGC CAC GACTGGCAAG GCAAGCGCAG AACOGTOTGG TCTCATAAAT GGTCCTGGTT T TOTA GC CA TTAGGCCCTG GOAAGTGAGG GTGOCACOTA TCTOTGGGCA GCAGCTGGCA AGGGGOTOCT TTGGACAOAC GCAGATGGAA CCATGCCGGC CAAACCTGGA GGTATTGAGG GGCCGCACCC AATTCCGGGA GAAOAACAGT TOCAATOTOT CTCOAAACAT GOTAGOCATO CCTTGCGCAG COAGOTCOT AAGATCOAGG CAAGCTGTGC TCOOOTGGGC GGCTGOTTGA GCAGGOOOTG TGCAGCTGGA GAAOTGGGAA CTTCGCCTAA TCCAGGAGAA GTGCTGCTCG COCAGOCAG GCCTTTTCCT TAA (SEQ ID ACTTAA.AGAG GAAGACGTCT GAGOTTCTA OAATTCTTCG TOTO GAOAT C AAAACTGACG AOGTAGAGGG AOTATOAAOC GTCTTOTGCT TGOAGAGCTT COGGOGGOG GCOCAGAGO GCGATGGOGC CACCCOGAGG TC CTGAGC GCCAAOTCCA GAAGGGATAT CTCCCGAC TGGOOCCTGC TAA; (SEQ GOTCTATAAT GATCGATGAA ATTATACATO AOTTAAAGAG COTTTGCTGG ACCOGA.AOAA CCTOAATGAC GAAGAOGTCT GGATOGAAAO CTTOGACTTC OAAACOTGGA GAGOTTOGTA AGAAOTTAGA AAATGOATCA GGTATTGAGG OAATTCTTCG CCATGTOTGC CCTOTGCCAC GGOCGCACO TCTOGACATC CAAGGOAGGT GACTGGOAAG AATTOOGGGA AAAAOTGAOG TTACOOTTGA GCAAGOGCAG GAAOAAOAGT AOGTAGAGGG TCCOOGGGTG AAOOGTCTGG TCCAATOTCT AOTATOAAOO GTCTAAAGAA TCTOATAAAT OTOCAAACAT GTCTATGGCC AGOOCACOCA GGGTGOCATG CCGGCCTTCG CCTOTGCTTT GOAGGAGGGG TCOTGGTTGC TAGCCATCTG CAGAGOTTOC GTAOOGOGTT OTAOGOOAOO TTGCGOAGCO OGGOGGOGGC OTAOACCATT AGGOCCTGCC AGCTCCCTGC-CCCAGAGCTT TCTTTAGAGC AAGTGAGGAA GATCCAGGGO GATGGCGCAG GAAGOTGTGT GCCACOTACA AGOTGTGOCA COOGAGGAG TOGGACACTO TCTGGGOATC CCCTGGGOTO COCTGAGCTC CAGGCCOTGC AGCTGGCAGG CTGCTTGAGC OAACTOOATA COtOTACOAG GGGCTOOTGC AGGOCCTGGA AGGGATATCC GTOOOACOTT GGAOACACTG CAGCTGGACG TCGCCGACTT ATCTGGCAGO AGATGGAAGA ACTGGGATAA TAA; (SEQ WO 97/12985 WO 9712985PCT/US96'1 5774 1 ATGGCTAACT 51 ACCACCTGCA 101 CTATCCTGAT 151 AGGGCTGTCA 201 TAATCTCCAA 251 CAATCkTCAT 301 TTCTA'YC-TGG 351 CGGTGGAGGC 401 CGTCTCCTCC 451 GGTGCCATGC 501 CCTGGTTGCT 551 TACGCCACcT 601 GGCCCTGCCA 651 AGTGAGGAAG 701 CCACCTACAA 751 CTGGGCATCC 801 GCTGGCAGGC 851 GGCTCCTGCA 901 GACACACTGC 951 GATGGAAGAA ID NO:159) GCTCTATAAT CCTTTGCTGG GGATCGAAAC AGAACTTAGA CC AT GT C TGC CAAGGCAGGT TTAC C CTT GA TCCCCGGGTG GTCTAAAGAA CGGCCTTCGC AGCCATCTGC TGCGCAGCCC GCTCCCTGCC ATCCAGGGCG GCTGTGCCAC CCTGGGCTCC TGCTTGAGCC GGCCCTGGAA AGCTGGACGT CTGGGAATGG GATCGATGAA ACCCGAACAA CTTCGACTTC AAATGCATCA CCTCTGCCAC GACTGGCAAG GCAAGCGCAG AACCGTCTGG TCTCATAAAT CTCTGCTTTC AGAGCTTCCT GGCGGCGGCT CCAGAGCTTC ATGGCGCAGC CCCGAGGAGC CCTGAGCTCC AACTCCATAG GGGATATCCC CGCCGACTTT CCCCTGCCCT ATTATACATC CCTCAATGAC CAAACCTGGA GGTATTGAGG GGCCGCACCC AATTCCGGGA GAACAACAGT- TCCAATCTCT CTCCAAACAT CAGCGCCGGG GGAGGTGTCG CTGACATGGC CTGCTCAAGT GCTCCAGGAG TGGTGCTGCT TGCCCCAGCC CGGCCTVT1TC CCGAGTTGGG GCCACCACCA GCAGCCCTAA ACTTAAAGAG GAAGACGTCT GAG CTT CGTA CAATTCTTCG TCTCGACATC AAAACTGACG ACGTAGAGGG ACTATCAACC GTCTACCCAG CAGGAGGGGT TACCGCGTTC TACACCATTA CTTTAGAGCA AAGCTGTGTG CGGACACTCT AGGCCCTGCA CTCTACCAGG TCCCACCTTG TCTGGCAGCA TAA; (SEQ GCACGTTTAGACAGATAAATATAAAACCTGCACCT TTCGACGAACTATAGAGCTTTTCGTGCGACT CGCTCACTGGGTCTAGGTTAGATAAATCTAG ATGGCATTCTACCACATTTCCCGCCGCCCCC CGCTC.TACTAGCGTATGAGATCGAAATAGT TATCTGGTTA'CCTTGAGCAAGCGCAGGAACAACAGTACGTAGAGGGCGGTGGAGGCTCC CCGTACGCGTCACCATACACGCCTCTTAGAC CATAAATCTCCAAACATGGGACCCACTTGCCTCTCATCCCTCCTGGGGCAGCTTTCTGGA CAGGTCCGTCTCCTCC TTGGGGCCCTGCAGAGCCTCCTTGGAACCCAGCTTCCTCCACAG GGCAGGACCACAGCTCACAGGATCCCATGCCATCTTCCTGAGCTTCCAJACACCTGCTC CGAGGAAAGGTGCGTTTCCTGATGCTTGTAGGAGGGTCCACCCTCTGCGTCAGGGAATTC GGCGGCAACATGGCGTCTCCGGCGCCGCCTGCTTGTGACCTCCGAGTCCTCAGTAAACTG CTTCGTGACTCCCATGTCCTTCACAGCAGACTGAGCCAGTGCCCAGAGGTTCACCCTTTG CCAACGCTCGCTCGGATTGCTGAATGAACCAGATG GAGGAGACCAAGGCACAGGACATTCTGGGAGCAGTGACCCTTCTGCTGGAGGGAGTGATG GCAGCACGGGGACAACTG (SEQ ID NO: 124); GCACGTTTAGTGTAATTCTATAAAACACGAC TTGCTGGACCCGAACAACCTCAATGACGAAGACGTCTCTATCCTGATGGACCGAAACCTT CGCTCACTGGGTCTAGGTTAGATAAATCTAG