IP Library › Patent Application 16653652

Patent Application

App. No. 16/653,652

ANTIGEN BINDING MOLECULES COMPRISING A TRIMERIC TNF FAMILY LIGAND

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Patent No.: US None
App. No.: 16/653,652

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Abstract

The invention relates to novel TNF family ligand trimer-containing antigen binding molecules comprising (a) at least one moiety capable of specific binding to a target cell antigen, (b) a polypeptide comprising three ectodomains of a TNF ligand family member or fragments thereof that are connected to each other by peptide linkers and (c) a Fc domain composed of a first and a second subunit capable of stable association, and to methods of producing these molecules and to methods of using the same.

Claims (92)

1 . A TNF family ligand trimer-containing antigen binding molecule comprising

(a) at least one moiety capable of specific binding to a target cell antigen,

(b) a polypeptide comprising three ectodomains of a TNF ligand family member or fragments thereof that are connected to each other, optionally by peptide linkers, and

2 . The TNF family ligand trimer-containing antigen binding molecule of claim 1 comprising

(a) at least one moiety capable of specific binding to a target cell antigen,

(b) a polypeptide comprising three ectodomains of a TNF ligand family member or fragments thereof that are connected to each other by peptide linkers and

3 . The TNF family ligand trimer containing antigen binding molecule of claim 1 or 2 comprising

(a) at least one moiety capable of specific binding to a target cell antigen,

(b) a polypeptide comprising three ectodomains of a TNF ligand family member or fragments thereof that are connected to each other by peptide linkers and

(c) a Fc domain composed of a first and a second subunit capable of stable association, wherein the polypeptide comprising the three ectodomains of a TNF ligand family member or fragments thereof that are connected to each other by peptide linkers is fused to the N- or C-terminal amino acid of one of the two subunits of the Fc domain, optionally through a peptide linker.

4 . The TNF family ligand trimer-containing antigen binding molecule of any one of claims 1 to 3 , wherein the TNF ligand family member costimulates human T-cell activation.

5 . The TNF family ligand trimer-containing antigen binding molecule of any one of claims 1 to 4 , wherein the TNF ligand family member is selected from 4-1BBL and OX40L.

6 . The TNF family ligand trimer-containing antigen binding molecule of any one of claims 1 to 5 , wherein the TNF ligand family member is 4-1BBL.

7 . The TNF family ligand trimer-containing antigen binding molecule of any one of claims 1 to 6 , wherein the ectodomain of a TNF ligand family member comprises 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:99, SEQ ID NO: 100, SEQ ID NO:101 and SEQ ID NO:102, particularly the amino acid sequence of SEQ ID NO:1 or SEQ ID NO:99.

8 . The TNF family ligand trimer-containing antigen binding molecule of any one of claims 1 to 6 , comprising

(a) at least one moiety capable of specific binding to a target cell antigen and

(b) a polypeptide comprising the amino acid sequence of SEQ ID NO:5 or SEQ ID NO:103, and

9 . The TNF family ligand trimer-containing antigen binding molecule of any one of claims 1 to 5 , wherein the TNF ligand family member is OX40L.

10 . The TNF family ligand trimer-containing antigen binding molecule of any one of claim 1 to 5 or 9 , wherein the ectodomain of a TNF ligand family member comprises the amino acid sequence selected from the group consisting of SEQ ID NO:6 and SEQ ID NO:7, particularly the amino acid sequence of SEQ ID NO:6.

11 . The TNF family ligand trimer-containing antigen binding molecule of any one of claim 1 to 5 or 9 or 10 , comprising

(a) at least one moiety capable of specific binding to a target cell antigen and

(b) a polypeptide comprising the amino acid sequence of SEQ ID NO:8, and

12 . The TNF family ligand trimer-containing antigen binding molecule of any one of claims 1 to 11 , wherein the polypeptide comprising three ectodomains of a TNF ligand family member or fragments thereof is fused at the C-terminal amino acid to a N-terminal amino acid of one of the subunits of the Fc domain.

13 . The TNF family ligand trimer-containing antigen binding molecule of any one of claims 1 to 11 , wherein the polypeptide comprising three ectodomains of a TNF ligand family member or fragments thereof is fused at the N-terminal amino acid to a C-terminal amino acid of one of the subunits of the Fc domain.

