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NZ758119B2 - Immunomodulating polynucleotides, antibody conjugates thereof, and methods of their use - Google Patents
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NZ758119B2 - Immunomodulating polynucleotides, antibody conjugates thereof, and methods of their use - Google Patents

Immunomodulating polynucleotides, antibody conjugates thereof, and methods of their use Download PDF

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Publication number
NZ758119B2
NZ758119B2 NZ758119A NZ75811918A NZ758119B2 NZ 758119 B2 NZ758119 B2 NZ 758119B2 NZ 758119 A NZ758119 A NZ 758119A NZ 75811918 A NZ75811918 A NZ 75811918A NZ 758119 B2 NZ758119 B2 NZ 758119B2
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NZ
New Zealand
Prior art keywords
conjugate
oligonucleotide
cell
cpg
immunomodulating
Prior art date
Application number
NZ758119A
Other versions
NZ758119A (en
Inventor
Curt W Bradshaw
Iacono Giuseppe Dello
Laxman Eltepu
Edward Hyungsuk Ha
Ayman Kabakibi
Son Lam
Bin Liu
Dingguo Liu
Bryan R Meade
Sukumar Sakamuri
Original Assignee
Tallac Therapeutics Inc
Filing date
Publication date
Application filed by Tallac Therapeutics Inc filed Critical Tallac Therapeutics Inc
Priority claimed from PCT/EP2018/059554 external-priority patent/WO2018189382A1/en
Publication of NZ758119A publication Critical patent/NZ758119A/en
Publication of NZ758119B2 publication Critical patent/NZ758119B2/en

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    • A61K2039/507—Comprising a combination of two or more separate antibodies
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Abstract

Immunomodulating polynucleotides are disclosed. The immunomodulating polynucleotides may contain 5-modified uridine, 5-modified cytidine, a total of from 6 to 16 nucleotides, and/or one or more abasic spacers and/or internucleoside phosphotriesters. Also disclosed are conjugates containing a targeting moiety and one or more immunomodulating polynucleotides. The immunomodulating polynucleotides and conjugates may further contain one or more auxiliary moieties. Also disclosed are compositions containing the immunomodulating polynucleotides or the conjugates containing one or more stereochemically enriched internucleoside phosphorothioates. Further disclosed are pharmaceutical compositions containing the immunomodulating polynucleotides or the conjugates and methods of their use.

Claims (333)

What we claim is:
1. An ucleotide of Formula (A): or a stereoisomer, a mixture of two or more reomers, a tautomer, or a mixture of two or more ers thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein: each XN is independently a nucleotide; X3’ is a 3’ terminal nucleotide; X5’ is a 5’ terminal nucleotide; YP is an internucleoside phosphotriester; and b and c are each an integer ranging from about 0 to about 25; with the proviso that their sum is no less than 5; wherein X5’ comprises a 5-halo-2’-deoxyuridine; and n the ucleotide comprises one, two, or three CG dinucleotides.
2. The oligonucleotide of claim 1, wherein b is an integer ranging from about 1 to about
3. The oligonucleotide of claim 1, wherein b is an integer of about 3, about 4, about 11, or about 14.
4. The oligonucleotide of claim 1, wherein b is an integer of about 3.
5. The oligonucleotide of claim 1, wherein b is an integer of about 4.
6. The oligonucleotide of claim 1, wherein b is an integer of about 11.
7. The oligonucleotide of claim 1, wherein b is an integer of about 14.
8. The oligonucleotide of any one of claims 1 to 7, wherein c is an integer ranging from about 0 to about 10.
9. The oligonucleotide of any one of claims 1 to 7, wherein c is an integer of about 0 or about 8.
10. The ucleotide of any one of claims 1 to 7, wherein c is an integer of about 0.
11. The oligonucleotide of any one of claims 1 to 7, wherein c is an integer of about 8.
12. The oligonucleotide of any one of claims 1 to 11, wherein the sum of b and c is ranging from about 5 to about 20.
13. The oligonucleotide of any one of claims 1 to 11, wherein the sum of b and c is ranging from about 5 to about 15.
14. The oligonucleotide of any one of claims 1 to 11, wherein the sum of b and c is about 8, about 9, about 10, about 11, about 12, about 13, or about 14.
15. The oligonucleotide of any one of claims 1 to 11, wherein the sum of b and c is about 11 or about 14.
16. The oligonucleotide of any one of claims 1 to 11, wherein the sum of b and c is about 11.
17. The oligonucleotide of any one of claims 1 to 11, wherein the sum of b and c is about 14.
18. The oligonucleotide of any one of claims 1 to 17, wherein each XN is independently a 2’-deoxyribonucleotide.
19. The ucleotide of any one of claims 1 to 17, wherein each XN is independently 2’-deoxyadenosine, 2’-deoxyguanosine, 2’-deoxycytidine, a 5-halo-2’-deoxycytidine, 2’- deoxythymidine, 2’-deoxyuridine, or a 5-halo-2’-deoxyuridine.
20. The oligonucleotide of any one of claims 1 to 17, wherein each XN is ndently 2’-deoxyadenosine, 2’-deoxyguanosine, 2’-deoxycytidine, 2’-deoxythymidine, 5-bromo-2’- deoxyuridine, or -2’-deoxyuridine.
21. The oligonucleotide of any one of claims 1 to 20, wherein X3’ is a 2’- deoxyribonucleotide.
22. The oligonucleotide of any one of claims 1 to 20, wherein X3’ is 2’-deoxyadenosine, 2’-deoxyguanosine, 2’-deoxycytidine, a 5-halo-2’-deoxycytidine, 2’-deoxythymidine, 2’- deoxyuridine, or a -2’-deoxyuridine.
23. The oligonucleotide of any one of claims 1 to 20, wherein X3’ is 2’- deoxythymidine.
24. The oligonucleotide of any one of claims 1 to 20, wherein X3’ is a 2’-modified ribonucleotide.
25. The oligonucleotide of any one of claims 1 to 20, wherein X3’ is a 2’-methoxy ribonucleotide or 2’-ethoxymethoxy ribonucleotide.
26. The ucleotide of any one of claims 1 to 25, wherein X5’ comprises 5-bromo- 2’-deoxyuridine or 5-iodo-2’-deoxyuridine.
27. The oligonucleotide of any one of claims 1 to 26, wherein X5’ comprises a 3’- phosphorothioate group.
28. The oligonucleotide of claim 27, wherein the 3’-phosphorothioate is chiral.
29. The oligonucleotide of claim 27, wherein the 3’-phosphorothioate has a chirality of
30. The oligonucleotide of claim 27, wherein the 3’-phosphorothioate has a chirality of
31. The ucleotide of any one of claims 1 to 26, wherein X5’ comprises a 3’- phosphorothioate group having a chirality of Rp and X3’ is a 2’-methoxy cleotide or 2’- ethoxymethoxy ribonucleotide.
