Anti c-Met antibodies
The present invention relates to antibodies that specifically bind to the human c-Met receptor protein and that act as strict antagonists of hepatocyte growth factor (HGF)-mediated activation of the c-Met receptor and also inhibit HGF-independent activation of the human c-Met protein.
1. A method of treating cancer in a human patient which comprises administering to a patient in need thereof a therapeutically effective amount of an isolated antibody, or an antigen binding fragment thereof, that specifically binds human c-Met protein, wherein the antibody or antigen binding fragment thereof comprises a heavy chain variable domain comprising CDRH3, CDRH2, and CDRH1 regions, and a light chain variable domain comprising CDRL3, CDRL2, and CDRL1 regions, wherein the CDRH3, CDRH2, CDRH1, CDRL3, CDRL2, and CDRL1 regions comprise the amino acid sequences set forth in SEQ ID NOs: 21, 83, 19, 33, 32, and 31, respectively, and wherein said administering inhibits dimerization of human c-Met receptors, thereby treating the cancer.
2. The method of claim 1 , wherein the cancer is an HGF-independent c-Met-associated cancer.
3. The method of claim 1 , wherein the cancer is an HGF-dependent activated c-Met-associated cancer.
4. The method of claim 1 , wherein the cancer is selected from the group consisting of gastric carcinomas; esophageal carcinomas; medulloblastomas; liver metastases from colon carcinoma; papillary renal carcinomas; head and neck squamous cell carcinomas; thyroid, ovarian, pancreatic, prostate, renal cell, hepatocellular, breast, and colorectal carcinomas; glioblastomas; rhabdomyosarcomas; and osteosarcomas.
5. A method of treating cancer in a human patient which comprises administering to a patient in need thereof a therapeutically effective amount of an isolated antibody, or an antigen binding fragment thereof, that specifically binds human c-Met protein, wherein the antibody or antigen binding fragment thereof comprises a heavy chain variable domain and a light chain variable domain, the heavy chain variable domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 92, 94, and 96, and wherein said administering inhibits dimerization of human c-Met receptors, thereby treating the cancer.
6. The method of claim 5 , wherein the heavy chain variable domain comprises the amino acid sequence set forth in SEQ ID NO: 92.
7. The method of claim 5 , wherein the heavy chain variable domain comprises the amino acid sequence set forth in SEQ ID NO: 94.
8. The method of claim 5 , wherein the heavy chain variable domain comprises the amino acid sequence set forth in SEQ ID NO: 96.
9. The method of claim 5 , wherein the cancer is an HGF-independent c-Met-associated cancer.
10. The method of claim 5 , wherein the cancer is an HGF-dependent activated c-Met-associated cancer.
11. The method of claim 5 , wherein the cancer is selected from the group consisting of gastric carcinomas; esophageal carcinomas; medulloblastomas; liver metastases from colon carcinoma; papillary renal carcinomas; head and neck squamous cell carcinomas; thyroid, ovarian, pancreatic, prostate, renal cell, hepatocellular, breast, and colorectal carcinomas; glioblastomas; rhabdomyosarcomas; and osteosarcomas.
12. A method of treating cancer in a human patient which comprises administering to a patient in need thereof a therapeutically effective amount of an isolated antibody, or an antigen binding fragment thereof, that specifically binds human c-Met protein, wherein the antibody or antigen binding fragment thereof comprises a heavy chain variable domain and a light chain variable domain, the light chain variable domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 93, 95, and 97, and wherein said administering inhibits dimerization of human c-Met receptors, thereby treating the cancer.
13. The method of claim 12 , wherein the light chain variable domain comprises the amino acid sequence set forth in SEQ ID NO: 93.
14. The method of claim 12 , wherein the light chain variable domain comprises the amino acid sequence set forth in SEQ ID NO: 95.
15. The method of claim 12 , wherein the light chain variable domain comprises the amino acid sequence set forth in SEQ ID NO: 97.
16. The method of claim 12 , wherein the cancer is an HGF-independent c-Met-associated cancer.
17. The method of claim 12 , wherein the cancer is an HGF-dependent activated c-Met-associated cancer.
18. The method of claim 12 , wherein the cancer is selected from the group consisting of gastric carcinomas; esophageal carcinomas; medulloblastomas; liver metastases from colon carcinoma; papillary renal carcinomas; head and neck squamous cell carcinomas; thyroid, ovarian, pancreatic, prostate, renal cell, hepatocellular, breast, and colorectal carcinomas; glioblastomas; rhabdomyosarcomas; and osteosarcomas.
19. A method of treating cancer in a human patient which comprises administering to a patient in need thereof a therapeutically effective amount of an isolated antibody, or an antigen binding fragment thereof, that specifically binds human c-Met protein, wherein the antibody or antigen binding fragment thereof comprises a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain and the light chain variable domain comprise the amino acid sequences set forth in SEQ ID NOs: 92 and 93; 94 and 95; or 96 and 97, respectively, and wherein said administering inhibits dimerization of human c-Met receptors, thereby treating the cancer.
20. The method of claim 19 , wherein the heavy chain variable domain and the light chain variable domain comprise the amino acid sequences set forth in SEQ ID NOs: 92 and 93, respectively.
21. The method of claim 19 , wherein the heavy chain variable domain and the light chain variable domain comprise the amino acid sequences set forth in SEQ ID NOs: 94 and 95, respectively.
22. The method of claim 19 , wherein the heavy chain variable domain and the light chain variable domain comprise the amino acid sequences set forth in SEQ ID NOs: 96 and 97, respectively.
23. The method of claim 19 , wherein the cancer is an HGF-independent c-Met-associated cancer.
24. The method of claim 19 , wherein the cancer is an HGF-dependent activated c-Met-associated cancer.
25. The method of claim 19 , wherein the cancer is selected from the group consisting of gastric carcinomas; esophageal carcinomas; medulloblastomas; liver metastases from colon carcinoma; papillary renal carcinomas; head and neck squamous cell carcinomas; thyroid, ovarian, pancreatic, prostate, renal cell, hepatocellular, breast, and colorectal carcinomas; glioblastomas; rhabdomyosarcomas; and osteosarcomas.