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NZ767674B2 - Antigen binding molecules comprising a tnf family ligand trimer - Google Patents
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NZ767674B2 - Antigen binding molecules comprising a tnf family ligand trimer - Google Patents

Antigen binding molecules comprising a tnf family ligand trimer Download PDF

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Publication number
NZ767674B2
NZ767674B2 NZ767674A NZ76767415A NZ767674B2 NZ 767674 B2 NZ767674 B2 NZ 767674B2 NZ 767674 A NZ767674 A NZ 767674A NZ 76767415 A NZ76767415 A NZ 76767415A NZ 767674 B2 NZ767674 B2 NZ 767674B2
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New Zealand
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seq
amino acid
acid sequence
antigen binding
binding molecule
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NZ767674A
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NZ767674A (en
Inventor
Maria Amann
Peter Bruenker
Christina Claus
Koller Claudia Ferrara
Richards Sandra Grau
Christian Klein
Viktor Levitski
Ekkehard Moessner
Joerg Thomas Regula
Pablo Umana
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F Hoffmann La Roche Ag
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Publication of NZ767674A publication Critical patent/NZ767674A/en
Publication of NZ767674B2 publication Critical patent/NZ767674B2/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6849—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/70575—NGF/TNF-superfamily, e.g. CD70, CD95L, CD153, CD154
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/70596—Molecules with a "CD"-designation not provided for elsewhere
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2815—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD8
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2896—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against molecules with a "CD"-designation, not provided for elsewhere
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/30—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
    • C07K16/3007—Carcino-embryonic Antigens
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/40—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against enzymes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/46—Hybrid immunoglobulins
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/33—Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/35—Valency
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/52—Constant or Fc region; Isotype
    • C07K2317/522—CH1 domain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/52—Constant or Fc region; Isotype
    • C07K2317/524—CH2 domain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/52—Constant or Fc region; Isotype
    • C07K2317/526—CH3 domain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/565—Complementarity determining region [CDR]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/60—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/30—Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/33—Fusion polypeptide fusions for targeting to specific cell types, e.g. tissue specific targeting, targeting of a bacterial subspecies

Abstract

The invention relates to novel TNF family ligand trimer-containing antigen binding molecules comprising (a) two Fab molecules capable of specific binding to a target cell antigen, an IgG Fc domain composed of a first and a second subunit capable of stable association, each subunit comprising CH2 and CH3 IgG heavy chain constant domains, and (b) a first and a second polypeptide that are linked to each other by a disulfide bond, characterized in that the first polypeptide comprises two ectodomains of a TNF ligand family member selected from 4-1BBL and OX40L that are connected to each other by a peptide linker and in that the second polypeptide comprises only one ectodomain of said TNF ligand family member, connected via peptide linker to the C-terminus of the other CH3 domain.

Claims (9)

