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. An antibody or antigen binding fragment thereof that specifically binds a human folate receptor, wherein the antibody or antigen binding fragment thereof 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 antibody or antigen binding fragment thereof of claim 1 , wherein the antibody or antigen binding fragment thereof comprises a LC variable domain comprising an amino acid sequence at least about 95% identical to SEQ ID NO:10.
3. The antibody or antigen binding fragment thereof of claim 2 , wherein the antibody or antigen binding fragment thereof comprises a LC comprising an amino acid sequence at least about 95% identical to SEQ ID NO:12.
4. The antibody or antigen binding fragment thereof of claim 2 , wherein the LC variable domain comprises an amino acid sequence at least about 99% identical to SEQ ID NO:10.
5. The antibody or antigen binding fragment thereof of claim 4 , wherein the antibody or antigen binding fragment thereof comprises a LC comprising an amino acid sequence at least about 99% identical to SEQ ID NO:12.
6. The antibody or antigen binding fragment thereof of claim 1 , wherein the antibody or antigen binding fragment thereof comprises a LC variable domain comprising an amino acid sequence at least about 95% identical to SEQ ID NO:10 with conservative amino acid substitutions.
7. The antibody or antigen binding fragment thereof of claim 6 , wherein the antibody or antigen binding fragment thereof comprises a LC comprising an amino acid sequence at least about 95% identical to SEQ ID NO:12 with conservative amino acid substitutions.
8. The antibody or antigen binding fragment thereof of claim 6 , wherein the LC variable domain comprises an amino acid sequence at least about 99% identical to SEQ ID NO:10 with conservative amino acid substitutions.
9. The antibody or antigen binding fragment thereof of claim 8 , wherein the antibody or antigen binding fragment thereof comprises a LC comprising an amino acid sequence at least about 99% identical to SEQ ID NO:12 with conservative amino acid substitutions.
10. The antibody or antigen binding fragment thereof of claim 1 , wherein the antibody or antigen binding fragment thereof comprises a LC variable domain comprising the amino acid sequence of SEQ ID NO:10.
11. The antibody or antigen binding fragment thereof of claim 10 , wherein the antibody or antigen binding fragment thereof comprises a LC comprising the amino acid sequence of SEQ ID NO:12.
12. The antibody or antigen binding fragment thereof of claim 1 , wherein the antibody or antigen binding fragment thereof comprises a LC variable domain comprising an amino acid sequence at least about 95% identical to SEQ ID NO: 11.
13. The antibody or antigen binding fragment thereof of claim 12 , wherein the antibody or antigen binding fragment thereof comprises a LC comprising an amino acid sequence at least about 95% identical to SEQ ID NO:13.
14. The antibody or antigen binding fragment thereof of claim 12 , wherein the LC variable domain comprises an amino acid sequence at least about 99% identical to SEQ NO:11.
15. The antibody or antigen binding fragment thereof of claim 14 , wherein the antibody or antigen binding fragment thereof comprises a LC comprising an amino acid sequence at least about 99% identical to SEQ ID NO:13.
16. The antibody or antigen binding fragment thereof of claim 1 , wherein the antibody or antigen binding fragment thereof comprises a LC variable domain comprising an amino acid sequence at least about 95% identical to SEQ ID NO:11 with conservative amino acid substitutions.
17. The antibody or antigen binding fragment thereof of claim 16 , wherein the antibody or antigen binding fragment thereof comprises a LC comprising an amino acid sequence at least about 95% identical to SEQ NO:13 with conservative amino acid substitutions.
18. The antibody or antigen binding fragment thereof of claim 16 , wherein the LC variable domain comprises an amino acid sequence at least about 99% identical to SEQ ID NO:11 with conservative amino acid substitutions.
19. The antibody or antigen binding fragment thereof of claim 18 , wherein the antibody or antigen binding fragment thereof comprises a LC comprising an amino acid sequence at least about 99% identical to SEQ NO:13 with conservative amino acid substitutions.
20. The antibody or antigen binding fragment thereof of claim 1 , wherein the antibody or antigen binding fragment thereof comprises a LC variable domain comprising the amino acid sequence of SEQ ID NO:11.
21. The antibody or antigen binding fragment thereof of claim 20 , wherein the antibody or antigen binding fragment thereof comprises a LC comprising the amino acid sequence of SEQ ID NO:13.
22. The antibody or antigen binding fragment thereof of claim 1 , which is a full length antibody.
23. The antibody or antigen binding fragment thereof of claim 1 , which is an antigen binding fragment.
24. The antibody or antigen binding fragment thereof of claim 1 , wherein the antibody or antigen binding fragment thereof competes with the chimeric antibody chMov19 for specific binding to a human folate receptor.
