Folate receptor 1 antibodies and immunoconjugates and uses thereof
Novel anti-cancer agents, including, but not limited to, antibodies and immunoconjugates, that bind to human folate receptor 1 are provided. Methods of using the agents, antibodies, or immunoconjugates, such as methods of inhibiting tumor growth are further provided.
1. A method of treating cancer in a subject, comprising administering a therapeutically effective amount of an antibody that specifically binds a human folate receptor to the subject, wherein the antibody comprises:
(a) a heavy chain CDR1 comprising GYFMN (SEQ ID NO:1); a heavy chain CDR2 comprising RIHPYDGDTFYNQKFQG (SEQ ID NO:2); and a heavy chain CDR3 comprising YDGSRAMDY (SEQ ID NO:3); and
(b) a light chain CDR1 comprising KASQSVSFAGTSLMH (SEQ ID NO:7); a light chain CDR2 comprising RASNLEA (SEQ ID NO:8); and a light chain CDR3 comprising QQSREYPYT (SEQ ID NO:9).
2. The method of claim 1 , wherein the antibody competes with chimeric Mov19 for specific binding to a human folate receptor; and wherein the chimeric Mov19 comprises a heavy chain of SEQ ID NO:19 and a light chain of SEQ IS NO:20.
3. The method of claim 1 , wherein the antibody comprises a heavy chain variable domain of SEQ ID NO:4 and a light chain variable domain of SEQ ID NO:10 or SEQ ID NO:11.
4. The method of claim 1 , wherein the antibody comprises a heavy chain of SEQ ID NO:6 and a light chain of SEQ ID NO:12 or SEQ ID NO:13.
5. The method of claim 1 , wherein the antibody comprises a heavy chain encoded by the plasmid DNA deposited with the ATCC on Apr. 7, 2010 and having ATCC deposit no. PTA-10772 and a light chain encoded by the plasmid DNA deposited with the ATCC on Apr. 7, 2010 and having ATCC deposit no. PTA-10773 or 10774.
6. The method of claim 1 , wherein the cancer is selected from the group consisting of: ovarian cancer, breast cancer, uterine cancer, endometrial cancer, pancreatic cancer, renal cancer, and lung cancer.
7. The method of claim 6 , wherein the cancer is ovarian cancer.
8. The method of claim 6 , wherein the cancer is lung cancer.
9. The method of claim 6 , wherein the cancer is endometrial cancer.
10. The method of claim 1 , further comprising administering a second anti-cancer agent to the subject.
11. The method of claim 10 , wherein said second anti-cancer agent is a chemotherapeutic agent.
12. A method of inhibiting cancer growth in a subject, comprising administering a therapeutically effective amount of an immunoconjugate having the formula (A) -(L)-(C) to the subject, wherein:
(A) is an antibody or antigen binding fragment thereof that specifically binds a human folate receptor;
(L) is a linker; and
(C) is a cytotoxic agent;
wherein (L) links (A) to (C),
wherein the antibody or antigen binding fragment thereof comprises:
(a) a heavy chain CDR1 comprising GYFMN (SEQ ID NO:1); a heavy chain CDR2 comprising RIHPYDGDTFYNQKFQG (SEQ ID NO:2); and a heavy chain CDR3 comprising YDGSRAMDY (SEQ ID NO:3); and
(b) a light chain CDR1 comprising KASQSVSFAGTSLMH (SEQ ID NO:7); a light chain CDR2 comprising RASNLEA (SEQ ID NO:8); and a light chain CDR3 comprising QQSREYPYT (SEQ ID NO:9).
13. The method of claim 12 , wherein the antibody or antigen binding fragment thereof comprises a heavy chain variable domain of SEQ ID NO:4 and a light chain variable domain of SEQ ID NO:10 or SEQ ID NO:11.
14. The method of claim 12 , wherein the antibody comprises a heavy chain of SEQ ID NO:6 and a light chain of SEQ ID NO:12 or SEQ ID NO:13.
15. The method of claim 12 , wherein the antibody comprises a heavy chain encoded by the plasmid DNA deposited with the ATCC on Apr. 7, 2010 and having ATCC deposit no. PTA-10772 and a light chain encoded by the plasmid DNA deposited with the ATCC on Apr. 7, 2010 and having ATCC deposit no. PTA-10773 or PTA-10774.
16. The method of claim 12 , wherein the cancer is selected from the group consisting of: ovarian cancer, breast cancer, uterine cancer, endometrial cancer, pancreatic cancer, renal cancer, and lung cancer.
17. The method of claim 16 , wherein the cancer is ovarian cancer.
18. The method of claim 16 , wherein the cancer is lung cancer.
19. The method of claim 16 , wherein the cancer is endometrial cancer.
20. The method of claim 12 , further comprising administering a second anti-cancer agent to the subject.
21. The method of claim 20 , wherein said second anti-cancer agent is a chemotherapeutic agent.
22. The method of claim 12 , wherein (L) is a linker selected from the group consisting of a cleavable linker, a non-cleavable linker, a hydrophilic linker, and a dicarboxylic acid based linker.