1.Claims
2.A TNF family ligand trimer-containing antigen binding molecule sing (a) two Fab molecules capable of specific binding to a target cell antigen, an IgG Fc domain composed of a first and a second subunit e of stable 5 association, each subunit sing CH2 and CH3 IgG heavy chain constant domains, and (b) a first and a second polypeptide that are linked to each other by a disulfide bond, n the antigen binding molecule is characterized in that the first polypeptide ses two ectodomains of a TNF ligand family member selected from 4-1BBL comprising the amino acid sequence selected from the group consisting of SEQ ID 10 NO:1, SEQ ID NO: 2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:96, SEQ ID NO: 373, SEQ ID NO:374 and SEQ ID NO:375 or OX40L comprising the amino acid sequence of SEQ ID NO:53 or SEQ ID NO:54 that are connected to each other and to the C- terminus of the CH3 domain by a peptide linker and in that the second polypeptide comprises only one ectodomain of said TNF ligand family member selected from 4- 15 1BBL comprising the amino acid sequence selected from the group consisting of SEQ ID NO:1, SEQ ID NO: 2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:96, SEQ ID NO: 373, SEQ ID NO:374 and SEQ ID NO:375 or OX40L comprising the amino acid sequence of SEQ ID NO:53 or SEQ ID NO:54 connected via a peptide linker to C- terminus of the other CH3 domain. 20 2. The TNF family ligand trimer-containing antigen binding molecule of claim 1, wherein the TNF ligand family member costimulates human T-cell activation.
3. The TNF family ligand trimer-containing antigen binding molecule of claims 1 or 2, wherein the TNF ligand family member is 4-1BBL comprising the amino acid sequence selected from the group consisting of SEQ ID NO:1, SEQ ID NO: 2, SEQ ID NO:3, SEQ ID 25 NO:4, SEQ ID NO:96, SEQ ID NO: 373, SEQ ID NO:374 and SEQ ID NO:375.
4. The TNF family ligand trimer-containing antigen binding le of any one of claims 1 to 3, wherein the main of a TNF ligand family member comprises the amino acid sequence of SEQ ID NO:1 or SEQ ID NO:96.
5. The TNF family ligand trimer-containing antigen binding molecule of any one of claims 1 to 30 4, wherein the ectodomain of a TNF ligand family member comprises the amino acid sequence of SEQ ID NO:96.
6. The TNF family ligand -containing antigen binding molecule of any one of claims 1 to 5, comprising (a) two Fab molecules capable of specific binding to a target cell antigen and (b) a first and a second polypeptide that are linked to each other by a disulfide bond, wherein the n binding le is characterized in that the first ptide comprises the amino acid ce selected from the group consisting of SEQ ID NO:5, SEQ ID 5 NO:97, SEQ ID NO:98 and SEQ ID NO:99 and in that the second polypeptide comprises the amino acid sequence selected from the group consisting of SEQ ID NO:1, SEQ ID NO:96, SEQ ID NO:3 and SEQ ID NO:4.
7. The TNF family ligand trimer-containing antigen binding molecule of any one of claims 1 to 6, wherein the target cell antigen is Fibroblast Activation n (FAP). 10
8. The TNF family ligand trimer-containing antigen binding molecule of any one of claims 1 to 7, wherein the Fab molecules capable of specific binding to FAP comprise a VH domain comprising (i) CDR-H1 comprising the amino acid sequence of SEQ ID NO:7 or SEQ ID , (ii) CDR-H2 comprising the amino acid ce of SEQ ID NO:8 or SEQ ID NO:101, and (iii) CDR-H3 comprising the amino acid sequence of SEQ ID NO:9 or SEQ ID 15 NO:102, and a VL domain comprising (iv) CDR-L1 comprising the amino acid sequence of SEQ ID NO:10 or SEQ ID NO:103, (v) CDR-L2 comprising the amino acid sequence of SEQ ID NO:11 or SEQ ID , and (vi) CDR-L3 comprising the amino acid sequence of SEQ ID NO:12 or SEQ ID NO:105. 