ATTGAGGCAATTCTTCGTAATCTCCACCATGTCTGCCCTCTGCCACGGCCGCACCCTC T CGACATCCAATCATCATCA\GGCAGGTGACTGGCAAGAAJTTCCGGGAJA7ACTGACGTTC TACGTACTGGAGGAGACAATCTGGGGTGGCC CCGTACGCGTCACCATACACGCCTCTTAGAC CATAAATCTCCAAACATGGGZA3CCCAGCTTCCTCCACAGGGCAGGACCACAGCTCACAAG GATCCCAATGCCATCTTCCTGAGCTTCCAJACACCTGCTCCGAGGAAAGGTGCGTTTCCTG WO 97/12985 PCTIUS96/15774 600 ATGCTTGTAGGAGGCTCCACCC TCTGCGTCAGGGAATTCGGCGGCAACATGCCGTCTCCG GCGCCGCCTGCTTGTGACCTCCGAGTCCTCAGTAAACTGCTTCGTGACTCCCATGTCCTT CACAGCAGACTGAGCCAGTGCCCAGAGGTTCACCCTTTGCCTACACCTGTCCTGCTGCCT GCGGATTGTGGGAGAAACAAGAGGCAGCCGA ATTCTGGGAGCAGTGACCCTTCTGCTGGAGGGAGTGATGGCAGCACGGGGACAACTGGGA CCCACTTGCCTCTCATCCCTCCTGGGGCAGCTTTCTGGACAGGTCCGTCTCCTCCTTGGG GCCCTGCAGAGCCTCCTT (SEQ ID NO:125); GCTAACTGCTCTATAATGATCGATGAAATTATACATCACTTAAAGAGACCACCTGCACCT TTGCTGGACC CGAACAACCTCAATGACGAAGAC GTCTCTATCCTGATGGACCGAAACCTT CGCTCACTGGGTCTAGGTTAGATAAATCTAG ATTGAGGCAATTCTTCGTA&TCTCCAAJCCATGTCTGCCCTCTGCCACGGCCGCACCCTCT CGACATCCAATCATCATCAGGCAGGTGACTGGCAAGATTCCGGGAAACTGACGTTC TACGTACTGGAGGAGACAATCTGGGGTGGCC CCGGGTGAACCGTCTGGTCCATCTCTACTATCAAJCCCGTCTCCTCCGTCTAGAATCT CATAAATCTCCAACATGGGCAGGACCACAGCTCACAAGGATCCCAATGCCATCTTCCTG AGCTTCCAACACCTGCTCCGAGGA.JAGGTGCGTTTCCTGATGCTTGTAGGAGGGTCCAC C CTCTGCGTCAGGGAJATTCGGCGGCAJACATGGCGTCTCCGGCGC(:CCTGCTTGTGACCTC CGAGTCCTCAGTAAACTGCTTCGTGACTCCCATGTCCTTCACAGCAGACTGAGCCAGTGC CCAGAGGTTCACCCTTTGCCTACACCTGTCCTGCTGCCTGCTGTGGACTTTAGCTTGGGA GAATGGAAAACCCAGATGGAGGAGACCAAGGCACAGGACATTCTGGGAGCAGTGACCCTT CTGCTGGAGGGAGTGATGGCAGCACGGGGACAJACTGGGACCCACTTGCCTCTCATCCCTC CTGGGGCAGCTTTCTGGACAGGTCCGTCTCCTCCTTGGGGCCCTGCAGAGCCTCCTTGGA ACCCAGCTTCCTCCACAG (SEQ ID NO:126); GCTAACTGCTCTATAATGATCGATGAATTATACATCACTTAAAGAGACCACCTGCACCT TTCGACGAACTATAGAGCTTTTCGTGCGACT CGCTCACTGGGTCTAGGTTAGATAAATCTAG ATTGAGGCAATTCTTC GTAATCTCCAACCATGTCTGCCCTCTGCCACGGCCGCACCCTCT CGCTCACTACAGAGGCTGAGATCGAAATAGT TATCTGGTTACCCTTGAGCAAGCGCAGGACACAGTACGTAGAGGGCGGTGGAGGCTCC CCGGGTGAAC CGTCTGGTCCAATCTCTACTATCA.ACCCGTCTCCTCCGTCTAJAAGAJATCT CATAAATCTCCAAACATGGCTCACAAGGATCCCAAJTGCCATCTTCCTGAGCTTCCAJACAC CTGCTCCGAGGAAAGGTGCGTTTCCTGATGCTTGTAGGAGGGTCCACCCTCTGCGTCAGG GAATTCGGCGGCAACATGGCGTCTCCGGCGCCGCCTGCTTGTGACCTCCGAGTCCTCAGT AAACTGCTTCGTGACTCCCATGTCCTTCACAGCAGACTGAGCCAGTGCCCAGAGGTTCAC CCTTTGCCTACACCTGTCCTGCTGCCTGCTGTGGACTTTAGCTTGGGAGATGGAACC CAGATGGAGGAGACCAAGGCACAGGACATTCTGGGAGCAGTGACCCTTCTGCTGGAGGGA GTGATGGCAGCACGGGGACAACTGGGACCCACTTGCCTCTCATCCCTCCTGGGGCAGCTT TCTGGACAGGTCCGTCTCCTCCTTGGGGCCCTGCAGAGCCTCCTTGGAACCCAGCTTCCT CCACAGGGCAGGACCACA (SEQ ID NO: 127); GCACGTTTAGTGTAATAAACCTAGGCACGAC TTGCTGGACC CGAACAACCTCAATGACGAAGACGTCTCTATCCTGATGGACCGAAACCTT CGCTCACTGGGTCTAGCGCAACTGA.TCTAG ATTGAGGCAJATTCTTCGTATCTCCACCATGTCTGCCCTCTGCCACGGCCGCACCCTCT CGCTCACTACAGAGGCTGAGATCGAAATAGT TACGTACTGGAGGAGACAATCTGGGGTGG CC CCGTACGCGTCACCATACACGCCTCTTAGAC WO 97/12985 PCT[US96/15774 601 CATAAATCTCCAAACATGGATCCCAATGCCATCTTCCTGAGCTTCCAACACCTGCTCCGA GGAAAGGTGCGTTTCCTGATGCTTGTAGGAGGGTCCACCCTCTGCGTCAGGGAATTCGGC GGCAACATGGCGTCTCCGGCGCCGCCTGCTTGTGACCTCCGAGTCCTCAGTAAACTGCTT CGTGACTCCCATGTCCTTCACAGCAGACTGAGCCAGTGCCCAGAGGTTCACCCTTTGCCT ACACCTGTCCTGCTGCCTGCTGTGGACTTTAGCTTGGGAGAATGGAACCCAGATGGAG GAGACCAAGGCACAGGACATTCTGGGAGCAGTGACCCTTCTGCTGGAGGGAGTGATGGCA GCACGGGGACAACTGGGACCCACTTGCCTCTCATCCCTCCTGGGGCAGCTTTCTGGACAG GTCCGTCTCCmC'(CTTGGGGCCCTGCAGAGCCTCCTTGGAACCCAGCTTCCTCCACAGGGC AGGACCACAGCTCACAAG (SEQ ID NO: 128); 1 51 101 151 201 251 301 351 401 451 501 551 601 651 701 751 801 851 901 951 1 51 101 151 201 251 301 351 401 451 501 551 601 651 701 751 801 851 ATGGCTAACT GCCACCGCTG ATATCCTAAT CGTGCTGTCA AAATCTCCTG CAATCCATAT TTCTATCTGA CGGTGGAGGC CGTCTCCTCC GGTGCCATGC CCTGGTTGCT TACGCCACCT CTGCTCAAGT GCTCCAGGAG TGGTGCTGCT TGCCCCAGCC CGGCCTTTTC