23. The method of claim 12 , wherein (L) is a linker selected from the group consisting of N-succinimidyl 4-(2-pyridyldithio)pentanoate (SPP) or N-succinimidyl 4-(2-pyridyldithio)-2-sulfopentanoate (sulfo-SPP); N-succinimidyl 4-(2-pyridyldithio)butanoate (SPDB) or N-succinimidyl 4-(2-pyridyldithio)-2-sulfobutanoate (sulfo-SPDB); N-succinimidyl 4-(maleimidomethyl)cyclohexanecarboxylate (SMCC); N-sulfosuccinimidyl 4-(maleimidomethyl)cyclohexanecarboxylate (sulfoSMCC); N-succinimidyl-4-(iodoacetyl)-aminobenzoate (SIAB); and N-succinimidyl-[(N-maleimidopropionamido)-tetraethyleneglycol]ester (NHS-PEG4-maleimide).
24. The method of claim 23 , wherein (L) is N-succinimidyl 4-(2-pyridyldithio)butanoate (SPDB) or N-succinimidyl 4-(2-pyridyldithio)-2-sulfobutanoate (sulfo-SPDB).
25. The method of claim 12 , wherein (C) is a cytotoxic agent selected from the group consisting of a maytansinoid, benzodiazepine, taxoid, CC-1065, duocarmycin, calicheamicin, dolastatin, auristatin, tomaymycin, and leptomycin or a prodrug of the cytotoxic agent.
26. The method of claim 25 , wherein (C) is a maytansinoid.
27. The method of claim 12 , wherein (C) is N(2′)-deacetyl-N(2′)-(3-mercapto-1-oxopropyl)-maytansine or N(2′)-deacetyl-N(2′)-(4-mercapto-4-methyl-1-oxopentyl)-maytansine.
28. The method of claim 12 , wherein the immunoconjugates have an average of about 3 to about 4 (C) per (A).
29. The method of claim 12 , wherein the immunoconjugate comprises:
(A) a humanized antibody comprising the heavy chain variable domain of SEQ ID NO:4, and the light chain variable domain of SEQ ID NO:10 or SEQ ID NO:11;
(L) N-succinimidyl 4-(2-pyridyldithio)-2-sulfobutanoate (sulfo-SPDB); and
(C) N(2′)-deacetyl-N(2′)-(4-mercapto-4-methyl-1-oxopentyl)-maytansine.
30. A method of treating cancer in a subject, comprising administering a therapeutically effective amount of an immunoconjugate having the formula (A) -(L)-(C) to the subject, wherein:
(A) comprises a humanized antibody or antigen binding fragment thereof that specifically binds a human folate receptor;
(L) comprises the linker N-succinimidyl 4-(2-pyridyldithio)-2-sulfobutanoate (sulfo-SPDB); and
(C) comprises the cytotoxic agent N(2′)-deacetyl-N(2′)-(4-mercapto-4-methyl-1-oxopentyl)-maytansine;
wherein (L) links (A) to (C);
wherein the antibody or antigen binding fragment thereof comprises:
(a) a heavy chain CDR1 comprising GYFMN (SEQ ID NO:1); a heavy chain CDR2 comprising RIHPYDGDTFYNQKFQG (SEQ ID NO:2); and a heavy chain CDR3 comprising YDGSRAMDY (SEQ ID NO:3); and
(b) a light chain CDR1 comprising KASQSVSFAGTSLMH (SEQ ID NO:7); a light chain CDR2 comprising RASNLEA (SEQ ID NO:8); and a light chain CDR3 comprising QQSREYPYT (SEQ ID NO:9).
31. The method of claim 30 , wherein the antibody or antigen binding fragment thereof comprises a heavy chain variable domain of SEQ ID NO:4 and a light chain variable domain of SEQ ID NO:10 or SEQ ID NO:11.
32. The method of claim 31 , wherein the antibody or antigen binding fragment thereof comprises the light chain variable domain of SEQ ID NO:11.
33. The method of claim 30 , wherein the antibody comprises a heavy chain of SEQ ID NO:6 and a light chain of SEQ ID NO:12 or SEQ ID NO:13.
34. The method of claim 30 , wherein the cancer is selected from the group consisting of: ovarian cancer, breast cancer, uterine cancer, endometrial cancer, pancreatic cancer, renal cancer, and lung cancer.
35. The method of claim 34 , wherein the cancer is ovarian tumor.
36. The method of claim 34 , wherein the cancer is lung cancer.
37. The method of claim 34 , wherein the cancer is endometrial cancer.
38. The method of claim 30 , further comprising administering a second anti-cancer agent to the subject.
39. The method of claim 38 , wherein said second anti-cancer agent is a chemotherapeutic agent.
40. The method of claim 30 , wherein the immunoconjugates have an average of about 3 to about 4 (C) per (A).
41. The method of claim 12 , wherein the cancer is brain cancer, and wherein the immunoconjugate is administered intracranially.
42. The method of claim 41 , wherein the immunoconjugate is administered intrathecally or intraventricularly.
43. The method of claim 30 , wherein the cancer is brain cancer, and wherein the immunoconjugate is administered intracranially.
44. The method of claim 43 , wherein the immunoconjugate is administered intrathecally or intraventricularly.