Method of treating cancer comprising a VEGF-B antagonist

• US 8,822,644 B2
• Filed: 08/02/2005
• Issued: 09/02/2014
• Est. Priority Date: 08/02/2004
• Status: Active Grant

• Current Assignee: Zenyth Operations Pty. Ltd.
• Original Assignee: Zenyth Operations Pty. Ltd.
• Inventors: Nash, Andrew, Dunlop, Felicity Meredith, Baca, Manuel, Fabri, Louis Jerry, Scotney, Pierre David
• Primary Examiner(s): CANELLA, KAREN A
• Application Number:
  US11/659,179
• Publication Number:
  US 20080260729A1
• Time in Patent Office: 3,318 Days
• Field of Search: None
• US Class Current: 530/387.1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07K 16/22 against growth factors ; against growth regulators
• CPC Class Codes: C07K 2317/24 containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/55 Fab or Fab'
• CPC Class Codes: C07K 2317/73 Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
• CPC Class Codes: C07K 2317/76 Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Abstract

The present invention relates generally to the field of cancer therapy and prophylaxis. More particularly, the present invention provides growth factor antagonists which inhibit the growth of cancers including tumors and pre-cancerous tissue. Even more particularly, the present invention is directed to antagonists of vascular endothelial growth factor-B and their use to inhibit the growth of cancer including tumor tissue and pre-cancerous tissue.

Claims

1. An isolated anti-VEGF-B antibody that inhibits binding of VEGF-B to VEGFR-1 wherein the antibody binds human VEGF-B with a K_D value of 1×

10<sup>−

7</sup>M or less, wherein said antibody comprises all six CDR sequences from the heavy and light chain variable regions of mAb 2H10 as set forth in SEQ ID NOs;

5-10 in a human framework with a backmutation at position H73.

2. An antigen-binding fragment of an antibody of claim 1, wherein the fragment binds to VEGF-B.

3. The antigen-binding fragment of claim 2 wherein the antigen-binding fragment is selected from a Fv, Fab, F(ab′

)₂, a single chain Fv fragment, a disulphide stabilized Fv fragment, a minibody and a diabody.

4. The antigen binding fragment of claim 3 wherein the single chain Fv fragment is a sFv or scFv.

5. The antibody of claim 1 or an antigen-binding fragment of said antibody wherein the antibody or antigen-binding fragment is cross-reactive for human VEGF-B and VEGF-B from at least one other mammal.

6. The antibody or antigen-binding fragment of claim 5 wherein the antibody or antigen-binding fragment is cross-reactive for human VEGF-B and murine VEGF-B.

7. The isolated anti-VEGF-B antibody of claim 1, wherein the antibody binds human VEGF-B with a K_D value of 1×

10<sup>−

8</sup>M or less.

8. The isolated anti-VEGF-B antibody of claim 1, wherein the antibody binds human VEGF-B with a K_D value of 1×

10<sup>−

9</sup>M or less.

9. A composition comprising an antibody of claim 1.

10. An expression vector comprising a nucleic acid encoding the light chain of the antibody according to claim 1 and a nucleic acid encoding the heavy chain of the antibody according to claim 1, wherein said expression vector is capable of expressing the nucleic acids in prokaryotic or eukaryotic host cell.

11. A prokaryotic or eukaryotic host cell comprising an expression vector of claim 10.

12. A method for producing an anti-VEGF-B antibody comprising (a) culturing the prokaryotic or eukaryotic host cell of claim 11 for a period of time sufficient to allow for expression of the antibody and (b) purifying the expressed antibody.

13. An isolated anti-VEGF-B antibody according to claim 1 comprising a variable light chain sequence and a variable heavy chain having the sequences shown in SEQ ID NOs:

29 and 30.

14. A composition comprising the antibody according to claim 13.

15. An expression vector comprising a nucleic acid encoding the light chain of the antibody according to claim 13 and a nucleic acid encoding the heavy chain of the antibody according to claim 13, wherein said expression vector is capable of expressing said nucleic acid in prokaryotic or eukaryotic host cell.

16. A prokaryotic or eukaryotic host cell comprising an expression vector of claim 15.

17. A method for producing an anti-VEGF-B antibody comprising (a) culturing the prokaryotic or eukaryotic host cell of claim 16 for a period of time sufficient to allow for expression of the antibody and (b) purifying the expressed antibody.

18. An isolated anti-VEGF-B antibody that inhibits binding of VEGF-B to VEGFR-1 wherein the antibody binds human VEGF-B with a K_D value of 1×

10<sup>−

7</sup>M or less, wherein said antibody comprises (a) all six CDR sequences from the heavy and light chain variable regions of mAb 2F5 as set forth in SEQ ID NOs;

21-26, or (b) all six CDR sequences from the heavy and light chain variable regions of mAb 106 as set forth in SEQ ID NOs;

45-50.

19. The isolated anti-VEGF-B antibody of claim 18, wherein the antibody binds human VEGF-B with a K_D value of 1×

10<sup>−

8</sup>M or less.

20. The isolated anti-VEGF-B antibody of claim 18, wherein the antibody binds human VEGF-B with a K_D value of 1×

10<sup>−

9</sup>M or less.

21. The antibody any of claims 18-20 wherein the antibody is a monoclonal antibody.

22. The antibody of claim 21 wherein the antibody is humanized.

23. An antigen-binding fragment of an antibody of claim 22, wherein the fragment binds to VEGF-B.

24. The antigen-binding fragment of claim 23 wherein the antigen-binding fragment is selected from a Fv, Fab, F(ab′

)₂, a single chain Fv fragment, a disulphide stabilized Fv fragment, a minibody and a diabody.

25. The antigen binding fragment of claim 24 wherein the single chain Fv fragment is a sFv or scFv.

26. A composition comprising the antibody of claim 21.

27. An expression vector comprising a nucleic acid encoding the light chain of the antibody according to claim 21 and a nucleic acid encoding the heavy chain of the antibody according to claim 21, wherein said expression vector is capable of expressing the nucleic acids in prokaryotic or eukaryotic host cell.

28. A prokaryotic or eukaryotic host cell comprising an expression vector of claim 27.

29. A method for producing an anti-VEGF-B antibody comprising (a) culturing the prokaryotic or eukaryotic host cell of claim 28 for a period of time sufficient to allow for expression of the antibody and (b) purifying the expressed antibody.