CCGAGTTGGG GCCACCACCA GCAGCCCTAA ATGGCTAACT GCCACCGCTG ATATCCTGAT CGTGCTGTCA AAATCTCCTG CAATCATCAT TTCTATCTGA CGGTGGAGGC CGTCTCCTCC GGTGCCATGC CCTGGTTGCT TACGCCACCT CAGAGCTTCC TGGCGCAGCG CCGAGGAGCT CTGAGCTCCT ACTCCATAGC GGATATCCCC GCTCTAACAT CCGCTGCTGG GGACAATAAC AGTCTC TOCA CCATGTCTGC CAAGGACGGT AAACCTTGGA TCCCCGGGTG GTCTAAAGAA CGGCCTTCGC AGCCATCTGC TGCGCAGCCC CTTTAGAGCA AAGCTGTGTG CGGACACTCT AGGCCCTGCA CTCTACCAGG TCCCACCTTG TCTGGCAGCA GATCGATGAA ACTTCAACAA CTTCGTCGTC GAATGCATCA C GC TAGC CAC GACTGGAATG GAACGCGCAG AACCGTCTGG TCTCATAAAT CTCTGCTTTC AGAGCTTCCT TCTGGCGGCT AGTGAGAAAG CCACCTACAA CTGGGCATCC GCTGGCAGGC GGCTCCTGCA GACACACTGC GATGGAAGAA ATCATCACCC CCTCAATGGT CAAACCTCGA GCAATTGAGA GGCCGCACCC AATTCCGTCG GCTCaACAGT TCCAATCTCT CTCCAAACAT CAGCGCCGGG GGAGGTGTCG CTGGCGGCTC ATCCAGGGCG GCTGTGCCAC CCTGGGCTCC TGCTTGAGCC GGCCCTGGAA AGCTGGACGT CTGGGAATGG ACCTGAAGCA GAAGACCAAG GGCATTCAAC GCATTCTTAA ACGCGACATC TAAACTGACC ACGTAGAGG ACTATCAACC GGCTACCCAG CAGGAGGGGT TACCGCGTTC TCAGAGCTTC ATGGCGCAGC CCCGAGGAGC CCTGAGCTCC AACTCCATAG GGGATATCCC CGCCGACTTT CCCCTGCCCT TAA (SEQ ID NO:114); GCTCTAACAT CCGCTGCTGG GGAAAATAAC AGTCTCTGCA CCATGTCTGC CCGTGACGGT AAACCTTGGA TCCCCGGGTG GTCTAAAGAA CGGCCTTCGC AGCCATCTGC TGCGCAGCCC TGCTCAAGTC CTCCAGGAGA GGTGCTGCTC GCCCCAGCCA GGCCTTTTCC C GAGT TGG T GATCGATGAA ACTTCAACAA CTTCGTCGTC GAATGCATCA CCC TGGC CAC GACTGGAATG GAACGCGCAG AACCGTCTGG TCTCATAAAT CTCTGCTTTC AGAGCTTCCT ACACCATTGG TTTAGAGCAA AGCTGTGTGC GGACACTCTC GGCCCTGCAG TCTACCAGGG CCCACCTTGG AT CATCAC CC CCTCAATGGT CAAACCTCGA GCAATTGAGA GGCCGCACCC AATTCCGTCG GCTCAACAGT TCCAATCTCT CTCCAAACAT CAGCGCCGGG GGAGGTGTCG GCCCTGCCAG GTGAGAAAGA CACCTACAAG TGGGCATCCC CTGGCAGGCT GCTCCTGCAG AC ACAC TOCA ACCTGAAGCA GAAGACCAAO GGCATTCAAC GCATTCTTAA ACCGACAT C TAAACTGACC ACGTAOAOG ACTATCAACC GGCTACCCAG CAGGAGGGGT TACCGCGTTC CTCCCTGCCC TCCAGGGCGA CTGTGCCACC CTGGGCTCCC GCTTGAGCCA GCCCTGGAAG GCTGGACGTC WO 97/12985 PCTJUS96/1 5774 901 GCCGACTTTG CCACCACCAT 951 CCCTGCCCTG CAGCCCTAAT CTGGCAGCAG ATGGAAGAAC TGGGAATGGC AA (SEQ ID NO:115); 1 51 101 151 201 251 301 351 401 451 501 551 601 651 701 751 801 851 901 951 ATGGCTAACT GCCACCGCTG ATATCCTGAT CGTGCTGTCA AAATCTCCTG CAATCATCAT TTCTATCTGA CGGTGGAGGC CGTCTCCTCC GGTGCCATGC CCTGGTTGCT TACGC2CACCT CTGCTCAAGT GCTCCAGGAG TGGTGCTGCT TGCCCCAGCC CGGCCTTTTC CCGAGTTGGG GCCACCACCA GCAGCCCTAA GCTCTAACAT CCGCTGCTGG GGAAAATAAC AGTCTCTGCA CCATGTCTGC CCGTGACGGT AAACCTTGGA TCCCCGGGTG GTCTAAAGAA CGGCCTTCGC AGCCATCTGC TGCGCAGCCC CTTTAGAGCA AAGCTGTGTG CGGACACTCT AGGCC CTGCA CTCTACCAGG TCCCACCTTG TCTGGCAGCA GATCGATGAA ACTTCAACAA CTTCGTCGTC GAATGCATCA CCCTGGCCAC GACTGGAATG GAACGCGCAG AACCGTCTGG TCTCATAAAT CTCTGCTTTC AGAGCTTCCT TCTGGCGGCT AGTGAGAAAG CCACCTACAA CTGGGCATCC GCTGGCAGGC GGCTCCTGCA GACACACTGC GATGGAAGAA ATCATCACCC CC TCAATGGT CAAACCTC GA GCAATTGAGA GGCCGCACCC AATTCCGTCG GCTCAACAGT TCCAATCTCT CTCCAAACAT CAGCGCCGGG GGAGGTGTCG CTGGCGGCTC ATCCAGGGCG GCTGTGCCAC CCTGGGCTCC TGCTTGAGCC GGCCCTGGAA AGCTGGACGT CTGGGAATGG ACCTGAAGCA GAAGACCAAG GGCATTCAAC GCATTCTTAA AC GC GACAT C TAAACTGAC C ACGTAGAGGG ACTATCAAC C GGC TACCCAG CAGGAGGGGT TACCGCGTTC TCAGAGCTTC ATGGCGCAGC CCCGAGGAGC CCTGAGCTC C AACTCCATAG GGGATATCCC CGCCGACTTT CCCCTGCCCT TAA (SEQ ID NO:116); 1 51 101 151 201 251 301 351 401 451 501 551 601 651 701 751 801 851 901 951 ATGGCTALACT GCCACCGCTG ATATCCTAAT CGTGCTGTCA AAATCTCCTG CAATCCATAT TTCT AT C TGA CGGTGGAGGC CGTCTCCTCC GGTGCCATGC CCTGGTTGCT TACGCCACCT CAGAGCTTCC TGGCGCAGCG CCGAGGAGCT CTGAGCTCCT ACTCCATAGC GGATATCCCC GCCGACTTTG CCCTGCCCTG GCTCTAACAT CCGCTGCTGG GGACAATAAC AGTCTCTGCA CCATGTCTGC CAAGGACGGT AAACCTTGGA TCCCCGGGTG GTCTAAAGAA CGGCCTTCGC AGCCATCTGC TGCGCAGCCC TGCTCAAGTC CTCCAGGAGA GGTGCTGCTC