32. The oligonucleotide of any one of claims 1 to 26, wherein X5’ comprises a 3’- phosphorothioate group having a chirality of Sp and X3’ is a 2’-methoxy ribonucleotide or 2’- ethoxymethoxy ribonucleotide.
33. The oligonucleotide of any one of claims 1 to 32, wherein YP is: wherein Z is O or S; and d is an integer ranging from about 0 to about 50.
34. The oligonucleotide of any one of claims 1 to 32, wherein YP is: wherein Z is O or S; and d is an r ranging from about 0 to about 50.
35. The oligonucleotide of claim 33 or 34, wherein Z is O.
36. The oligonucleotide of claim 33 or 34, wherein Z is S.
37. The oligonucleotide of any one of claims 33 to 36, wherein d is an integer ranging from about 0 to about 10.
38. The oligonucleotide of claim 37, wherein d is an integer g from about 0 to about 5.
39. The oligonucleotide of claim 37, wherein d is an r of about 0, about 1, or about
40. The oligonucleotide of any one of claims 1 to 39, comprising an additional internucleoside phosphotriester.
41. The ucleotide of claim 40, wherein the onal internucleoside phosphotriester is an alkylphosphotriester.
42. The oligonucleotide of claim 40, wherein the additional internucleoside otriester is ethylphosphotriester.
43. The oligonucleotide of any one of claims 1 to 42, comprising one 5-halo-2’- deoxyuridine.
44. The oligonucleotide of claim 43, wherein the 5-halo-2’-deoxyuridine is 5-bromo-2’- deoxyuridine or 5-iodo-2’-deoxyuridine.
45. The oligonucleotide of any one of claims 1 to 44, comprising three or more 2’- deoxycytidines.
46. The oligonucleotide of any one of claims 1 to 45, comprising three 2’- deoxycytidines.
47. The oligonucleotide of any one of claims 1 to 46, comprising three or more 2’- deoxyguanosines.
48. The oligonucleotide of any one of claims 1 to 47, comprising four 2’- deoxyguanosines.
49. The oligonucleotide of any one of claims 1 to 48, comprising three 2’- deoxycytidines and three 2’-deoxyguanosines.
50. The oligonucleotide of any one of claims 1 to 49, comprising three 2’- deoxycytidines and four 2’-deoxyguanosines.
51. The oligonucleotide of any one of claims 1 to 50, comprising three or more 2’- deoxythymidines.
52. The oligonucleotide of claim 51, comprising three, four, five, six, seven, or eight 2’- deoxythymidines.
53. The oligonucleotide of claim 51, comprising three, four, five, or eight 2’- deoxythymidines.
54. The oligonucleotide of any one of claims 1 to 53, sing zero, one, or two 2’- deoxyadenosines.
55. The oligonucleotide of any one of claims 1 to 54, comprising one or more internucleoside phosphorothioates.
56. The oligonucleotide of claim 55, wherein at least one of the internucleoside phosphorothioates is chiral.
57. A compound of Formula (B): or a stereoisomer, a mixture of two or more diastereomers, a tautomer, or a mixture of two or more tautomers; or a pharmaceutically acceptable salt, e, or e thereof; wherein: Rx is a conjugating group; LN is a linker; each Q is independently the ucleotide of any one of claims 1-56; and e is an integer of 1, 2, 3, or 4.
58. The compound of claim 57, wherein Rx is .
59. The compound of claim 57, wherein Rx is –NH2.
60. A compound of Formula (C): or a stereoisomer, a e of two or more diastereomers, a tautomer, or a mixture of two or more tautomers thereof; or a ceutically acceptable salt, e, or hydrate thereof; wherein: Ab is an antibody; each LN is independently a linker; each Q is independently the oligonucleotide of any one of claims 1-56; each e is independently an integer of 1, 2, 3, or 4; and f is an integer of 1, 2, 3, or 4.
61. The compound of claim 60, wherein f is an integer of 1 or 2.
62. The compound of claim 60, wherein f is an integer of 1.
63. The compound of any one of claims 57 to 62, wherein LN is a linker comprising a polyethylene glycol.
64. The compound of any one of claims 57 to 63, wherein LN is , wherein d is an integer ranging from about 0 to about 50.
65. The compound of any one of claims 57 to 63, wherein LN is , wherein d is an integer ranging from about 0 to about 50.
66. The compound of claim 64 or 65, wherein d is an integer g from about 0 to about 10.
67. The compound of claim 66, wherein d is an integer ranging from about 0 to about 5.
68. The nd of claim 66, wherein d is an integer of about 0, about 1, or about 3.
69. The compound of any one of claims 57 to 68, wherein e is an integer of 1.
70. The oligonucleotide of claim 1, wherein the oligonucleotide comprises a sequence of N1N2CGN3CG(T)xGN4CGN5T, wherein: x is an integer ranging from 1 to 4; N1 is absent; N2 is a 5-halo-2’-deoxyuridine; N3 is 2’-deoxyadenosine or 2’-deoxythymidine, each optionally comprising a 3’- phosphotriester; N4 is 2’-deoxyadenosine or 2’-deoxythymidine; and N5 is 2’-deoxythymidine optionally comprising a 3’-phosphotriester.
71. The oligonucleotide of claim 70, wherein x is an integer of 1 or 4.
72. The oligonucleotide of claim 70 or 71, wherein x is an r of 1.
73. The oligonucleotide of any one of claims 70 to 72, wherein N2 is o-2’- deoxyuridine or 5-iodo-2’-deoxyuridine.
74. The oligonucleotide of any one of claims 70 to 73, wherein N3 is 2’-deoxyadenosine comprising a 3’-phosphotriester.
75. The ucleotide of any one of claims 70 to 73, wherein N3 is 2’-deoxythymidine.
76. The oligonucleotide of any one of claims 70 to 73, wherein N3 is 2’-deoxythymidine comprising a 3’-phosphotriester.
77. The oligonucleotide of any one of claims 70 to 76, wherein N4 is 2’-deoxyadenosine.
78. The oligonucleotide of any one of claims 70 to 76, n N4 is 2’-deoxythymidine.
79. The oligonucleotide of any one of claims 70 to 78, wherein N5 is 2’-deoxythymidine.
80. The oligonucleotide of any one of claims 70 to 78, n N5 is 2’-deoxythymidine comprising a 3’-phosphotriester.
81. The oligonucleotide of any one of claims 70 to 80, comprising one or more internucleoside phosphorothioates.
82. The oligonucleotide of claim 81, wherein at least one of the internucleoside orothioates is chiral.
83. The oligonucleotide of claim 70, having the sequence of SEQ ID NO: p236, p238, p243, p246, p275, p276, p361, or p362.