9. The TNF family ligand trimer-containing antigen binding molecule of any one of claims 1 to 20 8, wherein the Fab molecules capable of specific g to FAP comprise a variable heavy chain comprising an amino acid sequence of SEQ ID NO:16 and a variable light chain comprising an amino acid sequence of SEQ ID NO:17 or wherein the Fab molecules capable of specific binding to FAP comprise a variable heavy chain comprising an amino acid sequence of SEQ ID NO:106 and a variable light chain comprising an amino acid sequence 25 of SEQ ID NO:107. 10. The TNF family ligand trimer-containing n binding molecule of any one of claims 1 to 9, wherein the Fc domain is an IgG, particularly an IgG1 Fc domain or an IgG4 Fc domain. 11. The TNF family ligand trimer-containing antigen binding molecule of any one of claims 1 to 9, wherein the Fc domain is an IgG1 Fc domain comprising the amino acid substitutions at 30 positions 234 and 235 (EU numbering) and/or 329 (EU numbering). 12. The TNF family ligand trimer-containing antigen g molecule of claim 1, wherein the antigen binding molecule comprises (i) a first heavy chain comprising the amino acid sequence of SEQ ID NO:121, a second heavy chain comprising the amino acid ce of SEQ ID NO:122, and two light chains comprising the amino acid ce of SEQ ID NO:19, or (ii) a first heavy chain comprising the amino acid sequence of SEQ ID NO:123, a second 5 heavy chain comprising the amino acid sequence of SEQ ID NO:124, and two light chains comprising the amino acid sequence of SEQ ID NO:125, or (iii) a first heavy chain comprising the amino acid sequence of SEQ ID , a second heavy chain comprising the amino acid sequence of SEQ ID NO:127, and two light chains comprising the amino acid sequence of SEQ ID NO:125. 10 13. The TNF family ligand trimer-containing antigen binding molecule of any one of claims 1 to 6 and 10 to 11, wherein the target cell antigen is CEA. 14. The TNF family ligand trimer-containing n binding molecule of any one of claims 1 to 6, 10 to 11 and 13, wherein the Fab molecule capable of ic g to CEA comprises a VH domain comprising (i) CDR-H1 comprising the amino acid sequence of SEQ ID 15 NO:321, (ii) CDR-H2 comprising the amino acid sequence of SEQ ID NO:322, and (iii) CDR-H3 comprising the amino acid sequence of SEQ ID NO:323, and a VL domain comprising (iv) CDR-L1 comprising the amino acid sequence of SEQ ID NO:324, (v) CDRL2 comprising the amino acid sequence of SEQ ID NO:325, and (vi) CDR-L3 comprising the amino acid sequence of SEQ ID NO:326. 20 15. The TNF family ligand trimer-containing antigen binding molecule of any one of claims 1 to 6, 10 to 11 and 13 to 14, wherein the Fab molecule e of specific binding to CEA comprises a variable heavy chain sing an amino acid sequence of SEQ ID NO:329 and a variable light chain comprising an amino acid sequence of SEQ ID NO:330. 16. The TNF family ligand trimer-containing antigen binding molecule of any one of claims 1 to 25 6, 10 to 11 and 13 to 15, wherein the n binding molecule comprises (i) a first heavy chain comprising the amino acid sequence of SEQ ID NO:337, a second heavy chain comprising the amino acid sequence of SEQ ID NO:338, and two light chains comprising the amino acid sequence of SEQ ID NO:334, or (ii) a first heavy chain comprising the amino acid sequence of SEQ ID NO:341, a second 30 heavy chain comprising the amino acid sequence of SEQ ID , and two light chains comprising the amino acid sequence of SEQ ID NO:334. 17. The TNF family ligand trimer-containing antigen g molecule of any one of claims 1 to 2, 6 to 11 and 13 to 15, wherein the TNF ligand family member is OX40L comprising the amino acid sequence of SEQ ID NO:53 or SEQ ID NO:54. 18. The TNF family ligand trimer-containing antigen binding molecule of any one of claims 1 to 5 2, 6 to 11, 13 to 15 or 17, wherein the ectodomain of a TNF ligand family member comprises the amino acid sequence of SEQ ID NO:53. 19. The TNF family ligand trimer-containing antigen binding molecule of any one of claims 1 to 2, 6 to 11, 13 to 15, 17 or 18, sing (a) two Fab molecules capable of specific binding to a target cell antigen and 10 (b) a first and a second polypeptide that are linked to each other by a disulfide bond, wherein the antigen g molecule is characterized in that the first polypeptide comprises the amino acid sequence of SEQ ID NO:371 or SEQ ID:372 and in that the second polypeptide comprises the amino acid sequence of SEQ ID NO:53 or SEQ ID NO:54. 