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 human folate receptor 1 (FOLR1) to the subject, wherein the antibody comprises:
(a) a heavy chain (HC) CDR1 comprising the amino acid sequence of GYTFTGYFMN (SEQ ID NO: 132), a HC CDR2 comprising the amino acid sequence of RIHPYDGDTF (SEQ ID NO:131), and a HC CDR3 comprising the amino acid sequence of YDGSRAMDY (SEQ ID NO:3); and
(b) a light chain (LC) CDR1 comprising the amino acid sequence of KASQSVSFAGTSLMH (SEQ ID NO:7); a LC CDR2 comprising the amino acid sequence of RASNLEA (SEQ ID NO:8), and a LC CDR3 comprising the amino acid sequence of QQSREYPYT (SEQ ID NO:9).
2. The method of claim 1 , wherein the HC CDR2 comprises the amino acid sequence of RIHPYDGDTFYNQKFQG (SEQ ID NO:2).
3. The method of claim 1 , wherein the antibody comprises a HC variable domain comprising the amino acid sequence of SEQ ID NO:4.
4. The method of claim 3 , wherein the antibody comprises a HC comprising the amino acid sequence of SEQ ID NO:6.
5. The method of claim 1 , wherein the antibody comprises a LC variable domain comprising the amino acid sequence of SEQ ID NO:10 or SEQ ID NO:11.
6. The method of claim 5 , wherein the antibody comprises a LC comprising the amino acid sequence of SEQ NO:12 or SEQ ID NO:13.
7. The method of claim 1 , wherein the antibody comprises a HC encoded by the plasmid DNA deposited with the ATCC on Apr. 7, 2010 and having the ATCC deposit no. PTA-10772.
8. The method of claim 1 , wherein the antibody comprises a LC encoded by the plasmid DNA deposited with the ATCC on Apr. 7, 2010 and having the ATCC deposit no. PTA-10773 or PTA-10774.
9. The method of claim 1 , wherein the antibody competes with the chimeric antibody Mov19 (chMov19) for specific binding to human FOLR1.
10. The method of claim 1 , wherein the antibody binds human FOLR1 with the same affinity as chMov19, and wherein the binding affinity is measured by flow cytometry.
11. The method of claim 1 , wherein the antibody binds to human FOLR1 with a Kd of 1.0 nM or better, and wherein the binding affinity is measured by flow cytometry.
12. The method of claim 11 , wherein the antibody binds to human FOLR 1 with a Kd of about 0.06 nM to about 1.0 nM.
13. 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, peritoneal cancer, and lung cancer.
14. The method of claim 13 , wherein the cancer is ovarian cancer.
15. The method of claim 13 , wherein the cancer is lung cancer.
16. The method of claim 13 , wherein the cancer is endometrial cancer.
17. The method of claim 13 , wherein the cancer is peritoneal cancer.
18. 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) is an antibody or antigen binding fragment thereof that specifically binds human FOLR1;
(L) is a linker; and
(C) is a cytotoxic agent;
wherein (L) links (A) to (C); and
wherein the antibody or antigen binding fragment thereof comprises:
(a) a HC CDR1 comprising the amino acid sequence of GYTFTGYFMN (SEQ ID NO:132), a HC CDR2 comprising the amino acid sequence of RIHPYDGDTF (SEQ ID NO:131), and a HC CDR3 comprising the amino acid sequence of YDGSRAMDY (SEQ ID NO:3); and
(b) a LC CDR1 comprising the amino acid sequence of KASQSVSFAGTSLMH (SEQ ID NO:7), a LC CDR2 comprising the amino acid sequence of RASNLEA (SEQ ID NO:8) and a LC CDR3 comprising the amino acid sequence of QQSREYPYT (SEQ ID NO:9).
19. The method of claim 18 , wherein the HC CDR2 comprises the amino acid sequence of RIHPYDGDTFYNQKFQG (SEQ ID NO:2).
20. The method of claim 18 , wherein the antibody or antigen binding fragment thereof comprises a FTC variable domain comprising the amino acid sequence of SEQ ID NO:4.