GCCCCAGCCA GGCCTTTTCC CGAGTTGGGT C CACC AC CAT CAGCC CTAAT GATC CAT GAA ACTTCALACAA CTTCGTCGTC GAATGCATCA CGCTAGCCAC GACTGGAATG GAACGCGCAG AACCGTCTGG TCTCATAAAT CTCTGCTTTC AGAGCTTCCT ACACCATTGG TTTAGAGCAA AGCTGTGTGC GGACACTCTC GGCCCTGCAG TCTACCAGGG CCCACCTTGG CTGGCAGCAG AA (SEQ ID AT CAT CAC CC CCTCAATGGT CAAACCTCGA GCAATTGAGA GGCCGCACCC AATTCCGTCG GCTCAACAGT TCCAATCTCT CTCCAAACAT CAGCGCCGGG GGAGGTGTCG GCCCTGCCAG GTGAGAAAGA CACCTACAAG TGGGCATCCC CTGGCAGGCT GCTCCTGCAG ACACACTGCA ATGGAAGAAC NO:117); ACCTGAAGCA GAAGACCAAG GGCATTCAAC GCATTCTTAA ACGCGACATC TAAACTGACC ACGTAGAGGG ACTATCAACC GGCTACCCAG CAGGAGGGGT TACCGCGTTC CTCCCTGCCC TCCAGGGCGA CTGTGC CACC CTGGGCTCCC GCTTGAGCCA GCCCTGGAAG GCTGGACGTC TGGGAATGGC ATGGCTCTGG ACCCGAACAA CCTCAATGAC GAAGACGTCT CTATCCTGAT GGACCGAAAC CTTCGACTTC CAAACCTGGA GAGCTTCGTA AGGGCTGTCA WO 97/12985 WO 9712985PCT/US9615774 101 151 201 251 301 351 401 451 501 551 601 651 701 751 801 851 901 951 1 51 101 151 201 251 301 351 401 451 501 551 601 651 701 751 801 851 901 951 1 51 101 151 201 251 301 351 401 451 AGAACTTAGA C CATGCTC TGC CAAGCCAGGT TTACCCTTGA ATAATGATCG GTACGTAGAG CTACTATCAA ATGGCTACCC GGCAGGAGGG CGTACCGCGT TCTCAGAGCT CGATGGCGCA ACCCCGAGGA CCCCTGAGCT CCAACTCCAT AAGGGATATC GTCGCCGACT GGCCCCTGCC ATGGCTAATG TCTGCCCTCT CAGGTGACTG CTTGAGCAAG GATO 'ATGAA AOCCGAACAA CTTCGACTTC ATACGTAGAG OTACTATCAA ATGGC TAOC C GGCAGGAGGG CGTACCGCGT TCTCAGAGCT OGATGGCGCA ACCCGAGGA CCCCTGAGCT CCAACTCCAT AAGGGATATC GTCGCCGACT GGCCCCTGC ATGGCTGCAC AGAATTCCGG AGGAACAACA ATACATCACT CAATGACGAA ACCTGGAGAG ATTGAGGOAA OTACGTAGAG CTACTATCAA ATGGCTACCC AAATGCATCA CCTCTGCCAC GACTGGCAAG GCAAGCGCAG ATGAAATTAT GGCGGTGGAG CCCGTCTCCT AGGGTGC CAT GTCCTGGTTG TCTACGCOAC TCCTGCTCAA GCGCTCCAGG GCTGGTGCTG CC TGOC 00AG AGCGGCCTTT CCCCGAGTTG TTGCOACCAC CTGCAGCCCT CATCAGGTAT GCCACGGCCG GCAAGAATTC CGCAGGAACA ATTATACATO CCTCAATGAC CAAACCTGGA GGCGGTGGAG CCCGTOTCCT AGGGTGCCAT GTOCTGGTTG TCTACCCAC TCOTGCTCAA GOGCTCCAGG GCTGGTGCTG CO TGC CCC AG AGOGG C CTTT CC CCGAGTTG TTGCOAOOAC CTGCAGCOCT CTO T0GACA GAAAAACTGA GGGTGGTGGC TAAAGAGACC GACGTCTCTA OTTOGTAAGG TTCTTOGTAA GGCGGTGGAG CCCGTCTCCT AGGGTGOCAT GGTATTGAGG GOCCOCACC AATTCCGGGA GAACAACAGG ACATCACTTA GCTCCCOGGG CCGTCTAAAG GCCGGCCTTC OTAGOCATOT CTTGCGOAGC GTCTTTAGAG AGAAGCTGTG OTOGGACACT OOAGGCOCTG TOCTCTACCA GTCCACOT CATCTGGCAG AATAA (SEQ TGAGGCAATT CACOCTO TOG OGGGAAAAAC ACAGGGTGGT AOTTA-AAGAG GAAGACGTCT GAGOTTCGTA GCTCOOOGGG OCGTCTAAAG GOOGGOOTTO CTAGCCATOT OTTGCGCAGC GTOTTTAGAG AGAAGOTGTG OTOGGACACT COAGGCCCTG TO OTOTAO CA GGTCOOAOCT CATCTGGCAG AATAA (SEQ TCOAATOATO OGTTCTATOT TOTAACTGCT AOOTGCAOCT TCCTGATGGA GOTGTCAAGA TOTOCAACCA GOTCCCOGGG COGTOTAAAG GCCGGCCTTC CAATTCTTCG TCTCGACATC AAAACTGACG GTGGTGGCTC AAGAGACCAC TGAACCGTCT AATCTCATAA GOCTCTGCTT GOAGAGOTTO CCTCTGGCGG CAAGTGAGAA TGCCACCTAC CTCTGGGCAT CAGCTGGCAG GGGGCTCCTG TGGACACACT CAGATGGAAG ID NO:86); CTTCGTAATC ACATCOAATC TGACGTTCTA ,GGCTOTAACT ACCACCTGCA CTATCCTGAT AGGGCTGTCA TGAAOCGTCT AATCTCATAA GCCTCTGCTT GO AGAGCT TO CCTCTGGCGG OAAGTGAGAA TGCCACCTAC CT CTGGGC AT CAGOTGGCAG GGGGOTCCTG TGGACACACT CAGATGGAAG ID NO:87); AT OAAGGC AG GGTTACCCTT OTATAATGAT TTGOTGGACC OOGAAACOTT AOTTAGAAAA TGTOTGCOCT TGAAOOGTCT AATCTCATAA GCCTCTGCTT TAATCTCCAA CAATCATCAT T TO TAT CTGG TAACTGCTCT CT GCAC CTTT GGTCCAATCT ATCTCCAAAC TCCAGCGCCG CTGGAGGTGT CTCTGGOGGC AGATCCAGGG AAGCTGTGCC CCCCTGGGCT GOTGCTTGAG CAGGCCCTGG GCAGCTGGAC AAC TGGGAAT TOO AAC CAT C ATO AT CAAG C TOT GGTTAC C GCTCTATAAT CCTTTGCTGG GGACC GAAAC AGAACTTAGA GGTCCAATCT ATCTCCAAAC TOCAGOGOOG CTGGAGGTGT CTCTGGCGGC AGATCCAGGG AAGCTGTGCC CCCCTGGGCT GCTGCTTGAG CAGGCOTOG GCAGCTGGAC AACTGGGAAT GTGACTGGCA GAG CAAGC GO CGATGAAATT CGAACAACCT OGACTTCCAA