20. An isolated polynucleotide ng the TNF family ligand trimer-containing antigen 15 g molecule of any one of claims 1 to 19. 21. A vector, particularly an expression vector, comprising the isolated polynucleotide of claim 22. The vector of claim 21, wherein the vector is an expression vector. 23. An isolated host cell comprising the isolated polynucleotide of claim 20 or the vector of 20 claim 21 or 22. 24. A method for producing the TNF family ligand trimer-containing antigen binding molecule of any one of claims 1 to 19, comprising the steps of (i) culturing the host cell of claim 23 under conditions suitable for expression of the antigen binding molecule, and 25 (ii) recovering the antigen binding le. 25. A pharmaceutical composition comprising the TNF family ligand trimer-containing n binding le of any one of claims 1 to 19 and at least one pharmaceutically acceptable excipient. 26. The TNF family ligand -containing antigen binding molecule of any one of claims 1 to 19, or the pharmaceutical composition of claim 25, for use as a medicament. 27. The TNF family ligand trimer-containing antigen binding molecule of any one of claims 1 to 19, or the pharmaceutical composition of claim 25, for use in the treatment of cancer. 5 28. Use of the TNF family ligand trimer-containing antigen binding molecule of any one of claims 1 to 19 for the manufacture of a medicament for the treatment of cancer. 29. A TNF family ligand -containing antigen binding le as claimed in any one of claims 1 to 19, 26 and 27, substantially as bed herein and with reference to any e thereof. 10 30. An isolated polynucleotideas claimed in claim 20, substantially as described herein and with reference to any example thereof. 31. A vector as claimed in claim 21 or 22, substantially as described herein and with reference to any example thereof. 32. An isolated host cell as claimed in claim 23, substantially as described herein and with 15 reference to any example thereof. 33. A method as claimed in claim 24, substantially as bed herein and with reference to any example thereof. 34. A pharmaceutical composition as claimed in claim 25, substantially as described herein and with reference to any example thereof. 20 35. A use as claimed in claim 28, substantially as described herein and with reference to any example thereof. 599......9:99.39, 9mWGGGmGGGW 9.9_ 9:99... :mEE. mm mWGGGmGGGW mWGGGmGGGG mWGGGmGGGW9.9~ ~ .9 _ 9.9 9:99.... 999.9.9: :mEE 9.59 r 99.9.... 39, 9 9 9 9 ~ 9 9 9 9 9 ~ 9 , 9 9 9 9 «.9 9:99. :,,___,__..9 .. 599.39. ~ 9 9 mm9 9.39.9.9. 9 h 9 mWGGGmGGGW 9 mm: ~ 9 9 9 9 9 9 9 9 9 9 9 ~ 9 9 9
9. MWGGGmGGGW9. Z Z 9 99: a: 6: a: @w quw- Ta rm U =5 ._> 592. a» 55 5 GasmaE. r H & waggii __ s @8833 a mwmumvm?wwww may“: a a mmaéu?hai, __?ning p , a _, a mwmmuw r 21:: 88-3: ,,,,,,,mm3w§§; :gw??nq .9; 69 4mm_-¢=; ?qmm-_nv 4mm_-¢=; ?wqm-_nv z; ._m_m: <3; ?wqm-_nv ._m_m:- Ame qu? mmw E A E 2e Mdmm mmc=z2mmw 2 g — a) I H 8 E o E l— .E. '— + : BO 8 1' I 2 D a: D .5 o g 0 b c 'c C 3 a: z. 1- 8 "" 8 as = «s C > O > O z; 0 3 0 8 g z . ’00 O O O O o o o o O O O O 00 u: <- N 8 8 3 m w 00 N \- [papauoo auuaseq] [pamauoo q] Kusuam aouaosaJonH ;o uegpaw Kusuawl aouaosaJonH 4o uegpaw 0: H2 01.-. 8 .50 .E. '— 15 + ._51— '1: 0° “<1- cc 0 £8 .3 6 U c a: z.” a: u 0 0° > 8.2 cc)
NZ767674A 2015-11-13 Antigen binding molecules comprising a tnf family ligand trimer NZ767674B2 (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
EP14193260 2014-11-14
EP15183736 2015-09-03
EP15188142 2015-10-02
NZ730933A NZ730933B2 (en) 2015-11-13 Antigen binding molecules comprising a tnf family ligand trimer

Publications (2)

Publication Number Publication Date
NZ767674A NZ767674A (en) 2024-07-05
NZ767674B2 true NZ767674B2 (en) 2024-10-08

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