Anti-VEGF antibody compositions and methods
Disclosed are human antibodies that specifically inhibit VEGF binding to only one (VEGFR2) of the two primary VEGF receptors. The antibodies effectively inhibit angiogenesis and induce tumor regression, and yet have improved safety due to their specificity. The present invention thus provides new human antibody-based compositions, methods and combined protocols for treating cancer and other angiogenic diseases. Advantageous immunoconjugate compositions and methods using the new VEGF-specific human antibodies are also provided.
1. A method of inhibiting angiogenesis, comprising administering an antibody that binds to VEGF, or an immunoconjugate thereof, to an animal in an amount effective to inhibit angiogenesis in said animal
wherein the antibody that binds to VEGF comprises at least one heavy chain variable region that comprises three CDRs and at least one light chain variable region that comprises three CDRs, wherein said antibody comprises:
(a) a variable light (VL) CDR1 having the amino acid sequence of SEQ ID NO:8, a VL CDR2 having the amino acid sequence of SEQ ID NO:9, a VL CDR3 having the amino acid sequence of SEQ ID NO:10, a variable heavy (VH) CDR1 having the amino acid sequence of SEQ ID NO:5, a VH CDR2 having the amino acid sequence of SEQ ID NO:6, and a VH CDR3 having the amino acid sequence of SEQ ID NO:7; or
(b) a light chain variable region that has the amino acid sequence of SEQ ID NO:4, or a heavy chain variable region that has the amino acid sequence of SEQ ID NO:3.
2. The method of claim 1 , wherein said animal has cancer.
3. The method of claim 2 , wherein said cancer is selected from the group consisting of lung, breast, ovary, colorectal, kidney, bladder, small cell carcinomas and glioblastomas.
4. The method of claim 1 , wherein said animal has a disease associated with corneal, retinal or choroidal neovascularization.
5. The method of claim 1 , wherein said animal has an ocular neovascular disease, macular degeneration, age-related macular degeneration, diabetic retinopathy, neovascular glaucoma, arthritis, rheumatoid arthritis, atherosclerosis, thyroid hyperplasia, Grave's disease, hemangioma or psoriasis.
6. The method of claim 1 , wherein said animal is a human subject.
7. The method of claim 1 , wherein said antibody is attached to at least a first therapeutic agent.
8. The method of claim 7 , wherein the at least a first therapeutic agent is selected from the group consisting of radiotherapeutic agent, chemotherapeutic agent, anti-angiogenic agent, apoptosis-inducing agent, anti-tubulin drug, anti-cellular or cytotoxic agent, cytokine, chemokine and coagulant.
9. The method of claim 1 , further comprising administering a second therapeutic agent to said animal.
10. The method of claim 9 , wherein said second therapeutic agent is a chemotherapeutic agent.
11. The method of claim 9 , wherein said second therapeutic agent is selected from the group consisting of pyrimidine analogs, platinum coordination complexes, camptothecins, tyrosine kinase inhibitors and inhibitors of receptor tyrosine kinases.
12. The method of claim 9 , wherein said second therapeutic agent is 5-fluorouracil, capecitabine, oxaliplatin, cisplatin, carboplatin, irinotecan, axitinib, sunitinib, or paclitaxel.
13. The method of claim 1 , wherein said antibody comprises said VL CDR1 having the amino acid sequence of SEQ ID NO:8, said VL CDR2 having the amino acid sequence of SEQ ID NO:9, said VL CDR3 having the amino acid sequence of SEQ ID NO:10, said VH CDR1 having the amino acid sequence of SEQ ID NO:5, said VH CDR2 having the amino acid sequence of SEQ ID NO:6, and said VH CDR3 having the amino acid sequence of SEQ ID NO:7.
14. The method of claim 1 , wherein said antibody comprises said light chain variable region that has the amino acid sequence of SEQ ID NO:4.
15. The method of claim 1 , wherein said antibody comprises said heavy chain variable region that has the amino acid sequence of SEQ ID NO:3.
16. The method of claim 1 , wherein said antibody comprises said light chain variable region that has the amino acid sequence of SEQ ID NO:4 and said heavy chain variable region that has the amino acid sequence of SEQ ID NO:3.
17. The method of claim 1 , wherein said antibody comprises the amino acid sequence of SEQ ID NO:21.
18. The method of claim 1 , wherein said antibody is a fully human antibody.
19. The method of claim 1 , wherein said antibody is a whole antibody comprising an antibody constant region.
20. The method of claim 19 , wherein said antibody comprises a heavy chain that has the amino acid sequence of SEQ ID NO:24 and a light chain that has the amino acid sequence of SEQ ID NO:25.
21. The method of claim 1 , wherein said antibody is an antigen binding fragment of an antibody.
22. The method of claim 1 , wherein said antibody has a binding affinity for VEGF that corresponds to a Kd of less than 10 nM when said antibody is in IgG format.