84. An immunomodulating polynucleotide comprising the oligonucleotide of any one of claims 1 to 56.
85. A conjugate sing an antibody or an antibody nt and one or more immunomodulating polynucleotides, the antibody or the dy fragment comprising a Q-tag, and each of the immunomodulating polynucleotides ndently comprising the oligonucleotide of any one of claims 1 to 56 covalently bonded to the Q-tag.
86. The conjugate of claim 85, n the Q-tag is an N-terminal Q-tag.
87. The conjugate of claim 85, wherein the Q-tag is a C-terminal Q-tag.
88. The conjugate of any one of claims 85 to 87, wherein the Q-tag is disposed in a heavy chain of the antibody or the antibody fragment.
89. The conjugate of any one of claims 85 to 87, wherein the Q-tag is disposed in a light chain of the antibody or the antibody fragment.
90. A conjugate comprising a targeting moiety and one or more immunomodulating polynucleotides, each of the immunomodulating polynucleotides comprising independently the oligonucleotide of any one of claims 1 to 56 and a linker, wherein the targeting moiety is covalently bonded to the linker.
91. The conjugate of any one of claims 85 to 89, wherein at least one of the immunomodulating polynucleotides ses ne and guanosine as the second and third nucleosides.
92. The conjugate of any one of claims 85 to 89, wherein at least one of the immunomodulating polynucleotides comprises cytidine and ine as the third and fourth nucleosides.
93. The conjugate of any one of claims 85 to 92, wherein at least one of the immunomodulating polynucleotides comprises a total of from 6 to 16 nucleotides.
94. A conjugate comprising a targeting moiety and one or more immunomodulating polynucleotides, each of the immunomodulating polynucleotides comprising independently the oligonucleotide of any one of claims 1 to 56 and a linker, wherein the targeting moiety is covalently bonded to the linker, at least one of the immunomodulating polynucleotides comprising a total of 6 to 16 nucleotides.
95. A conjugate comprising a targeting moiety and one or more immunomodulating cleotides, each of the immunomodulating cleotides comprising independently the oligonucleotide of any one of claims 1 to 56 and a linker, wherein the targeting moiety is covalently bonded to the linker, at least one of the immunomodulating cleotides comprising one or more abasic spacers or internucleoside phosphotriesters.
96. The conjugate of claim 95, wherein at least one abasic spacer or at least one phosphotriester comprises the .
97. The conjugate of any one of claims 85 to 96, wherein at least one of the immunomodulating polynucleotides comprises one or more abasic spacers.
98. The conjugate of claim 97, wherein the one or more internucleoside abasic spacers are one or two abasic s.
99. The conjugate of any one of claims 95 to 98, n at least one of the abasic s is an internucleoside abasic spacer.
100. The conjugate of any one of claims 95 to 99, wherein at least one of the abasic spacers is a 3’-terminal abasic spacer.
101. The conjugate of any one of claims 85 to 100, wherein at least one of the immunomodulating polynucleotides comprises one or more ucleoside phosphotriesters.
102. The ate of claim 101, wherein the one or more internucleoside phosphotriesters are from one to five internucleoside phosphotriesters.
103. The conjugate of any one of claims 85 to 102, wherein the conjugate further comprises one or more auxiliary moieties bonded to the linker.
104. A conjugate comprising a targeting moiety, one or more auxiliary moieties, and one or more immunomodulating polynucleotides, each of the immunomodulating polynucleotides comprising independently the oligonucleotide of any one of claims 1 to 56 and a linker bonded to the targeting moiety.
105. The conjugate of claim 103 or 104, wherein at least of the one auxiliary moieties comprises a poly(ethylene glycol) (PEG) having a molecular weight of from 100 Da to 2,500 Da.
106. The conjugate of claim 105, wherein each PEG comprises independently a total of at least 3 ne glycol repeating units.
107. The conjugate of claim 105 or 106, wherein each PEG comprises ndently a total of at least 20 ethylene glycol repeating units.
108. The conjugate of any one of claims 105 to 107, wherein each PEG comprises independently a total of 50 or fewer ethylene glycol repearing units.
109. The conjugate of any one of claims 105 to 108, wherein the conjugate comprises from one to eight PEGs.
110. The conjugate of any one of claims 90 to 109, wherein the targeting moiety is an antigen-binding moiety, a polypeptide, an aptamer, or a group including one or more small molecules.
111. The conjugate of claim 110, wherein the targeting moiety is an antigen-binding moiety.
112. The conjugate of claim 110, wherein the targeting moiety is an antibody or an antigen-binding fragment thereof.
113. The conjugate of any one of claims 85 to 112, wherein a 5’-capping group in at least one of the immunomodulating polynucleotides is selected from the group consisting of monophosphate, diphosphate, triphosphate, an auxiliary moiety, a terminal odiester, a terminal phosphotriester, and a group –OR’, wherein R’ is selected from the group consisting of a bioreversible group, a non-bioreversible group, and an O-protecting group.
114. The conjugate of claim 113, wherein the 5’-capping group is monophosphate or the al phosphodiester comprising optionally substituted C1-6 alkyl bonded to phosphate, phosphorothioate, or phosphorodithioate.
115. The ate of any one of claims 85 to 114, wherein a 3’-capping group in at least one of the immunomodulating polynucleotides is selected from the group consisting of monophosphate, phate, triphosphate, an auxiliary moiety, a terminal phosphodiester, a terminal phosphotriester, and a group –OR’, wherein R’ is ed from the group consisting of a bioreversible group, a non-bioreversible group, and an O-protecting group.
116. The conjugate of claim 115, wherein the 3’-capping group is monophosphate or the terminal odiester sing optionally substituted C1-6 alkyl bonded to phosphate, orothioate, or phosphorodithioate.
117. The conjugate of any one of claims 85 to 116, wherein at least one of immunomodulating polynucleotides comprises a nucleobase bonded to the linker.
118. The conjugate of any one of claims 85 to 117, wherein the ate comprises from one to six immunomodulating polynucleotides.