14 . The TNF family ligand trimer-containing antigen binding molecule of any one of claims 1 to 13 , wherein the moiety capable of specific binding to a target cell antigen is selected from the group consisting of an antibody fragment, a Fab molecule, a crossover Fab molecule, a single chain Fab molecule, a Fv molecule, a scFv molecule, a single domain antibody, an aVH and a scaffold antigen binding protein.

15 . The TNF family ligand trimer-containing antigen binding molecule of any one of claims 1 to 14 , wherein the moiety capable of specific binding to a target cell antigen is a Fab molecule capable of specific binding to a target cell antigen.

16 . The TNF family ligand trimer-containing antigen binding molecule of any one of claims 1 to 15 , wherein the target cell antigen is selected from the group consisting of Fibroblast Activation Protein (FAP), Melanoma-associated Chondroitin Sulfate Proteoglycan (MCSP), Epidermal Growth Factor Receptor (EGFR), Carcinoembryonic Antigen (CEA), CD19, CD20 and CD33.

17 . The TNF family ligand trimer-containing antigen binding molecule of any one of claims 1 to 16 , wherein the target cell antigen is Fibroblast Activation Protein (FAP).

18 . The TNF family ligand trimer-containing antigen binding molecule of any one of claims 1 to 17 , wherein the moiety capable of specific binding to FAP comprises

(a) a VH domain comprising (i) CDR-H1 comprising the amino acid sequence of SEQ ID NO:9, (ii) CDR-H2 comprising the amino acid sequence of SEQ ID NO:10 and (iii) CDR-H3 comprising the amino acid sequence of SEQ ID NO:11, and a VL domain comprising (iv) CDR-L1 comprising the amino acid sequence of SEQ ID NO:12, (v) CDR-L2 comprising the amino acid sequence of SEQ ID NO:13 and (vi) CDR-L3 comprising the amino acid sequence of SEQ ID NO:14, or

(b) a VH domain comprising (i) CDR-H1 comprising the amino acid sequence of SEQ ID NO:104, (ii) CDR-H2 comprising the amino acid sequence of SEQ ID NO:105 and (iii) CDR-H3 comprising the amino acid sequence of SEQ ID NO:106, and a VL domain comprising (iv) CDR-L1 comprising the amino acid sequence of SEQ ID NO:107, (v) CDR-L2 comprising the amino acid sequence of SEQ ID NO:108 and (vi) CDR-L3 comprising the amino acid sequence of SEQ ID NO:109.

19 . The TNF family ligand trimer-containing antigen binding molecule of any one of claims 1 to 18 , wherein the moiety capable of specific binding to FAP comprises 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 moiety capable of specific binding to FAP comprises a variable heavy chain comprising an amino acid sequence of SEQ ID NO:110 and a variable light chain comprising an amino acid sequence of SEQ ID NO:111.

20 . The TNF family ligand trimer-containing antigen binding molecule of any one of claims 1 to 16 , wherein the target cell antigen is CEA.

21 . The TNF family ligand trimer-containing antigen binding molecule of any one of claim 1 to 16 or 20 , wherein the moiety capable of specific binding to CEA comprises a VH domain comprising (i) CDR-H1 comprising the amino acid sequence of SEQ ID NO:112, (ii) CDR-H2 comprising the amino acid sequence of SEQ ID NO:113 and (iii) CDR-H3 comprising the amino acid sequence of SEQ ID NO:114, and a VL domain comprising (iv) CDR-L1 comprising the amino acid sequence of SEQ ID NO:115, (v) CDR-L2 comprising the amino acid sequence of SEQ ID NO:116 and (vi) CDR-L3 comprising the amino acid sequence of SEQ ID NO:117.

22 . The TNF family ligand trimer-containing antigen binding molecule of any one of claim 1 to 16 or 20 or 21 , wherein the moiety capable of specific binding to CEA comprises a variable heavy chain comprising an amino acid sequence of SEQ ID NO:118 and a variable light chain comprising an amino acid sequence of SEQ ID NO:119.

23 . The TNF family ligand trimer-containing antigen binding molecule of any one of claims 1 to 16 , wherein the target cell antigen is CD19.