25. The antibody or antigen binding fragment thereof of claim 1 , wherein the antibody or antigen binding fragment thereof binds a human folate receptor with the same affinity as chMov19.
26. The antibody or antigen binding fragment thereof of claim 25 , wherein the binding affinity is measured by flow cytometry, Biacore, or radioimmunoassay.
27. The antibody or antigen binding fragment thereof of claim 1 , wherein the antibody or antigen binding fragment thereof binds to a human folate receptor 1 with a Kd of 1.0 nM or better.
28. The antibody or antigen binding fragment thereof of claim 27 , wherein the binding affinity is measured by flow cytometry, Biacore, or radioimmunoassay.
29. The antibody or antigen binding fragment thereof of claim 1 , wherein the antibody or antigen binding fragment thereof binds to a human folate receptor 1 with a Kd of about 0.06 nM to about 1.0 nM.
30. The antibody or antigen binding fragment thereof of claim 29 , wherein the binding affinity is measured by flow cytometry, Biacore, or radioimmunoassay.
31. The antibody or antigen binding fragment thereof of claim 1 , wherein the antibody or antigen binding fragment thereof is bispecific for different epitopes.
32. The antibody or antigen binding fragment thereof of claim 31 , wherein the different epitopes are different human folate receptor 1 epitopes.
33. The antibody or antigen binding fragment thereof of claim 31 , wherein the different epitopes are within different molecules.
34. The antibody or antigen binding fragment thereof of claim 1 , wherein the antibody or antigen binding fragment thereof is multispecific for different epitopes.
35. The antibody or antigen binding fragment thereof of claim 1 , wherein the antibody or antigen binding fragment thereof is modified to increase its serum half-life.
36. The antibody or antigen binding fragment thereof of claim 1 , wherein the antibody or antigen binding fragment thereof comprises a deletion or inactivation of a constant region domain.
37. The antibody or antigen binding fragment thereof of claim 36 , wherein the deletion or inactivation of the constant region domain reduces Fe receptor binding or effector function.
38. The antibody or antigen binding fragment thereof of claim 1 , wherein the antibody or antigen binding fragment thereof comprises a hinge region and a CH3 domain fused directly to the hinge region.
39. The antibody or antigen binding fragment thereof of claim 1 , wherein the antibody or antigen binding fragment thereof comprises a hinge region, a CH2 domain, and a peptide spacer between the hinge region and the CH2 domain.
40. The antibody or antigen binding fragment thereof of claim 1 , wherein the antibody or antigen hinging fragment thereof comprises a hinge region, a CH3 domain, and a peptide spacer between the hinge region and the CH3 domain.
41. The antibody or antigen binding fragment thereof of claim 40 , wherein the antibody or antigen binding fragment thereof lacks a CH2 domain.
42. An immunoconjugate having the formula (A)-(L)-(C), 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); 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).
43. The immunoconjugate of claim 42 , wherein the antibody or antigen binding fragment thereof comprises a LC variable domain comprising the amino acid sequence of SEQ ID NO:10.
44. The immunoconjugate of claim 43 , wherein the antibody or antigen binding fragment thereof comprises a LC comprising the amino acid sequence of SEQ ID NO:12.
45. The immunoconjugate of claim 42 , wherein the antibody or antigen binding fragment thereof comprises a LC variable domain comprising the amino acid sequence of SEQ ID NO: ii.
46. The immunoconjugate of claim 45 , wherein the antibody or antigen binding fragment thereof comprises a LC comprising the amino acid sequence of SEQ ID NO:13.
47. The immunoconjugate of claim 42 , wherein the antibody or antigen binding fragment thereof competes with chMov19 for specific binding to a human folate receptor.
48. The immunoconjugate of claim 42 , wherein the antibody or antigen binding fragment thereof binds a human folate receptor with the same affinity as chMov19.
49. The immunoconjugate of claim 48 , wherein the binding affinity is measured by flow cytometry, Biacore, or radioimmunoassay.
50. The immunoconjugate of claim 42 , wherein the antibody or antigen binding fragment thereof binds to a human folate receptor 1 with a Kd of 1.0 nM or better.
51. The immunoconjugate of claim 50 , wherein the binding affinity is measured by flow cytometry, Biacore, or radioimmunoassay.
52. The immunoconjugate of claim 42 , wherein the antibody or antigen binding fragment thereof binds to a human folate receptor 1 with a Kd of about 0.06 nM to about 1.0 nM.