119. The conjugate of claim 118, n the conjugate comprises from one to four immunomodulating polynucleotides.
120. The conjugate of claim 119, wherein the conjugate comprises only one immunomodulating polynucleotide.
121. The conjugate of claim 120, wherein the conjugate comprises only two immunomodulating polynucleotides.
122. The conjugate of any one of claims 85 to 121, wherein the conjugate comprises one ing moiety.
123. The ate of any one of claims 85 to 119, wherein the immunomodulating polynucleotide comprises a human immunostimulating sequence within four 5’-terminal nucleotides.
124. The conjugate of claim 123, wherein the human immostimulating sequence within four 5’-terminal nucleotides of the immunomodulating polynucleotide comprises ne comprising a 5’-carbon atom bonded to a phosphoester substituted with a nucleoside.
125. The conjugate of any one of claims 85 to 124, wherein at least one of the immunomodulating polynucleotides is hybridized to its ment.
126. A composition comprising the conjugate of any one of claims 85 to 125, wherein at least one of the immunomodulating polynucleotides comprises at least one stereochemically enriched internucleoside phosphorothioate.
127. A composition comprising a conjugate comprising a targeting moiety and one or more immunomodulating polynucleotides, each of the immunomodulating polynucleotides comprising independently the oligonucleotide of any one of claims 1 to 56 and a linker, wherein the targeting moiety is covalently bonded to the linker, at least one of the immunomodulating polynucleotides comprising at least one stereochemically enriched internucleoside phosphorothioate.
128. The composition of claim 126 or 127, wherein at least one stereochemically ed internucleoside phosphorothioate is disposed between a 5’-terminal nucleoside and cytidine of CpG in an immunostimulating sequence in the immunomodulating polynucleotide.
129. The composition of claim any one of claims 126 to 128, wherein the stereochemically enriched internucleoside phosphorothioate is S-stereogenic.
130. The ition of claim any one of claims 126 to 128, wherein the stereochemically enriched internucleoside phosphorothioate is R-stereogenic.
131. The ition of any one of claims 126 to 130, wherein at least one stereochemically enriched internucleoside phosphorothioate is bonded to 5’-carbon atom of cytidine of CpG in an immunostimulating sequence in the immunomodulating polynucleotide.
132. The composition of claim 131, wherein the stereochemically enriched internucleoside phosphorothioate is S-stereogenic.
133. The composition of claim 131, wherein the stereochemically enriched internucleoside phosphorothioate is R-stereogenic.
134. The composition of any one of claims 126 to 133, n at least one stereochemically enriched internucleoside phosphorothioate connects the first and the second nucleosides in the immunomodulating polynucleotide.
135. The composition of claim 134, wherein the stereochemically ed internucleoside phosphorothioate is S-stereogenic.
136. The composition of claim 134, wherein the stereochemically enriched internucleoside phosphorothioate is eogenic.
137. The composition of any one of claims 126 to 136, n at least one stereochemically enriched ucleoside phosphorothioate connects the fourth and the fifth nucleosides in the immunomodulating cleotide.
138. The composition of claim 137, n the stereochemically enriched internucleoside phosphorothioate is S-stereogenic.
139. The composition of claim 137, wherein the stereochemically enriched internucleoside orothioate is R-stereogenic.
140. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the immunomodulating polynucleotide of any one of claim 84, the conjugate of any one of claims 85 to 125, or the composition of any one of claims 126 to 139.
141. Use of the immunomodulating polynucleotide of claim 84, the conjugate of any one of claims 85 to 125, the composition of any one of claims 126 to 139, or the pharmaceutical composition of claim 140 in the manufacture of a medicament for modulating an endosomal tolllike receptor in a cell comprising the mal toll-like receptor.
142. The use of claim 141, wherein the immunomodulating polynucleotide is an immunostimulating cleotide, and wherein the method is for agonizing an endosomal toll-like receptor.
143. The use of claim 141, wherein the immunomodulating polynucleotide is an immunosuppressive cleotide, and wherein the method is for antagonizing an endosomal tolllike receptor.
144. Use of the immunomodulating polynucleotide of claim 84, the conjugate of any one of claims 85 to 125, the composition of any one of claims 126 to 139, or the pharmaceutical composition of claim 140 in the manufacture of a medicament for inducing one or more cytokines in an n-presenting cell comprising an mal toll-like receptor.
145. The use of claim 144, wherein the antigen-presenting cell is a B cell.
146. The use of claim 144 or 145, wherein at least one of the one or more cytokines is an inflammatory cytokine.
147. The use of claim 144, wherein the antigen-presenting cell is a plasmacytoid tic cell, and wherein the targeting moiety recognizes the plasmacytoid dendritic cell.
148. The use of claim 144, wherein the n-presenting cell is a macrophage.
149. The use of claim 144, wherein at least one of the cytokines is a type I interferon.
150. The use of any one of claims 141 to 148, wherein the toll-like receptor is TLR9.
151. Use of the immunomodulating polynucleotide of claim 84, the conjugate of any one of claims 85 to 125, the composition of any one of claims 126 to 139, or the pharmaceutical composition of claim 140 in the manufacture of a medicament for treating a liquid tumor, wherein the targeting moiety targets B cells, and n the immunomodulating polynucleotide is an immunostimulating polynucleotide that is a TLR9 agonist.
152. The use of claim 151, wherein the liquid tumor is a hematologic tumor.
153. The use of claim 152, wherein the hematologic tumor is a lymphoma.
154. The use of claim 153, wherein the lymphoma is a non-Hodgkin B-cell lymphoma.
155. The use of claim 153, wherein the ma is mantle cell lymphoma, diffuse large B cell ma, follicular lymphoma, chronic lymphocytic leukemia, or multiple myeloma.
156. Use of the composition of any one of claims 126 to 139 or the pharmaceutical composition of claim 140 in the manufacture of a medicament for the ent of a solid tumor, wherein the targeting moiety s plasmacytoid tic cells, and wherein the immunomodulating polynucleotide is an immunostimulating polynucleotide that is a TLR9 agonist.
157. The immunomodulating polynucleotide of claim 84, wherein the immunomodulating polynucleotide is an immunostimulating polynucleotide.
158. The conjugate of any one of claims 85 to 125, wherein the immunomodulating polynucleotide is an immunostimulating polynucleotide.
159. The ition of any one of claims 126 to 139, wherein the modulating polynucleotide is an immunostimulating polynucleotide.
160. The pharmaceutical composition of claim 140, wherein the immunomodulating polynucleotide is an immunoastimulating polynucleotide.
161. The immunomodulating polynucleotide of claim 84, wherein the immunomodulating polynucleotide is an immunosuppressive polynucleotide.
162. The ate of any one of claims 85 to 125, wherein the modulating polynucleotide is an immunosuppressive polynucleotide.