24 . The TNF family ligand trimer-containing antigen binding molecule of any one of claim 1 to 16 or 23 , wherein the moiety capable of specific binding to CD19 comprises

(a) a VH domain comprising (i) CDR-H1 comprising the amino acid sequence of SEQ ID NO:120, (ii) CDR-H2 comprising the amino acid sequence of SEQ ID NO:121 and (iii) CDR-H3 comprising the amino acid sequence of SEQ ID NO:122, and a VL domain comprising (iv) CDR-L1 comprising the amino acid sequence of SEQ ID NO:123, (v) CDR-L2 comprising the amino acid sequence of SEQ ID NO:124 and (vi) CDR-L3 comprising the amino acid sequence of SEQ ID NO:125, or

(b) a VH domain comprising (i) CDR-H1 comprising the amino acid sequence of SEQ ID NO:128, (ii) CDR-H2 comprising the amino acid sequence of SEQ ID NO:129 and (iii) CDR-H3 comprising the amino acid sequence of SEQ ID NO:130, and a VL domain comprising (iv) CDR-L1 comprising the amino acid sequence of SEQ ID NO:131, (v) CDR-L2 comprising the amino acid sequence of SEQ ID NO:132 and (vi) CDR-L3 comprising the amino acid sequence of SEQ ID NO:133.

25 . The TNF family ligand trimer-containing antigen binding molecule of any one of claim 1 to 16 or 23 or 24 , wherein the moiety capable of specific binding to CD19 comprises a variable heavy chain comprising an amino acid sequence of SEQ ID NO:126 and a variable light chain comprising an amino acid sequence of SEQ ID NO:127 or wherein the moiety capable of specific binding to FAP comprises a variable heavy chain comprising an amino acid sequence of SEQ ID NO:134 and a variable light chain comprising an amino acid sequence of SEQ ID NO:135.

26 . The TNF family ligand trimer-containing antigen binding molecule of any one of claims 1 to 25 , wherein the Fc domain is an IgG, particularly an IgG1 Fc domain or an IgG4 Fc domain.

27 . The TNF family ligand trimer-containing antigen binding molecule of claim 26 , wherein the Fc domain is an IgG1 Fc domain comprising the amino acid substitutions at positions 234 and 235 (EU numbering) and/or 329 (EU numbering).

28 . The TNF family ligand trimer-containing antigen binding molecule of any one of claims 1 to 27 , comprising one moiety capable of specific binding to a target cell antigen.

29 . The TNF family ligand trimer-containing antigen binding molecule of any one of claims 1 to 28 , wherein the antigen binding molecule comprises

(i) a first heavy chain comprising the VH domain of a Fab molecule capable of specific binding to a target cell antigen,

(ii) a light chain comprising the VL domain of a Fab molecule capable of specific binding to a target cell antigen, and

(iii) a second heavy chain comprising the amino acid sequence of SEQ ID NO:5 or SEQ ID NO:103 or SEQ ID NO:8.

30 . The TNF family ligand trimer-containing antigen binding molecule of any one of claims 1 to to 29 , wherein the antigen binding molecule comprises

(i) a first heavy chain comprising a VH domain comprising an amino acid sequence of SEQ ID NO:16 or a VH domain comprising an amino acid sequence of SEQ ID NO:110,

(ii) a light chain comprising a VL domain comprising an amino acid sequence of SEQ ID NO:17 or a VL domain comprising an amino acid sequence of SEQ ID NO:111, and

(iii) a second heavy chain comprising the amino acid sequence of SEQ ID NO:5 or SEQ ID NO:103 or SEQ ID NO:8.

31 . The TNF family ligand trimer-containing antigen binding molecule of any one of claims 1 to 29 , wherein the antigen binding molecule comprises

(i) a first heavy chain comprising a VH domain comprising an amino acid sequence of SEQ ID NO:118,

(ii) a light chain comprising a VL domain comprising an amino acid sequence of SEQ ID NO:119, and

(iii) a second heavy chain comprising the amino acid sequence of SEQ ID NO:5 or SEQ ID NO:103 or SEQ ID NO:8.

32 . The TNF family ligand trimer-containing antigen binding molecule of any one of claims 1 to 29 , wherein the antigen binding molecule comprises

(i) a first heavy chain comprising a VH domain comprising an amino acid sequence of SEQ ID NO:126 or a VH domain comprising an amino acid sequence of SEQ ID NO:134,

(ii) a light chain comprising a VL domain comprising an amino acid sequence of SEQ ID NO:127 or a VL domain comprising an amino acid sequence of SEQ ID NO:135, and

(iii) a second heavy chain comprising the amino acid sequence of SEQ ID NO:5 or SEQ ID NO:103 or SEQ ID NO:8.