TGCATCAGGT CTGCCACGGC GGTCCAATC T ATCTCCAAAC TCCAGCGCC G WO 97/12985 WO 9712985PCTIUS96I1 5774 604 501 551 601 651 701 751 801 851 901 951 1 51 101 151 201 251 301 351 401 451 501 551 601 651 701 751 801 851 901 951 (SEQ 1 51 101 151 201 251 301 351 401 451 501 551 601 651 701 751 801 GGCAGGAGGG CGTACCGCGT TCTCAGAGCT CGATGGCGCA ACCCCGAGGA CCCCTGAGCT CCAACTCOAT AAGGGATATC GTOGCCGACT GGCCCCTGC ATGGCTfCTGG GGACCGAAAO AGAACTTAGA CCATGTCTGC CAAGGCAGGT TTAOOCTTGA AG C GGOGGOG CTTAAAGAGA CGGGTGAACC AAAGAAT CT C CTTCGOCTCT ATCTGCAGAG CAGCCCTCTG AGAGCAAGTG TGTGTGCCAC CAOTCTCTGG CCTGCAGCTG ACCAGGGGCT AOOTTGGACA GCAGCAGATG ID ATGGCTAATG TCTGOCCTCT CAGGTGACTG CTTGAGCAAG CGGCGGTTCT AGAGACCACC GTCTCTATCC CGTAAGGGCT CGGGTGAAC AAAGAATCTC CTTCGCCTCT ATCTGCAGAG CAGCCCTCTG AGAGCAAGTG TGTGTGCCAC CACTCTCTGG CCTGCAGCTG GTCCTGGTTG TOTACGCOAC TCCTGCTCAA GO GOT C CAGG GOTGGTGCTG CCTGCCCCAG AGOGGOCTTT CC COGAGTTG TTGCOACCAC OTGCAGCOCT ACCCGAACAA CTTCGAOTTO AAATGOATCA CCTCTGCOAC GACTGGCAAG GCAAGCGCAG GTTCTAACTG CC ACC0T GCAC GTCTGGTOCA ATAAATCTCC GCTTTOOAGC O TT C CTGGAG GOGGOTCTGG AGAAAGATOC CTACAAGCTG GOATCOOOTG GCAGGCTGOT CCTGCAGGCC OACTGCAGCT GAAGAACTGG OATCAGGTAT GOOACGGCCG GCAAGAATTC CGCAGGAACA AACTGCTCTA TGCACCTTTG TGATGGAOOG GTCAAGAACT GTCTGGTCCA ATAAATCTCC GOTTTCOAGC CTTCCTGGAG GGGC TTGG AGAAAGATCC CTACAAGCTG GCATCCCTG GCAGGCTGCT OTAGCCATCT OTTGCGCAGC GTCTTTAGAG AGAAGCTGTG CT CGGAC AC T C CAGGOC CCTG TOCTCTACCA GGTCOACOT CATCTGGCAG AATAA (SEQ 00 TCAAT GAO CAAACCTGGA GGTATTGAGG GGOOGCACCC AATTCCGGGA GAACAACAGG CTCTATAATG OTTTGTAOGT ATCTCTACTA AAACATGGCT GCCGGGCAGG GTGTCGTACC OGGOTOTOAG AGGGCGATGG TGCCACCCCG GGCTCOCTG TGAGCCAACT CTGGAAGGGA GGAOGTC GC GAAT GGC 0 0 TGAGGCAATT CACCOTOTOG CGGGAAAAAC ACAGGGTGGT TAATGATCGA CT GGAC C CGA AAACCTTCGA TAGAATACGT ATOTOTACTA AAACATGGCT GOCGGGOAGG GTGTOGTACC OGGOTCTCAG AGGGCGATGG T GOCACC CC G GGCTCCCCTG TGAGOOAACT GCAGAGCTTC CCTCTGGCGG CAAGTGAGAA TGC CAC CT AC CTOTGGGCAT CAGCTGGOAG GGGGCTCCTG TGGACACAOT CAGATGGAAG ID NO:88); GAAGAOGTOT GAGCTTCGTA CAATTCTTCG TOTOGACATC AAAACTGACG GTGGTGGOTO ATCGATGAAA AGAGGGCGGT TCAACCCGTC ACCCAGGGTG AGGGGTOOTG GCGTTCTACG AG CTTOOT GO CGCAGOGOTC AGGAGCTGGT AG OTOCTGC C COATAGOGGO TATOCCOCGA GACTTTGOCA TGOOOTGOAG CTTCGTAATC ACATCCAATC TGACGTTCTA GGCTCTGGCG TGAAATTATA ACAACCTCAA CTTCCAAACC AGAGGGOGGT TO AAC CCG TO AOOCAGGGTG AGGGGTOOTG GCGTTCTACG AGCTTOOTGO CGOAGOGOTC AGGAGCTOCT AG CTOCCTG CC COATAGCGGO CTGGAGGTGT OTCTGGOGGC AGATCCAGGG AAGCTGTGCC CCCCTGGGCT GCTGOTTGAG CAGGCCCTGG GCAGCTGGAC AAOTGGGAAT OTATOCTGAT AGGGCTGTOA TAATCTOOAA CAATCATCAT TTOTATCTGG TGGOGGTGGC TTATACATCA GGAGGCTCCO TCOTOCGTCT CCATGCCGGC GTTGCTAGOCC COACOTTGOG TOAAGTCTTT OAGGAGAAGO GOTGCTOGGA C CAG CCAGG C OTTTTOCTOT GTTGGGTOOO CCACCATCTG COOTAATAA TCOAACOATG ATOATOAAGG TCTGGTTAC GTGGCAGOGG CATOAOTTAA TGACGAAGAC TGGAGAGCTT GGAGGOT CC C TCOTCCGTCT COATOCOGGO GTTGCTAGCC CCAOOTTGCG TCAAGTOTTT CAGGAGAAGC GOTGOTOGGA COAGCCAGGC CTTTTCCTCT WO 97/12985 PCTIUS96/15774 605 851 ACCAGGGGCT CCTGCAGGCC CTGGAAGGGA TATCCCCCGA GT TGGGTCCC 901 ACCTTGGACA CACTGCAGCT GGACGTCGCC GACTTTGCCA CCACCATCTG 951 GCAGQ"ACATG GAACAACTGC GAATGGCCCC TGCCCTGCAG CCCTAATAA (SEQ ID NO:91); GCTAACTGCTCTATAATGATCGATGAAATTATACATCACTTAAAGAGACCACCTGCACCT TTGCTGGACCCGAACAACCTCAATGACGAAGACGTCTCTATCCTGATGACCGACCTT CGACTTCCAAACCTGGAGAGCTTCGTAAGGGCTGTCAAGAACTTAGAAJATGCATCAGGT ATTGAGGCAATTCTTCGTAATCTCCAACCATGTCTGCCCTCTGCCACGGCCGCACCCTCT CGACATCCAATCATCATCAAGGCAGGTGACTGGCAAGAATTCCGGGAAAAACTGACGTTC TATCTGGTTACCCTTGAGCAAGCGCAGGAACAACAGTACGTAGAGGGCGGTGGAGCCTC C CCGGGTGAACCGTCTGGTCCAATCTCTACTATCAACCCGTCTCCTCCGTCTAAGAJATCT CATAAATCTC CAAACATCCGACCCACTTGCCTCTCATCCCTCCTGGGGCAGCTTTCTGGA