163. The composition of any one of claims 126 to 139, wherein the immunomodulating polynucleotide is an immunosuppressive polynucleotide.
164. The pharmaceutical composition of claim 140, wherein the immunomodulating polynucleotide is an immunosuppressive polynucleotide.
165. Use of a eutically effective amount of the immunomodulating polynucleotide of claim 84, the conjugate of any one of claims 85 to 125, the composition of any one of claims 126 to 139, or the pharmaceutical composition of claim 140 in the manufacture of a medicament for the treatment of .
166. The use of claim 165, wherein the cancer is liquid tumor.
167. The use of claim 166, n the liquid tumor is a hematologic tumor.
168. The use of claim 167, wherein the hematologic tumor is a lymphoma.
169. The use of claim 168, wherein the lymphoma is a non-Hodgkin B-cell lymphoma, a mantle cell lymphoma, a diffuse large B-cell ma, a follicular ma, a chronic lymphocytic leukemia, or multiple myeloma.
170. The use of claim 165, wherein the cancer is a solid tumor.
171. The use of claim 170, wherein the solid tumor is a colon carcinoma, a melanoma, or a head&neck .
172. The use of claim 165, wherein the targeting moiety is an antibody or antibody
173. The use of any one of claims 165 to 172, wherein the targeting moiety binds an antigen on an antigen presenting cell (APC).
174. The use of claim 173, wherein the APC is a B-cell, a plasmacytoid dendritic cell (pDC) or a macrophage.
175. The use of claim 173, wherein the antigen is CD19, CD20, CD22, CD30, CD38, CD79 or CD79b. CD205, BDCA2, BDCA4 or PD-L1.
176. The use of any one of claims 165 to 175, wherein the treatment comprises administering the conjugate systemically.
177. The use of claim 176, wherein the treatment comprises administering the conjugate by intravenous injection (i.v.).
178. The use of any one of claims 165 to 177, wherein the immunomodulating polynucleotide is a TLR9 agonist.
179. The use of any one of claims 165 to 178, wherein the amount is effective to raise an adaptive immune se to the cancer.
180. The use of claim 179, wherein the amount is effective to increase cell-mediated immunity.
181. The use of claim 179, wherein the amount is effective to increase T-cell tumor infiltrates in a solid tumor.
182. The use of claim 181, wherein the T-cell is a CD4+ or CD8+ T-cell.
183. The use of claim 179, wherein the amount is effective to raise a sustained anti-tumor immunity in the patient.
184. The use of any one of claims 165 to 183, wherein the amount is effective to inhibit tumor growth or reduce tumor size in the subject.
185. The use of any one of claims 165 to 184, wherein the administration of the conjugate results in a lesser increase of an inflammatory cytokine in the subject relative to an administration of the immunomodulating polynucleotide in an unconjugated form.
186. The use of claim 185, wherein the inflammatory ne is IL-6, IL-10 or TNF?.
187. The use of any one of claims 165 to 186, n the amount is not effective to activate the complement pathway in the subject.
188. The use of claim 187, wherein the amount is not effective to activate complement C3 in the subject.
189. The use of any one of claims 165 to 188, wherein the cancer is a oint inhibitor relapsed or refractory .
190. The use of claim 189, wherein the checkpoint inhibitor is a PD-1 inhibitor, PD-L1 inhibitor, or CTLAinhibitor.
191. The use of any of claims 165 to 190, wherein the treatment comprises administering a oint inhibitor to the subject.
192. The use of claim 191, wherein the checkpoint inhibitor is a PD-1 inhibitor, a PD-L1 inhibitor or a CTLA-4 inhibitor.
193. The use of claim 191, wherein the checkpoint inhibitor is an anti-PD1 antibody, an anti-PD-L1 dy or an anti-CTLA-4 antibody.
194. The use of any one of claims 165 to 193, wherein the treatment comprises administering a T-cell agonist to the subject.
195. The use of claim 194, n the T-cell agonist is a OX-40, ICOS, or 4-1 BB agonist.
196. Use of the immunomodulating polynucleotide of claim 84, the conjugate of any one of claims 85 to 125, the composition of any one of claims 126 to 139, or the ceutical ition of claim 140 to the subject in the manufacture of a medicament for treating a non B- cell tumor, wherein the ing moiety binds to a B-cell antigen.
197. Use of the modulating polynucleotide of claim 84, the conjugate of any one of claims 85 to 125, the composition of any one of claims 126 to 139, or the pharmaceutical composition of claim 140 in the manufacture of a medicament for the treatment of a solid tumor, wherein the targeting moiety binds to a B-cell antigen.
198. Use of the immunomodulating cleotide of claim 84, the conjugate of any one of claims 85 to 125, the composition of any one of claims 126 to 139, or the pharmaceutical composition of claim 140 to the subject in the manufacture of a medicament for the treatment of a liquid tumor, wherein the targeting moiety binds an APC antigen.
199. The use of claim 198, wherein the APC antigen is a pDC or a macrophage antigen.
200. Use of the immunomodulating polynucleotide of claim 84, the conjugate of any one of claims 85 to 125, the composition of any one of claims 126 to 139, or the pharmaceutical composition of claim 140 and a checkpoint inhibitor in the cture of a medicament for treating cancer.
201. The use of claim 200, wherein the checkpoint inhibitor is a PD-1 inhibitor, a PD-L1 inhibitor or a CTLA-4 inhibitor.
202. The use of claim 201, wherein the checkpoint inhibitor is an anti-PD1 antibody, an anti-PD-L1 antibody or an anti-CTLA-4 antibody.
203. Use of the modulating polynucleotide of claim 84, the conjugate of any one of claims 85 to 125, the composition of any one of claims 126 to 139, or the pharmaceutical composition of claim 140 and a T-cell agonist in the manufacture of a medicament for the treatment of cancer.
204. The use of claim 203, wherein the T-cell agonist is a OX-40, ICOS, or 4-1 BB agonist.
205. A pharmaceutical ition, comprising the immunomodulating polynucleotide of claim 84, the ate of any one of claims 85 to 125, the ition of any one of claims 126 to 139, or the pharmaceutical composition of claim 140, and a checkpoint inhibitor.
206. The pharmaceutical composition of claim 205, further comprising a pharmaceutically acceptable excipient or solvent.
207. A pharmaceutical ition, comprising the immunomodulating polynucleotide of claim 84, the conjugate of any one of claims 85 to 125, the composition of any one of claims 126 to 139, or the pharmaceutical composition of claim 140, and a T-cell agonist.