21. The method of claim 20 , wherein the antibody comprises a HC comprising the amino acid sequence of SEQ ID NO:6.
22. The method of claim 18 , wherein the antibody or antigen binding fragment thereof comprises a LC variable domain comprising the amino acid sequence of SEQ ID NO:10 or SEQ ID NO:11.
23. The method of claim 22 , wherein the antibody comprises a LC comprising the amino acid sequence of SEQ ID NO:12 or SEQ ID NO: 13.
24. The method of claim 18 , wherein the antibody comprises a HC encoded by the plasmid DNA deposited with the ATCC on Apr. 7, 2010 and having the ATCC deposit no. PTA-10772.
25. The method of claim 18 , wherein the antibody comprises a LC encoded by the plasmid DNA deposited with the ATCC on Apr. 7, 2010 and having the ATCC deposit no. PTA-10773 or PTA-10774.
26. The method of claim 18 , wherein the cancer is selected from the group consisting of: ovarian cancer, breast cancer, uterine cancer, endometrial cancer, pancreatic cancer, renal cancer, peritoneal cancer, and lung cancer.
27. The method of claim 26 , wherein the cancer is ovarian cancer.
28. The method of claim 26 , wherein the cancer is lung cancer.
29. The method of claim 26 , wherein the cancer is endometrial cancer.
30. The method of claim 26 , wherein the cancer is peritoneal cancer.
31. The method of claim 18 , wherein the cancer is brain cancer, and wherein the immunoconjugate is administered intracranially.
32. The method of claim 31 , wherein the immunoconjugate is administered intrathecally or intraventricularly.
33. The method of claim 18 , wherein (L) is a cleavable linker.
34. The method of claim 18 , wherein (L) is a non-cleavable linker.
35. The method of claim 18 , wherein (L) is a hydrophilic.
36. The method of claim 18 , wherein (L) is a dicarboxylic acid based linker.
37. The method of claim 18 , wherein (L) is a linker selected from the group consisting of: N-succinimidyl 4-(2-pyridyldithio)pentanoate (SPP); N-succinimidyl 4-(2-pyridyldithio)-2-sulfopentanoate (sulfo-SPP); N-succinimidyl 4-(2-pyridyldithio)butanoate (SPDB); 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 (SLAB); and N-succinimidyl-[(N-maleimidopropionamido)-tetraethyleneglycol]ester (NHS-PEG4-maleimide).
38. The method of claim 37 , wherein (L) is N-succinimidyl 4-(2-pyriclyldithio)-2-sulfobutanoate(sulfo-SPDB).
39. The method of claim 37 , wherein (L) is N-succinimidyl 4-(2-pyridyldithio)butanoate(SPDB).
40. The method of claim 18 , wherein (C) is a cytotoxic agent selected from the group consisting of: maytansinoid, benzodiazepine, taxoid, CC-1065, duocarmycin, calicheamicin, dolastatin, auristatin, tomaymycin, and leptomycin or a prodrug of the cytotoxic agent.
41. The method of claim 40 , wherein (C) is a maytansinoid.
42. The method of claim 41 , wherein (C) is N(2′)-deacetyl-N(2′)-(3-mercapto-1-oxopropyl)-maytansine (DM1).
43. The method of claim 41 , wherein (C) is N(2′)-deacetyl-N(2)-(4-mercapto-4-methyl-1-oxopentyl)-maytansine (DM4).
44. The method of claim 18 , wherein the immunoconjugate comprises 1-10 (C).
45. The method of claim 18 , wherein the immunoconjugate comprises 2-6 (C).
46. 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) is an antibody or antigen binding fragment thereof that specifically binds human FOLR1;
(L) is the linker N-succinimidyl 4-(2-pyridyldithio)-2-sulfobutanoate (sulfo-SPDB); and
(C) is the cytotoxic agent N(2)-deacetyl-N(2′)-(4-mercapto-4-methyl-1-oxopentyl)-maytansine (DM4);
wherein (L) links (A) to (C); and
wherein the antibody or antigen binding fragment thereof comprises:
(a) a HC CDR1comprising the amino acid sequence of GYTFTGYFMN (SEQ ID NO:132), a HC CDR2 comprising the amino acid sequence of RIHPYDGDTF (SEQ ID NO:131), and a HC CDR3 comprising the amino acid sequence of YDGSRAMDY (SEQ ID NO:3); and
(b) a LC CDR1 comprising the amino acid sequence of KASQSVSFAGTSLMH (SEQ ID NO:7), a LC CDR2 comprising the amino acid sequence of RASNLEA (SEQ ID NO:8) and a LC CDR3 comprising the amino acid sequence of QQSREYPYT (SEQ ID NO: 9).