23. A method for inhibiting angiogenesis in the treatment of an animal that has a disease characterized by excessive or pathological angiogenesis, said method comprising administering an antibody that binds to VEGF, or an immunoconjugate thereof, to said animal in an amount effective to inhibit said angiogenesis, thereby treating said disease in said animal
wherein the antibody that binds to VEGF comprises at least one heavy chain variable region that comprises three CDRs and at least one light chain variable region that comprises three CDRs, wherein said antibody comprises:
(a) a variable light (VL) CDR1 having the amino acid sequence of SEQ ID NO:8, a VL CDR2 having the amino acid sequence of SEQ ID NO:9, a VL CDR3 having the amino acid sequence of SEQ ID NO:10, a variable heavy (VH) CDR1 having the amino acid sequence of SEQ ID NO:5, a VH CDR2 having the amino acid sequence of SEQ ID NO:6, and a VH CDR3 having the amino acid sequence of SEQ ID NO:7; or
(b) a light chain variable region that has the amino acid sequence of SEQ ID NO:4, or a heavy chain variable region that has the amino acid sequence of SEQ ID NO:3.
24. The method of claim 23 , wherein said disease is cancer.
25. The method of claim 24 , wherein said cancer is selected from the group consisting of lung, breast, ovary, colorectal, kidney, bladder, small cell carcinomas and glioblastomas.
26. The method of claim 23 , wherein said disease is associated with corneal, retinal or choroidal neovascularization.
27. The method of claim 23 , wherein said disease is ocular neovascular disease, macular degeneration, age-related macular degeneration, diabetic retinopathy, neovascular glaucoma, arthritis, rheumatoid arthritis, atherosclerosis, thyroid hyperplasia, Grave's disease, hemangioma or psoriasis.
28. The method of claim 23 , wherein said animal is a human subject.
29. The method of claim 23 , wherein said antibody is attached to at least a first therapeutic agent.
30. The method of claim 29 , wherein the at least a first therapeutic agent is selected from the group consisting of radiotherapeutic agent, chemotherapeutic agent, anti-angiogenic agent, apoptosis-inducing agent, anti-tubulin drug, anti-cellular or cytotoxic agent, cytokine, chemokine and coagulant.
31. The method of claim 23 , further comprising administering a second therapeutic agent to said animal.
32. The method of claim 24 , further comprising administering a second therapeutic agent to said animal, wherein said second therapeutic agent is an anti-cancer agent.
33. The method of claim 32 , wherein said second therapeutic agent is an anti-cancer agent selected from the group consisting of pyrimidine analogs, platinum coordination complexes, camptothecins, tyrosine kinase inhibitors and inhibitors of receptor tyrosine kinases.
34. The method of claim 32 , wherein said second anti-cancer agent is 5-fluorouracil, capecitabine, oxaliplatin, cisplatin, carboplatin, irinotecan, axitinib, sunitinib, or paclitaxel.
35. The method of claim 23 , wherein said antibody comprises said VL CDR1 having the amino acid sequence of SEQ ID NO:8, said VL CDR2 having the amino acid sequence of SEQ ID NO:9, said VL CDR3 having the amino acid sequence of SEQ ID NO:10, said VH CDR1 having the amino acid sequence of SEQ ID NO:5, said VH CDR2 having the amino acid sequence of SEQ ID NO:6, and said VH CDR3 having the amino acid sequence of SEQ ID NO:7.
36. The method of claim 23 , wherein said antibody comprises said light chain variable region that has the amino acid sequence of SEQ ID NO:4.
37. The method of claim 23 , wherein said antibody comprises said heavy chain variable region that has the amino acid sequence of SEQ ID NO:3.
38. The method of claim 23 , wherein said antibody comprises said light chain variable region that has the amino acid sequence of SEQ ID NO:4 and said heavy chain variable region that has the amino acid sequence of SEQ ID NO:3.
39. The method of claim 23 , wherein said antibody comprises the amino acid sequence of SEQ ID NO:21.
40. The method of claim 23 , wherein said antibody is a fully human antibody.
41. The method of claim 23 , wherein said antibody is a whole antibody comprising an antibody constant region.
42. The method of claim 41 , wherein said antibody comprises a heavy chain that has the amino acid sequence of SEQ ID NO:24 and a light chain that has the amino acid sequence of SEQ ID NO:25.
43. The method of claim 23 , wherein said antibody is an antigen binding fragment of an antibody.
44. The method of claim 23 , wherein said antibody has a binding affinity for VEGF that corresponds to a Kd of less than 10 nM when said antibody is in IgG format.
45. A method for treating cancer characterized by excessive angiogenesis in an animal, said method comprising administering an antibody that binds to VEGF, or an immunoconjugate thereof, to said animal in an amount effective to inhibit said angiogenesis, thereby treating said cancer in said animal; wherein the antibody that binds to VEGF comprises at least one heavy chain variable region that comprises three CDRs and at least one light chain variable region that comprises three CDRs, wherein said antibody comprises:
(a) a variable light (VL) CDR1 having the amino acid sequence of SEQ ID NO:8, a VL CDR2 having the amino acid sequence of SEQ ID NO:9, a VL CDR3 having the amino acid sequence of SEQ ID NO:10, a variable heavy (VH) CDR1 having the amino acid sequence of SEQ ID NO:5, a VH CDR2 having the amino acid sequence of SEQ ID NO:6, and a VH CDR3 having the amino acid sequence of SEQ ID NO:7; or
(b) a light chain variable region that has the amino acid sequence of SEQ ID NO:4, or a heavy chain variable region that has the amino acid sequence of SEQ ID NO:3.