208. The pharmaceutical ition of claim 207, further comprising a ceutically acceptable excipient or solvent.
209. A conjugate of any one of claims 85 to 125, the ition of any one of claims 126 to 139, or the pharmaceutical composition of claim 140, wherein the targeting moiety binds to an APC antigen and wherein the conjugate is e of suppressing proliferation of a liquid tumor or a solid tumor in a subject.
210. A conjugate of any one of claims 85 to 125, the composition of any one of claims 126 to 139, or the pharmaceutical ition of claim 140, wherein the targeting moiety binds to a B-cell antigen and wherein the conjugate is capable of suppressing proliferation of a B-cell tumor in a subject.
211. A conjugate of any one of claims 85 to 125, the composition of any one of claims 126 to 139, or the pharmaceutical composition of claim 140, wherein the targeting moiety binds to a B-cell antigen and wherein the conjugate is capable of suppressing proliferation of a non-B-cell tumor in a subject.
212. A conjugate of any one of claims 85 to 125, the composition of any one of claims 126 to 139, or the pharmaceutical composition of claim 140, wherein the targeting moiety binds to a B-cell antigen and wherein the conjugate is capable of suppressing proliferation of a solid tumor in a subject.
213. A conjugate of any one of claims 85 to 125, the composition of any one of claims 126 to 139, or the pharmaceutical composition of claim 140, wherein the targeting moiety binds to a pDC or hage antigen and wherein the conjugate is capable of ssing proliferation of a liquid tumor in a subject.
214. A conjugate of any one of claims 85 to 125, the composition of any one of claims 126 to 139, or the pharmaceutical composition of claim 140, wherein the targeting moiety binds to a pDC or hage antigen and wherein the conjugate is capable of suppressing proliferation of a solid tumor in a subject.
215. A conjugate of any one of claims 85 to 125, the composition of any one of claims 126 to 139, or the ceutical ition of claim 140, wherein the conjugate is capable of increasing cell-mediated immunity.
216. A conjugate of any one of claims 85 to 125, the composition of any one of claims 126 to 139, or the pharmaceutical ition of claim 140, wherein the conjugate is capable of increasing T-cell tumor infiltration in a subject.
217. The ate, composition, or pharmaceutical composition of claim 216, wherein the T-cell is a CD4+ or a CD8+ .
218. A conjugate of any one of claims 85 to 125, the composition of any one of claims 126 to 139, or the pharmaceutical composition of claim 140, wherein the conjugate is capable of raising adaptive anti-tumor immunity in a subject.
219. A conjugate of any one of claims 85 to 125, the composition of any one of claims 126 to 139, or the pharmaceutical composition of claim 140, wherein the conjugate is capable of stimulating IFN? secretion or expression in a subject.
220. A conjugate of any one of claims 85 to 125, the composition of any one of claims 126 to 139, or the pharmaceutical composition of claim 140, wherein the conjugate does not activate the complement y in a subject.
221. A conjugate of any one of claims 85 to 125, the composition of any one of claims 126 to 139, or the pharmaceutical composition of claim 140, wherein the conjugate does not activate complement C3 in the subject.
222. Use of a therapeutically effective amount of a CpG-Ab immunoconjugate in the manufacture of a medicament for the treatment of , wherein the CpG-Ab immunoconjugate comprises the oligonucleotide of any one of claims 1 to 56, and wherein the CpG-Ab conjugate does not bind to a tumor associate antigen (TAA).
223. The use of claim 222, wherein the CpG-Ab immunoconjugate specifically binds to a target antigen associated with a normal immune cell that expresses at least one ike receptor.
224. The use of claim 223, wherein the normal immune cell expresses TLR9.
225. The use of claim 223 or 224, wherein the normal immune cell is an n ting cell (APC).
226. The use of claim 225, wherein the APC is a B cell, a dendritic cells or a macrophage.
227. The use of claim 226, wherein the target antigen is selected from the group consisting of a MHC molecule, a T cell costimulatory molecule, an immune checkpoint le, a B cell specific antigen, a dendritic cell antigen specific antigen and a macrophage specific antigen.
228. The use of claim 227, n the MHC molecule is selected from MHC class I and MHC class II molecules.
229. The use of claim 227 or 228, wherein the T cell costimulatory molecule is selected from the list consisting of OX40, CD2, CD27, CDS, ICAM-1, CD11a/CD18, ICOS/CD278, 4-1BB/CD137, GITR, CD30, CD40, BAFFR, HVEM, CD7, LIGHT, NKG2C, SLAMF7, NKp80, CD160, B7-H3, and CD83.
230. The use of any one of claims 227 to 229, wherein the immune checkpoint molecule is selected from the list consisting of PD-1, PD-L1, PD-L2, TIM-3, LAG-3, CEACAM-1, CEACAM-5, CLTA-4, VISTA, BTLA, TIGIT, LAIR1, CD47, CD160, 2B4, CD172a, and TGFR.
231. The use of any one of claims 227 to 230, wherein the target antigen is selected from the group consisting of CD1, CD2, CD5, CD6, CD9, CD11, CD17, CD18, CD19, CD20, CD21, CD22, CD23, CD24. CD25, CD26, CD27, CD30, CD38, CD40, CD44, CD45R (B220), CD49, CD52, CD56, CD74, CD79b, CD93, CD123, CD138, CD163, CD205, CD206, CD274, CD303, and CD304.
232. The use of any one of claims 222 to 231, wherein the CpG-Ab conjugates comprises an immunostimulating cleotide selected from Table 2.
233. The use of claim 232, wherein the CpG-Ab immunoconjugates comprises an immunostimulating polynucleotide selected from the group consisting of p236, p238, p243, p246, p275, p276, p361, and p362.
234. The use of any one of claims 222 to 233, wherein the CpG-Ab immunoconjugates is not conjugated to a T cell epitope.
235. The use of any one of claims 222 to 233, wherein the T cell epitope is an e of ovalbumin (OVA).
236. Use of a therapeutically effective amount of a CpG-Ab conjugate in the manufacture of a medicament for the treatment of cancer, wherein the CpG-Ab immunoconjugate ses the oligonucleotide of any one of claims 1 to 56, and wherein the CpG-Ab immunoconjugate specifically binds to a tumor associated antigen (TAA), wherein the TAA is not an antigen selected from the group consisting of CD19, CD20, CD22, STAT3, exportin 7, Her2, Src, EGFR, CD52, CXCR-4, Muc-1 and DNA.
237. The use of claim 236, wherein binding of the CpG-Ab immunoconjugate to the TAA facilitates internalization of the CpG-Ab immunoconjugate into a cancer cell expressing the TAA.