47. The method of claim 46 , wherein the HC CDR2 comprises the amino acid sequence of RIHPYDGDTFYNQICFQG (SEQ ID NO:2).
48. The method of claim 46 , wherein the antibody or antigen binding fragment thereof comprises a HC variable domain comprising the amino acid sequence of SEQ ID NO:4.
49. The method of claim 48 , wherein the antibody comprises a HC comprising the amino acid sequence of SEQ ID NO:6.
50. The method of claim 46 , wherein the antibody or antigen binding fragment thereof comprises a LC variable domain comprising the amino acid sequence of SEQ ID NO:10 or SEQ ID NO:11.
51. The method of claim 50 , wherein the antibody comprises a LC comprising the amino acid sequence of SEQ ID NO: 12 or SEQ ID NO:13.
52. The method of claim 46 , wherein the immunoconjugate comprises 1-10 (C).
53. The method of claim 46 , wherein the cancer is selected from the group consisting of ovarian cancer, breast cancer, uterine cancer, endometrial cancer, pancreatic cancer, renal cancer, peritoneal cancer, and lung cancer.
54. The method of claim 53 , wherein the cancer is ovarian cancer.
55. The method of claim 53 , wherein the cancer is lung cancer.
56. The method of claim 53 , wherein the cancer is endometrial cancer.
57. The method of claim 53 , wherein the cancer is peritoneal cancer.
58. The method of claim 46 , wherein the cancer is brain cancer, and wherein the immunoconjugate is administered intracranially.
59. The method of claim 19 , wherein the antibody comprises a HC encoded by the plasmid DNA deposited with the ATCC on Apr. 7, 2010 and having the ATCC deposit no, PTA-10772 and a LC encoded by the plasmid DNA deposited with the ATCC on Apr. 7, 2010 and having the ATCC deposit no. PTA-10774.
60. The method of claim 40 , wherein the antibody comprises a HC encoded by the plasmid DNA deposited with the ATCC on Apr. 7, 2010 and having the ATCC deposit no. PTA-10772 and a LC encoded by the plasmid DNA deposited with the ATCC on Apr. 7, 2010 and having the ATCC deposit no. PTA-10774.
61. The method of claim 46 , wherein the antibody comprises a HC encoded by the plasmid DNA deposited with the ATCC on Apr. 7, 2010 and having the ATCC deposit no, PTA-10772 and a LC encoded by the plasmid DNA deposited with the ATCC on Apr. 7, 2010 and having the ATCC deposit no. PTA-10774.
62. The method of claim 61 , wherein the immunoconjugate comprises 1-10 (C).
63. The method of claim 61 , wherein the cancer is selected from the group consisting of: ovarian cancer, breast cancer, uterine cancer, endometrial cancer, pancreatic cancer, renal cancer, peritoneal cancer, and lung cancer.
64. The method of claim 63 , wherein the cancer is ovarian cancer.
65. The method of claim 63 , wherein the cancer is uterine cancer.
66. The method of claim 63 , wherein the cancer is endometrial cancer.
67. The method of claim 63 , wherein the cancer is peritoneal cancer.
68. The method of claim 61 , wherein the cancer is brain cancer, and wherein the immunoconjugate is administered intracranially.
69. The method of claim 62 , wherein the cancer is selected from the group consisting of: ovarian cancer, breast cancer, uterine cancer, endometrial cancer, pancreatic cancer, renal cancer, peritoneal cancer, and lung cancer.
70. The method of claim 69 , wherein the cancer is ovarian cancer.
71. The method of claim 69 , wherein the cancer is uterine cancer.
72. The method of claim 69 , wherein the cancer is endometrial cancer.
73. The method of claim 69 , wherein the cancer is peritoneal cancer.
74. The method of claim 62 , wherein the cancer is brain cancer, and wherein the immunoconjugate is administered intracranially.