CAGGTCCGTCTCCTCCTTGGGGCCCTGCAGAGCCTCCTTGGAACCCAGCTTCCTCCACAG GGCAGGACCACAGCTCACAAGGATCCCAATGCCATCTTCCTGAGCTTCCAACACCTGCTC CGAGGAAAGGTGCGTTTCCTGATGCTTGTAGGAGGGTCCAC CCTCTGCGTCAGGGAATTC GGCAACATGGCGTCTCCCGCTCCGCCTGCTTGTGACCTCCGAGTCCTCAGTA\ACTGCTT CGTGACTCCCATGTCCTTCACAGCAGACTGAGCCAGTGCCCAGAGGTTCACCCTTTGCC T ACACCTGTCCTGCTGC CTGCTGTGGACTTTAGCTTGGGAGAATGGAAAACCCAGATGGAG GAGACCAAGGCACAGGACATTCTGGGAGCAGTGACCCTTCTGCTGGAGGGAGTGATGGCA GCACGGGGACAACTG (SEQ ID NO:136); GCTAACTGCT CTATAATGATCGATGAAATTATACATCACTTAAAGAGACCACCTGCACCT TTGCTGGACCq GAACAACCTCAATGACGAAGACGTCTCTATCCTGATGGACCGAAACCTT CGACTTCCAAAC:'.CTGGAGAGCTTCGTAAGGGCTGTCAAGAACTTAGAAAATGCATCAGGT ATTGAGGCAATTCTTCGTAATCTCCAACCATGTCTGCCCTCTGCCACGGCCGCACCCTCT CGACATCCAATCATCATCAAGGCAGGTGACTGGCAAGAATTCCGGGAAAAACTGACGTTC TATCTGGTTACCCTTGAGCAAGCGCAGGA&CAACAGTACGTAGAGGGCGGTGGAGGCTCC CCGGGTGAACCGTCTGGTCCAATCTCTACTATCAACCCGTCTCCTCCGTCTAAAGAATCT CATAAATCTCCAAACATGGGAACCCAGCTTCCTCCACAGGGCAGGACCACAGCTCACAAG GATCCCAATGCCATCTTCCTGAGCTTCCAACACCTGCTCCGAGGAAAGGTGCGTTTCCTG ATGCTTGTAGGAGGGTCCACCCTCTGCGTCAGGGAATTCGGCAACATGGCGTCTCCCGCT CCGCCTGCTTGTGACCTCCGAGTCCTCAGTAAACTGCTTCGTGACTCCCATGTCCTTCAC AGCAGACTGAGCCAGTGCCCAGAGGTTCACCCTTTGCCTACACCTGTCCTGCTGCCTGCT GTGGACTTTAGCTTGGGAGAATGGAAAACCCAGATGGAGGAGACCAAGGCACAGGACATT CTGGGAGCAGTGACCCTTCTGCTGGAGGGAGTGATGGCAGCACGGGGACAACTGGGACCC ACTTGCCTCTCATCCCTCCTGGGGCAGCTTTCTGCACAGGTCCGTCTCCTCCTTGGGGCC CTGCAGAGCCTCCTT (SEQ ID NO:137); GCTAACTGCTCTATAATGATCGATGAAATTATACATCACTTAAAGAGACCACCTGCACC T TTGCTGGACCCGAACAACCTCAATGACGAAGACGTCTCTATCCTGATGGACCGAAACCTT CGACTTCCAAACCTGGAGAGCTTCGTAAGGGCTGTCAAGAACTTAGAAAATGCATCAGGT ATTGAGGCAATTCTTCGTAATCTCCAACCATGTCTGCCCTCTGCCACGGCCGCACCCTCT CGACATCCAATCATCATCAAGGCAGGTGACTGGCAAGAATTCCGGGAAAAACTGACGTTC TATCTGGTTACCCTTGAGCAAGCGCAGGAACAACAGTACGTAGAGGGCGGTGGAGGCTCC CCGCGTGAAC CGTCTGGTCCAATCTCTACTATCAACCCGTCTCCTCCGTCTAAAGAATCT CATAAATCTCCAAACATGGGACCCACTTGCCTCTCATCCCTCCTGGGGCAGCTTTCTGGA CAGGTCCGTCTCCTCCTTGGGGCCCTGCAGAGCCTCCTTGGAACCCAGCTTCCTCCACAG GGCAGGACCACAGCTCACAAGGATCCCAATGCCATCTTCCTGAGCTTCCAACACCTGCTC CGAGGAAAGGTGCGTTTCCTGATGCTTGTAGGAGGGTCCACCCTCTGCGTCAGGGAATTC WO 97/12985 PCTIUS96/15774 606 GGCGGCAACGGCGGCAACATGGCGTCCCCAGCGCCGCCTGCTTGTGACCTCCGAGTCCTC AGTAAACTGC TTCGTCACTCCCATGTCCTTCACAGCAGACTGAGCCAGTGCCCAGAGGTT CACCCTTTGCCTACACCTGTCCTGCTGCCTGCTGTGGACTTTAGCTTGGGAGATGAAA ACCCAGATGGAGGAGACQ7AAGGCACAGGACATTCTGGGAGCAGTGACCCTTCTGCTGGAG GGAGTGATGGCAGCACGGGGACAACTG (SEQ ID NO: 148); GCTAACTGCTCTATAATGATCGATGATTATACATCACTTAOAGACCACCTGCACC T TTGCTGGACCCGAACAACCTCAATGACGAGACGTCTCTATCCTGATQGACCGAAACCTT CGACTTCCAAACCTGGAGAGCTTCGTAAGGGCTGTCAAGAJCTTAGAAATGCATCAGGT ATTGAGGCAATTCTTCGTATCTCCAACCATGTCTGCCCTCTGCCACGGCCGCACCCTCT CGACATCCAATCATCATCAGGCAGGTGACTGGCAAGAJATTCCGGGAAAAACTGACGTTC TACGTACTGGAGGAGACAATCTGGGGTGG CC CCGGGTGAACCGTCTGGTCCATCTCTACTATCACCCGTCTCCTCCGTCTAGAATCT CATAAATCTCCAAACATGGGAACCCAGCTTCCTCCACAGGGCAGGACCACAGCTCACAJAG -GATCCCAATGCCATCTTCCTGAGCTTCCAJCACCTGCTCCGAGGAAA2GGTGCGTTTCCTG ATGCTTGTAGGAGGGTCCACCCTCTGCGTCAGGGAATTCGGCCJCGGCGGCAACATG GCGTCCCCAGCGCCGCCTGCTTGTGACCTCCGAGTCCTCAGTAAACTGCTTCGTGACTCC CAGCTCCGAATACATCCAAGTAC=TCTCCTT CTGCTGCCTGCTGTGGACTTTAGCTTGGGAGAATGGJAAACCCAGATGGAGGAGACCAAG GCACAGGACATTCTGGGAGCAGTGACCCTTCTGCTGGAGGGAGTGATGGCAGCACGGGGA CAACTGGGACCCACTTGCCTCTCATCCCTCCTGGGGCAGCTTTCTGGACAGGTCCGTCTC CTCCTTGGOGCCCTGCAGAGCCTCCTT (SEQ ID NO: 149); GCTAACTGCTCTATAATGATCGATGATTATACATCACTTAAA2GAGACCACCTGCACCT TTGCTGGACCCGAACAACCTCAATGACGAAJGACGTCTCTATCCTGATGGACCGAAACCTT CGACTTCCAAACCTGGAGAGCTTCGTAAGGGCTGTCAGACTTAGAAATGCATCAGGT ATTGAGGCAATTCTTCGTAATCTCCJACCATGTCTGCCCTCTGCCACGGCCGCACCCTCT CGCTCACTACAGAGGCTGAGATCGAAATAGT TATCTGGTTACCCTTGAGCAAGCGCAGGJACAACAGTACGTAGAGGGCGGTGGAGGCTCC CCGTACGCGTCACCATACACGCCTCTTAGAC