238. The use of claim 236 or 237, wherein binding of the CpG-Ab conjugate to the TAA facilitates transportation of the CpG-Ab immunoconjugate to endosome of the cancer cell sing the TAA.
239. The use of any one of claims 236 to 238, wherein binding of the CpG-Ab immunoconjugate to the TAA facilitates activation of a TLR9 signaling pathway in a cancer cell expressing the TAA.
240. The use of claim 239, wherein the TAA and the TLR9 are located on a same cellular membrane of the cancer cell expressing the TAA.
241. The use of claim 240 wherein both the TAA and the TLR9 are located on the cell membrane of the cancer cell expressing the TAA.
242. The use of claim 240, wherein both the TAA and the TLR9 are located on the endosomal membrane of the cancer cell expressing the TAA.
243. The use of any one of claims 236 to 242, wherein binding of the CpG-Ab immunoconjugate to the TAA induces apoptosis of the cancer cell expressing the TAA.
244. The use of any one of claims 236 to 243, wherein the TAA is not expressed by a normal immune cell.
245. The use of any one of claims 236 to 243, wherein the TAA is sed by a normal immune cell.
246. The use of claim 245, wherein the normal immune cell is an antigen presenting cell (APC).
247. The use of any one of claims 236 to 246, wherein the TAA is selected from the group consisting of CD8, CD11b, CD11c, CD14, CD33, CD40, CD123, CD157, CD168, CD169, CD172a, CD200, CD204, CD205, CD301, CD302, CD303, CD304, CD205 and CD206.
248. The use of any one of claims 236 to 247, wherein the CpG-Ab immunoconjugate is not conjugated to the TAA or any other TAA expressed by the cancer.
249. The use of any one of claims 236 to 249, wherein the CpG-Ab immunoconjugates ses an stimulating polynucleotide selected from Table 2.
250. The use of claim 249, wherein the CpG-Ab immunoconjugates comprises an immunostimulating polynucleotide selected from the group consisting of p236, p238, p243, p246, p275, p276, p361, and p362.
251. The use of any one of claims 236 to 250, wherein the CpG-Ab immunoconjugate is not conjugated to a T cell epitope.
252. The use of claim 251, wherein the T cell e is ovalbumin (OVA).
253. Use of a therapeutically effective amount of a CpG-Ab immunoconjugate in the manufacture of a medicament for the treatment of an therapy ant or refractory cancer, wherein the CpG-Ab immunoconjugate comprises the oligonucleotide of any one of claims 1 to 56.
254. The use of claim 253, where the CpG-Ab immunoconjugate does not bind to a tumor associated antigen.
255. The use of claim 254, wherein the CpG-Ab immunoconjugate specifically binds to a target antigen ated with a normal immune cell that expresses at least one toll-like receptor.
256. The use of claim 253, wherein the CpG-Ab immunoconjugate specifically binds to a tumor associated antigen.
257. The use of any one of claims 253 to 256, wherein the cancer is resistant to treatment with an immune checkpoint modulator.
258. The use of claim 257, wherein the treatment further ses inistering to the subject the immune checkpoint modulator.
259. The use of any one of claims 253 to 258, wherein the CpG-Ab immunoconjugate comprises an immunostimulating polynucleotide selected from Table 2.
260. The use of claim 259, wherein the CpG-Ab immunoconjugate comprises an immunostimulating polynucleotide selected from the group consisting of p236, p238, p243, p246, p275, p276, p361, and p362.
261. Use of a therapeutically effective amount of a CpG-Ab immunoconjugate in the manufacture of a medicament for preventing cancer, wherein the CpG-Ab immunoconjugate comprises the oligonucleotide of any one of claims 1 to 56, and wherein the CpG-Ab immunoconjugate specifically binds to a target antigen associated with a normal immune cell expressing at least one toll-like or.
262. The use of claim 261, wherein the preventing further comprises co-administering a tumor associated n with the CpG-Ab immunoconjugate.
263. The use of claim 262, wherein the CpG-Ab immunoconjugate is not conjugated to the tumor associated antigen.
264. The use of any one of claims 261 to 263, wherein the normal immune cell expresses TLR9.
265. The use of any one of claims 261 or 264, wherein the normal immune cell is an antigen presenting cell (APC).
266. The use of any one of claims 261 to 265, wherein the CpG-Ab immunoconjugates comprises an immunostimulating polynucleotide selected from Table 2.
267. The use of claim 266, wherein the CpG-Ab immunoconjugates comprises an immunostimulating polynucleotide selected from the group consisting of p236, p238, p243, p246, p275, p276, p361, and p362.
268. Use of a therapeutically effective amount of a CpG-Ab immunoconjugate in the manufacture of a medicament for co-administration with a cancer e for preventing cancer, wherein the CpG-Ab immunoconjugate comprises the oligonucleotide of any one of claims 1 to 56, and wherein the CpG-Ab immunoconjugate specifically binds to a target antigen associated with a normal immune cell expressing at least one toll-like receptor.
269. The use of claim 268, wherein the CpG-Ab immunoconjugate is formulated as an adjuvant of the cancer e.
270. Use of a therapeutically effective amount of a CpG-Ab immunoconjugate in the manufacture of a ment for inducing an adaptive immune response in a subject, wherein the CpG-Ab immunoconjugate comprises the oligonucleotide of any one of claims 1 to 56, and n the CpG-Ab immunoconjugate specifically binds to a target antigen associated with a normal immune cell expressing at least one toll-like receptor.
271. The use of claim 270, wherein the subject has cancer.
272. The use of claim 271, n the target antigen is not a TAA.
273. The use of claim 271, wherein the target n is a TAA that is not an antigen selected from the group consisting of CD19, CD20, CD22, STAT3, exportin 7, Her2, Src, EGFR, CD52, , Muc-1 and DNA.
274. The use of claim 270, n the subject has an infectious disease.
275. The use of any one of claims 270 to 274, wherein the normal immune cell expresses TLR9.
276. The use of any one of claims 270 to 275, wherein the normal immune cell is an antigen presenting cell (APC).
277. The use of any one of claims 270 to 276, wherein the ve immune response is CD8+ T cell ent.
278. The use of any one of claims 270 to 277, wherein the CpG-Ab immunoconjugates comprises an immunostimulating polynucleotide selected from Table 2.
279. The use of claim 278, wherein the CpG-Ab immunoconjugates comprises an immunostimulating polynucleotide selected from the group consisting of p236, p238, p243, p246, p275, p276, p361, and p362.
280. Use of a CpG-Ab immunoconjugate in the manufacture of a ment for treating cancer, wherein the CpG-Ab immunoconjugate comprises the oligonucleotide of any one of claims 1 to 56, and wherein the CpG-Ab immunoconjugate is selected from Tables 6-A and 6-B.
