Human anti-VEGFR-2/KDR antibodies
The invention relates to antibodies that bind to VEGFR-2. The antibodies are used for treating neoplastic diseases, hyperproliferative disorders, and angiogenic disorders and can be used alone or in combination with other agents.
1. An isolated antibody or fragment thereof that binds to human VEGFR2, comprising a heavy chain variable domain comprising a CDR-1H, CDR-2H, and CDR-3H sequence and a light chain variable domain comprising a CDR-1L, CDR-2L, and CDR-3L sequence, wherein:
(i) the CDR-1H sequence consists of residues 26 to 35 of SEQ ID NO: 4;
(ii) the CDR-2H sequence consists of residues 50 to 66 of SEQ ID NO: 4;
(iii) the CDR-3H sequence is SEQ ID NO:3;
(iv) the CDR-1L, CDR-2L, and CDR-3L sequences are selected from the group consisting of:
SEQ ID NO:5, SEQ ID NO:6, and SEQ ID NO:7;
SEQ ID NO:21, SEQ ID NO:22, and SEQ ID NO:23;
SEQ ID NO:25, SEQ ID NO:26, and SEQ ID NO:27;
SEQ ID NO:29, SEQ ID NO:30, and SEQ ID NO:31;
SEQ ID NO:33, SEQ ID NO:34, and SEQ ID NO:35;
SEQ ID NO:37, SEQ ID NO:38, and SEQ ID NO:39;
SEQ ID NO:41, SEQ ID NO:42, and SEQ ID NO:43; and
SEQ ID NO:45; SEQ ID NO:46, and SEQ ID NO:47.
2. A method of neutralizing activation of VEGFR2 comprising contacting a cell with an effective amount of an antibody of claim 1 .
3. A method of inhibiting angiogenesis in a mammal comprising administering to a mammal in need thereof an effective amount of an antibody of claim 1 .
4. The method of claim 3 , which further comprises administering to the mammal an antineoplastic agent.
5. The method of claim 4 , wherein the antineoplastic agent is an epidermal growth factor receptor (EGFR) antagonist.
6. The method of claim 3 , which further comprises administering to the mammal a second angiogenesis inhibitor.
7. The method of claim 3 , which further comprises administering to the mammal an anti-inflammatory agent or an immunosuppressant.
8. A method of reducing tumor growth in a mammal comprising administering to a mammal in need thereof an effective amount of an antibody of claim 1 .
9. The method of claim 8 , which further comprises administering to the mammal in need thereof an amount of an epidermal growth factor receptor (EGFR) antagonist effective in inhibiting EGFR-dependent signal transduction.
10. The method of claim 8 , which further comprises administering to the mammal in need thereof an amount of an fms-like tyrosine kinase receptor (flt-1) antagonist effective to reduce VEGF-induced or PlGF-induced activation of VEGFR-1.
11. The method of claim 8 , which further comprises administering to the mammal in need thereof an amount of a matrix metalloproteinase antagonist effective in increasing tumor cell apoptosis.
12. The method of claim 8 , which further comprises administering to the mammal an antineoplastic agent.
13. The method of claim 12 , wherein the antineoplastic agent is an epidermal growth factor receptor (EGFR) antagonist.
14. The method of claim 8 , which further comprises administering to the mammal a second angiogenesis inhibitor.
15. The method of claim 8 , which further comprises administering to the mammal an anti-inflammatory agent or an immunosuppressant.
16. The antibody of claim 1 , wherein the CDR-1L sequence is SEQ ID NO:5, the CDR-2L sequence is SEQ ID NO:6, and the CDR-3L sequence is SEQ ID NO:7.
17. The antibody of claim 1 , wherein the CDR-1L sequence is SEQ ID NO:21, the CDR-2L sequence is SEQ ID NO:22, and the CDR-3L sequence is SEQ ID NO:23.
18. The antibody of claim 1 , wherein the CDR-1L sequence is SEQ ID NO:25, the CDR-2L sequence is SEQ ID NO:26, and the CDR-3L sequence is SEQ ID NO:27.
19. The antibody of claim 1 , wherein the CDR-1L sequence is SEQ ID NO:29, the CDR-2L sequence is SEQ ID NO:30, and the CDR-3L sequence is SEQ ID NO:31.