CATAAATCTCCAAACATGGGCAGGACCACAGCTCACAAGGATCCCAATGCCATCTTCCTG AGCTTCCAACACCTGCTCCGAGGAAAGGTGCGTTTCCTGATGCTTGTAGGAGGGTCCACC CTCTGCGTCAGGGAATTCGGCGGCJAACGGCGGCAACATGGCGTCCCCAGCGCCGCCTGCT TGTGACCTCCGAGTCCTCAGTAAACTGCTTCGTGACTCCCATGTCCTTCACAGCAGACTG AGCCAGTGCCCAGAGGTTCACCCTTTGCCTACACCTGTCCTGCTGCCTGCTGTGGACTTT AGCTTGGGAGAATGGAAACCCAGATGGAGGAGACCAAG~GCACAGGACATTCTGGGAGCA GTGACCCTTCTGCTGGAGGGAGTGATGGCAGCACGGGGACZAJCTGGGACCCACTTGCCTC TCATCCCTCCTGGGGCAGCTTTCTGGACAGGTCCGTCTCCTCCTTGGGGCCCTGCAGAGC CTCCTTGGAACCCAGCTTCCTCCACAG (SEQ ID NO:15 0); GCACGTTTAGTGTAATAAACCTAGGCACGAC TTGCTGGACCCGAACAACCTCAATGACGAAGACGTCTCTATCCTGATGGACCGAAACCTT CGCTCACTGGGTCTAGGTTAGATAAATCTAG ATTGAGGCAATTCTTCGTAATCTCCAJACCATGTCTGCCCTCTGCCACGGCCGCACCCTCT CGCTCACTACAGAGGCTGAGATCGAAATAGT TACGTACTGACACCG C=CGAGAAGGGTGGCC CCGGGTGAACCGTCTGGTCCAATCTCTACTATCAACCCGTCTCCTCCGTCTAAAGAATCT CATAAATCTCCAACATGGCTCACJGGATCCCAATGCCATCTTCCTGAGCTTCCAJACAC CTGCTCCGAGGAAAGGTGCGTTTCCTGATGCTTGTAGGAGGGTCCACCCTCTGCGTCAGG WO 97/12985 PCTIUS96/15774 607 GAATTCGGCGGCAACGGCGGCACATGGCGTCCCCAGCGCCGCCTGCTTGTGACCTCCGA GTCCTCAGTAAACTGCTTCGTGACTCCCATGTCCTTCACAGCAGACTGAGCCAGTGCCCA GAGGTTCACCCTTTGCCTACACCTGTCCTGCTGCCTGCTGTGGACTTTAGCTTGGGAGAA TGGAAAACCCAGATGGAGGAGACCAAGGCACAGGACATTCTGGGAGCAGTGACCCTTCTG CTGGAGGGAGTGATGGCAGCACGGGGACAACTGGGACCCACTTGCCTCTCATCCCTCCTG GCCAGCTTTCTGGACAGGTCCGTCTCCTCCTTGGGGCCCTGCAGAGCCTCCTTGGAACC CAOCTTCCTCCACAGGGCAGGACCACA (SEQ ID NO:151); GCTAACTGCTCTATAATGATCGATGAAATTATACATCACTTAAGAGACCACCTGCACCT TTGCTGGACCCGACACCTCATGACGAGACGTCTCTATCCTGATGGACCGAAACCTT CGCTCACTGGGTCTAGGTTAGATAAATCTAG ATTGAGGCAATTCTTC GTAATCTCCAACCATGTCTGCCCTC TGCCACGGCCGCACCCTCT CGCTCACTACAGAGGCTGAGATCGAAATAGT TATCTGGTTACCCTTGAGCAL.JGCGCAGGAJACAJCAGTACGTAGAGGGCGGTGGAGGCTCC CCGGGTGAACCGTCTGGTCCAATCTCTACTATCAACCCGTCTCCTCCGTCTAAGATCT CATAAATCTCCAAACATGGATCCC3\TGCCATCTTCCTGAGCTTCCAJACACCTGCTCCGA GGAAAGGTGCGTTTCCTGATGCTTGTAGGAGGGTCCACCCTCTGCGTCAGGGAATTCGGC GGCAACGGCGGnCAACATGGCGTCCCCAGCGCCGCCTGCTTGTGC*CTCCGAGTCCTCAGT AAACTGCTTCGT.LGACTCCCATGTCCTTCACAGCAGACTGAGCCAGTGCCCACAGGTTCAC CCTTTGCCTACACCTGTCCTGCTGCCTGCTGTGGACTTTAGCTTGGGAGATGGAAAACC CAGATGGAGGAGACCAAGGCACAGGACATTCTGGGAGCAGTGACCCTTCTGCTGGAGGGA GTGATGGCAGCACGGGGACAACTGGGACCCACTTGCCTCTCATCCCTCCTGGGGCAGCTT TCTGGACAGGTCCGTCTCCTCCTTGGGGCCCTGCAGAGCCTCCTTGGJACCCAGCTTCCT CCACAGGGCAGGACCACAGCTCACAAG (SEQ ID NO: 152); GCACGTTTAGTGTA.TAAACCTAGGCACGAC TTCGACGAACTATAGAGCTTTTCGTGCGACT CGCTCACTGGGTCTAGGTTAGATAAATCTAG ATTGAGGCAATTCTTCGTAATCTCCAJACCATGTCTGCCCTCTGCCACGGCCGCACCCTCT CGCTCACTACAGAGGCTGAGATCGAAATAGT TATCTGGTTACCCTTGAGCAJAGCGCAGGSL.JCCAGTACGTAGAGGGCGGTGGAGGCTCC CCGTACGCGTCACCATACACGCCTCTTAGAC CATAAATCTCCACATGGCCATCTTCCTGAGCTTCCAJACACCTGCTCCGAGGAAAGGTG CGTTTCCTGATGCTTGTAGGAGGGTCCACCCTCTGCGTCAGGGATTCGGCGGCAACGGC GGCAACATGGCGTCCCCAGCGCCGCCTGCTTGTGACCTCCGAGTCCTCAGTAAACTGCTT CGTGACTCCCATGTCCTTCACAGCAGACTGAGCCAGTGCCCAGAGGTTCACCCTTTGCCT ACACCTGTCCTGCTGCCTGCTGTGGACTTTAGCTTGGGAGAJATGGAAAACCCAGATGGAG GAGACCAAGGCACAGGACATTCTGGGAGCAGTGACCCTTCTGCTGGAGGGAGTGATGGCA GCACGGGGACAACTGGGACCCACTTGCCTCTCATCCCTCCTGGGGCAGCTTTCTGGACAG GTCCGTCTCCTCCTTGGGGCCCTGCAGAGCCTCCTTGACCCAGCTTCCTCCACAGGGC AGGACCACAGCTCACAAGGATCCCAAT (SEQ ID NO: 153); and GCTAACTGCTCTATAATGATCGATGAJATTATACATCACTTAAGAGACCACCTGCACCT TTCGACGAACTATAGAGCTTTTCGTGCGACT CGCTCACTGGGTCTAGGTTAGATAAATCTAG ATTGAGGCAATTCTTCGTATCTCCACCATGTCTGCCCTCTGCCACGGCCGCACCCTCT CGCTCACTACAGAGGCTGAGATCGAAATAGT TATCTGGTTACCCTTGAGCAAGCGCAGGAJACJCAGTACGTAGAGGGCGGTGGAGGCTCC CCGTACGCGTCACCATACACGCCTCTTAGAC WO 97/12985 PCT/US96/1 5774 608 CATAAATCTCCAAACATGGATCCCAATGCCATCTTCCTGAGCTTCCAACACCTGCTCCGA GGAAAGGTGCGTTTCCTGATGCTTGTAGGAGGGTCCACCCTCTGCGTCAGGGAATTCGGC GGCAACATGGCGTCTCCCGCTCCGCCTGCTTGTGACCTCCGAGTCCTCAGTAAACTGCTT CGTGACTCCCATGTCCTTCACAGCAGACTGAGCCAGTGCCCAGAGGTTCACCCTTTGCCT ACACCTGTCC:'GCTGCCTGCTGTGGACTTTAGCTTGGGAGAATGGAAAACCCAGATGGAG GAGACCAAGGCACAGGACATTCTGGGAGCAGTGACCCTTCTGCTGGAGGGAGTGATGGCA GCACGGGGACAACTGGGACCCACTTGCCTCTCATCCCTCCTGGGGCAGCTTTCTGGACAG GTCCGTCTCCTCCTTGGGGCCCTGCAGAGCCTCCTTGGAACCCAGGGCAGGACCACAGCT CACAAG (SEQ ID NO:154). 