281. The use of claim 280, wherein the CpG-Ab immunoconjugates binds to a tumor associated antigen (TAA).
282. The use of claim 280, wherein the CpG-Ab immunoconjugates binds to a target antigen other than the TAA.
283. The use of any one of claims 280 to 282, wherein the CpG-Ab immunoconjugates binds to the target antigen associated with a normal immune cell expressing a TLR receptor.
284. The use of any one of claims 280 to 283, n the CpG-Ab immunoconjugates is selected from the group consisting of CpG-Ab conjugates comprising p236, p238, p243, p246, p275, p276, p361, and p362.
285. The use of any one of claims 222 to 284, n the treatment, preventing or inducing further comprises co-administering a therapeutic effective amount of at least one additional cancer therapeutic agent.
286. The use of 285, wherein the at least one additional cancer therapeutic agent is selected from a second TAA, a T cell costimulatory le, and an immune checkpoint modulator.
287. The use of claim 286, wherein the second TAA is the same as the TAA.
288. The use of claim 286, wherein the second TAA is different from the TAA.
289. The use of any one of claims 286 to 288, wherein the T cell costimulatory molecule is selected from the list consisting of OX40, CD2, CD27, CDS, ICAM-1, CD11a/CD18, ICOS/CD278, 4-1BB/CD137, GITR, CD30, CD40, BAFFR, HVEM, CD7, LIGHT, NKG2C, , NKp80, CD160, B7-H3, and CD83 or an ligand thereof.
290. The use of claim 289, wherein the T cell costimulatory molecule is an anti-OX40 dy, anti-ICOS/CD278 antibody or anti1BB/CD137 antibody, or an antigen-binding fragment thereof.
291. The use of any one of claims 286 to 290, wherein the immune checkpoint modulator is an inhibitor of immune checkpoint molecules selected from the list consisting of PD-1, PD-L1, PD-L2, TIM-3, LAG-3, CEACAM-1, CEACAM-5, CLTA-4, VISTA, BTLA, TIGIT, LAIR1, CD47, CD160, 2B4, CD172a, and TGFR.
292. The use of claim 291, n the immune checkpoint tor is an anti-CD47 antibody, anti-PD-1 antibody, anti-PD-L1 antibody, or an antigen-binding fragment f.
293. The use of any one of claims 222 to 292, wherein the cancer is a solid tumor.
294. The use of any one of claims 222 to 292, wherein the cancer is a liquid tumor.
295. The use of any one of claims 222 to 294, wherein the cancer is recurrent cancer.
296. The use of any one of claims 222 to 295, wherein the treatment, preventing or ng comprises administering or co-administering the CpG-Ab immunoconjugate by systemic administration.
297. The use of any one of claims 222 to 296, wherein the therapeutic effective amount of the CpG-Ab immunoconjugate is not effective to activate the complement pathway in the subject.
298. The use of claim 297, wherein the amount is not effective to activate complement C3 in the subject.
299. The use of any one of claims 222 to 298, wherein the CpG-Ab immunoconjugate comprises a compound according to claim 60.
300. The use of any one of claims 222 to 300, wherein the CpG-Ab immunoconjugate comprises a nd according to claim 57.
301. The use of any one of claims 222-300, wherein the CpG-Ab immunoconjugate is ed from SB-342, SB-343, SB-341, SB-340, SB-179, SB-181, , , SB-228, SB- 229, SB-242, SB-263, SB-337, SB-267, SB-284, SB-312, SB-313, SB-347, SB-373, SB-382, SB- 388, SB-389, SB-408, SB-416, SB-419, SB-421, SB-423, SB-426, SB-427, SB-428, SB-429 and SB-430.
302. An oligonucleotide according to claim 1 substantially as herein described or exemplified.
303. A compound according to claim 57 substantially as herein described or exemplified.
304. A nd according to claim 60 substantially as herein bed or exemplified.
305. An oligonucleotide according to claim 70 substantially as herein described or exemplified.
306. An immunomodulating polynucleotide according to claim 84 substantially as herein described or exemplified.
307. A conjugate according to claim 85 substantially as herein described or ified.
308. A conjugate ing to claim 90 substantially as herein described or exemplified.
309. A conjugate according to claim 94 substantially as herein bed or exemplified.
310. A conjugate according to claim 95 substantially as herein described or exemplified.
311. A conjugate according to claim 104 substantially as herein described or exemplified.
312. A ition according to claim 126 substantially as herein described or exemplified.
313. A ition according to claim 127 substantially as herein described or ified.
314. A pharmaceutical composition according to claim 140 substantially as herein described or exemplified.
315. A use according to claim 141 ntially as herein described or exemplified.
316. A use according to claim 144 substantially as herein described or exemplified.
317. A use according to claim 151 substantially as herein described or exemplified.
318. A use according to claim 156 substantially as herein described or exemplified.
319. A use according to claim 165 substantially as herein described or exemplified.
320. A use according to claim 196 ntially as herein bed or exemplified.
321. A use according to claim 197 substantially as herein described or exemplified.
322. A use according to claim 198 substantially as herein described or exemplified.
323. A use according to claim 200 substantially as herein described or exemplified.
324. A use according to claim 203 substantially as herein described or exemplified.
325. A pharmaceutical composition ing to claim 205 substantially as herein described or exemplified.
326. A pharmaceutical composition according to claim 207 ntially as herein described or exemplified.
327. A use according to claim 222 substantially as herein described or exemplified.
328. A use according to claim 236 substantially as herein described or exemplified.
329. A use according to claim 253 substantially as herein described or ified.
330. A use according to claim 261 substantially as herein described or exemplified.
331. A use according to claim 268 substantially as herein described or exemplified.
332. A use according to claim 270 substantially as herein described or exemplified.
333. A use according to claim 280 substantially as herein described or exemplified. 1 /1 05 tBuDS—Ph (ortho) z = 0 (P0) or 8 (PS) 0?» Butyl triester (R = n-butyl) PEG3-NH2 triester (n = 1) Ethyl triester (R = ethyl) Z = 0 (P0) or 8 (PS) opargyl er (R = homopropargyl) PEG2--NH2 triester (n = 0) DBCO-TEG O Z: 0 (PO))or S( O DBCO-T (x=o, R'=H) 01:: DBCO-t (x=s, R'=H) DBCO--T(X=—o R'=n-butyl) HNUQ DBCO-t (x:s R'=n-butyl) wmw OH R; DBCO-NH-PEG3 triester (n =1) O \
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