20. The antibody of claim 1 , wherein the CDR-1L sequence is SEQ ID NO:33, the CDR-2L sequence is SEQ ID NO:34, and the CDR-3L sequence is SEQ ID NO:35.
21. The antibody of claim 1 , wherein the CDR-1L sequence is SEQ ID NO:37, the CDR-2L sequence is SEQ ID NO:38, and the CDR-3L sequence is SEQ ID NO:39.
22. The antibody of claim 1 , wherein the CDR-1L sequence is SEQ ID NO:41, the CDR-2L sequence is SEQ ID NO:42, and the CDR-3L sequence is SEQ ID NO:43.
23. The antibody of claim 1 , wherein the CDR-1L sequence is SEQ ID NO:45, the CDR-2L sequence is SEQ ID NO:46, and the CDR-3L sequence is SEQ ID NO:47.
24. The antibody of claim 1 , wherein the heavy chain variable domain sequence is SEQ ID NO:4 or a sequence that is at least 95% identical to SEQ ID NO:4 and the light chain variable domain sequence is selected from the group consisting of SEQ ID NO:8, a sequence that is at least 95% identical to SEQ ID NO:8, SEQ ID NO:24, a sequence that is at least 95% identical to SEQ ID NO:24, SEQ ID NO:28, a sequence that is at least 95% identical to SEQ ID NO:28, SEQ ID NO:32, a sequence that is at least 95% identical to SEQ ID NO:32, SEQ ID NO:36, a sequence that is at least 95% identical to SEQ ID NO:36, SEQ ID NO:40, a sequence that is at least 95% identical to SEQ ID NO:40, SEQ ID NO:44, a sequence that is at least 95% identical to SEQ ID NO:44, SEQ ID NO:48, and a sequence that is at least 95% identical to SEQ ID NO:48.
25. The antibody of claim 1 , wherein the light chain variable domain sequence is selected from the group consisting of SEQ ID NO:8 and a sequence that is at least 95% identical to SEQ ID NO:8.
26. The antibody of claim 1 , wherein the light chain variable domain sequence is selected from the group consisting of SEQ ID NO:24 and a sequence that is at least 95% identical to SEQ ID NO:24.
27. The antibody of claim 1 , wherein the light chain variable domain sequence is selected from the group consisting of SEQ ID NO:28 and a sequence that is at least 95% identical to SEQ ID NO:28.
28. The antibody of claim 1 , wherein the light chain variable domain sequence is selected from the group consisting of SEQ ID NO:32 and a sequence that is at least 95% identical to SEQ ID NO:32.
29. The antibody of claim 1 , wherein the light chain variable domain sequence is selected from the group consisting of SEQ ID NO:36 and a sequence that is at least 95% identical to SEQ ID NO:36.
30. The antibody of claim 1 , wherein the light chain variable domain sequence is selected from the group consisting of SEQ ID NO:40 and a sequence that is at least 95% identical to SEQ ID NO:40.
31. The antibody of claim 1 , wherein the light chain variable domain sequence is selected from the group consisting of SEQ ID NO:44 and a sequence that is at least 95% identical to SEQ ID NO:44.
32. The antibody of claim 1 , wherein the light chain variable domain sequence is selected from the group consisting of SEQ ID NO:48 and a sequence that is at least 95% identical to SEQ ID NO:48.
33. An isolated antibody or fragment thereof that binds to human VEGFR2, comprising a heavy chain variable domain comprising a CDR-1H, CDR-2H, and CDR-3H sequence and a light chain variable domain comprising a CDR-1L, CDR-2L, and CDR-3L sequence, wherein:
(i) the CDR-1H sequence consists of residues 26 to 35 of SEQ ID NO: 12;
(ii) the CDR-2H sequence consists of residues 50 to 66 of SEQ ID NO: 12;
(iii) the CDR-3H sequence is SEQ ID NO:11;
(iv) the CDR-1L sequence is SEQ ID NO:13;
(v) the CDR-2L sequence is SEQ ID NO:14;
(vi) the CDR-3L sequence is SEQ ID NO:15.
34. The antibody of claim 33 , wherein the heavy chain variable domain sequence is selected from the group consisting of SEQ ID NO:12 and a sequence that is at least 95% identical with SEQ ID NO:12 and wherein the light chain variable domain sequence is selected from the group consisting of SEQ ID NO:16 and a sequence that is at least 95% identical with SEQ ID NO:16.