32. A method of producing a hematopoietic protein comprising: growing under suitable nutrient conditions, a host cell transformed or transfected with a replicable vector comprising a nucleic acid molecule of claim 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 in a manner allowing expression of said hematopoietic protein and recovering said hematopoietic protein. 33. A pharmaceutical composition comprising; the hematopoietic protein according to claim 1, 2, 3, 4, 5, 6, 7, 8, 10, 11, 12, 13 or 14 and a pharmaceutically acceptable carrier. 34. A method of stimulating the production of hematopoietic cells in a patient comprising the step of; administering an effective amount of the hematopoietic protein as recited in claim 1, 2, 3, 4, 5, 6, 7, 8, 10, 11, 12, 13 or 14 to said patient. 35. A method of stimulating the production of hematopoietic cells in a patient comprising the step of; administering an effective amount of the hematopoietic protein as recited in claim 9 to said patient. 36. A method for selective ex vivo expansion of stem cells, comprising the steps of; separating stem cells from other cells; WO 97/12985 PCTIUS96/1 5774 609 culturing said separated stem cells with a selected culture medium comprising; the hematopoietic protein of claim 1, 2, 3, 4, 5, 6, 7, 8, 10, 11, 12, 13 or 14; and harvesting said cultured cells. 37. A method for selective ex vivo expansion of stem cells, comprising the steps of; separating stem cells from other cells; culturing said separated stem cells with a selected culture meuium comprising; the hematopoietic protein of claim 9; and harvesting said cultured cells. 38. A method for treatment of a patient having a hematopoietic disorder, comprising the steps of; removing stem cells; separating stem cells from other cells; culturing said separated stem cells with a selected culture medium comprising; the hematopoietic protein of claim 1, 2, 3, 4, 5, 6, 7, 8, 10, 11, 12, 13 or 14; harvesting said cultured cells; and transplanting said cultured cells into said patient. 39. A method for treatment of a patient having a hematopoietic disorder, comprising the steps of; removing stem cells; separating stem cells from other cells; culturing said separated stem cells with a selected culture medium comprising; the hematopoietic protein of claim 9; harvesting said cultured cells; and transplanting said cultured cells into said patient. WO 97/12985 PCT/US96/15774 610 A method of human gene therapy, comprising the steps of; removing stem cells from a patient; separating said stem cells from other cells; culturing said separated stem cells with a selected culture medium comprising; the hematopoietic protein of claim 1, 2, 3, 4, 5, 6, 7, 8, 10, 11, 12, 13 or 14; introducing DNA into said cultured cells; harvesting said transduced cells; and transplanting said transduced cells into said patient. 41. A method of human gene therapy, comprising the steps of; removing stem cells from a patient; separating said stem cells from other cells; culturing said separated stem cells with a selected culture medium comprising; the hematopoietic protein of claim 1, 2, 3, 4, 5, 6, 7, 8, 10, 11, 12, 13 or 14; introducing DNA into said cultured cells; harvesting said transduced cells; and transplanting said transduced cells into said patient.