33 . The TNF family ligand trimer-containing antigen binding molecule of any one of claims 1 to 27 , comprising two moieties capable of specific binding to a target cell antigen.

34 . The TNF family ligand trimer-containing antigen binding molecule of any one of claim 1 to 27 or 33 , wherein the antigen binding molecule comprises

(i) a first heavy chain comprising a VH domain of a Fab molecule capable of specific binding to a target cell antigen,

(ii) two light chains comprising each the VL domain of a Fab molecule capable of specific binding to a target cell antigen, and

(iii) a second heavy chain comprising a VH domain of a Fab molecule capable of specific binding to a target cell antigen and the amino acid sequence of SEQ ID NO:5 or SEQ ID NO:103 or SEQ ID NO:8.

35 . The TNF family ligand trimer-containing antigen binding molecule of claim 34 , wherein the antigen binding molecule comprises

(i) a first heavy chain comprising a VH domain comprising an amino acid sequence of SEQ ID NO:16 or a VH domain comprising an amino acid sequence of SEQ ID NO:110,

(ii) two light chains comprising each a VL domain comprising an amino acid sequence of SEQ ID NO:17 or a VL domain comprising an amino acid sequence of SEQ ID NO:111, and

(iii) a second heavy chain comprising a VH domain comprising an amino acid sequence of SEQ ID NO:16 or a VH domain comprising an amino acid sequence of SEQ ID NO:110 and the amino acid sequence of SEQ ID NO:5 or SEQ ID NO:103 or SEQ ID NO:8.

36 . The TNF family ligand trimer-containing antigen binding molecule of claim 34 , wherein the antigen binding molecule comprises

(i) a first heavy chain comprising a VH domain comprising an amino acid sequence of SEQ ID NO:118,

(ii) two light chains comprising each a VL domain comprising an amino acid sequence of SEQ ID NO:119, and

(iii) a second heavy chain comprising a VH domain comprising an amino acid sequence of SEQ ID NO:118 and the amino acid sequence of SEQ ID NO:5 or SEQ ID NO:103 or SEQ ID NO:8.

37 . The TNF family ligand trimer-containing antigen binding molecule of claim 34 , wherein the antigen binding molecule comprises

(i) a first heavy chain comprising a VH domain comprising an amino acid sequence of SEQ ID NO:126 or a VH domain comprising an amino acid sequence of SEQ ID NO:134,

(ii) two light chains comprising a VL domain comprising an amino acid sequence of SEQ ID NO:127 or a VL domain comprising an amino acid sequence of SEQ ID NO:135, and

(iii) a second heavy chain comprising a VH domain comprising an amino acid sequence of SEQ ID NO:126 or a VH domain comprising an amino acid sequence of SEQ ID NO:134 and the amino acid sequence of SEQ ID NO:5 or SEQ ID NO:103 or SEQ ID NO:8.

38 . An isolated polynucleotide encoding the TNF family ligand trimer-containing antigen binding molecule of any one of claims 1 to 37 .

39 . A vector, particularly an expression vector, comprising the isolated polynucleotide of claim 38 .

40 . A host cell comprising the isolated polynucleotide of claim 38 or the vector of claim 39 .

41 . A method for producing the TNF family ligand trimer-containing antigen binding molecule of any one of claims 1 to 37 , comprising the steps of

(i) culturing the host cell of claim 40 under conditions suitable for expression of the antigen binding molecule, and

(ii) recovering the antigen binding molecule.

42 . A pharmaceutical composition comprising the TNF family ligand trimer-containing antigen binding molecule of any one of claims 1 to 37 and at least one pharmaceutically acceptable excipient.

43 . The TNF family ligand trimer-containing antigen binding molecule of any one of claims 1 to 37 , or the pharmaceutical composition of claim 38 , for use as a medicament.

44 . The TNF family ligand trimer-containing antigen binding molecule of any one of claims 1 to 37 , or the pharmaceutical composition of claim 42 , for use in the treatment of cancer.

45 . Use of the TNF family ligand trimer-containing antigen binding molecule of any one of claims 1 to 37 for the manufacture of a medicament for the treatment of cancer.

46 . A method of treating a disease in an individual, comprising administering to said individual a therapeutically effective amount of a composition comprising a TNF family ligand trimer-containing antigen binding molecule of any one of claims 1 to 37 in a pharmaceutically acceptable form.

47 . The method of claim 46 , wherein said disease is cancer.