53. The immunoconjugate of claim 52 , wherein the binding affinity is measured by flow cytometry, Biacore, or radioimmunoassay.
54. The immunoconjugate of claim 42 , 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.
55. The immunoconjugate of claim 54 , 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) 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 (STAB); and N-succinimidyl-[(N-maleimidopropionamido)-tetraethyleneglycol ester (NHS-PEG4-maleimide).
56. The immunoconjugate of claim 55 , wherein (L) is N-succinimidyl 4-(2-pyridyldithio)-2-sulfobutanoate (sulfo-SPDB).
57. The immunoconjugate of claim 55 , wherein (L) is N-succinimidyl 4-(2-pyridyldithio)butanoate (SPDB).
58. The immunoconjugate of claim 55 , wherein (L) is N succinimidyl-RN-maleimidopropionamido)-tetraethyleneglycol] ester (NHS-PEG4-maleimide).
59. The immunoconjugate of claim 55 , wherein (L) is N-succinimidyl 4-(2-pyridyldithio)pentanoate (SPP).
60. The immunoconjugate of claim 55 , wherein (L) is N-succinimidyl 4-(maleimidomethyl) cyclohexanecarboxylate (SMCC).
61. The immunoconjugate of claim 42 , wherein (C) is a cytotoxic agent that inhibits microtubule formation in mammalian cells.
62. The immunoconjugate of claim 42 , 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.
63. The immunoconjugate of claim 62 , wherein (C) is a maytansinoid.
64. The immunoconjugate of claim 63 , wherein (C) is N(2′)-deacetyl-N(2′)-(3-mercapto-1-oxopropyl)-maytansine (DM1).
65. The immunoconjugate of claim 63 , wherein (C) is N(2′)-deacetyl-N(2′)-(4-mercapto-1-oxopentyl)-maytansine (DM3).
66. The immunoconjugate of claim 63 , wherein (C) is N(2′)-deacetyl-N2-(4-mercapto-4-methyl-1-oxopentyl)-maytansine (DM4).
67. The immunoconjugate of claim 63 , wherein (C) is an indolinobenzodiazepine or oxazolidinobenzodiazepine.
68. The immunoconjugate of claim 42 , wherein the immunoconjugate further comprises a second (C).
69. The immunoconjugate of claim 68 , wherein the immunoconjugate further comprises a third (C).
70. The immunoconjugate of claim 69 , wherein the immunoconjugate further comprises a fourth (C).
71. The immunoconjugate of claim 42 , wherein the immunoconjugate comprises 1-10 (C).
72. The immunoconjugate of claim 42 , wherein the immunoconjugate comprises 2-6 (C).
73. The immunoconjugate of claim 42 , wherein the immunoconjugate comprises 3-4 (C).
74. An immunoconjugate having the formula (A)-(L)-(C), wherein:
(A) is an antibody or antigen binding fragment thereof that specifically binds a human folate receptor;
(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 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).
75. The immunoconjugate of claim 74 , wherein the antibody or antigen binding fragment thereof comprises a LC variable domain comprising the amino acid sequence of SEQ ID NO:10.
76. The immunoconjugate of claim 75 , wherein the antibody or antigen binding fragment thereof comprises a LC comprising the amino acid sequence of SEQ ID NO:12.
77. The immunoconjugate of claim 74 , wherein the antibody or antigen binding fragment thereof comprises a LC variable domain comprising the amino acid sequence of SEQ ID NO: 11.
78. The immunoconjugate of claim 77 , wherein the antibody or antigen binding fragment thereof comprises a LC comprising the amino acid sequence of SEQ NO:13.
79. The immunoconjugate of claim 74 , wherein the antibody or antigen binding fragment thereof competes with chMov19 for specific binding to a human folate receptor.
80. The immunoconjugate of claim 74 , wherein the antibody or antigen binding fragment thereof binds a human folate receptor with the same affinity as chMov19.
81. The immunoconjugate of claim 80 , wherein the binding affinity is measured by flow cytometry, Biacore, or radioimmunoassay.
82. The immunoconjugate of claim 74 , wherein the antibody or antigen binding fragment thereof binds to a human folate receptor 1 with a Kd of 1.0 nM or better.
83. The immunoconjugate of claim 82 , wherein the binding affinity is measured by flow cytometry, Biacore, or radioimmunoassay.
84. The immunoconjugate of claim 74 , wherein the antibody or antigen binding fragment thereof binds to a human folate receptor 1 with a Kd of about 0.06 nM to about 1.0 nM.
85. The immunoconjugate of claim 84 , wherein the binding affinity is measured by flow cytometry, Biacore, or radioimmunoassay.
86. The immunoconjugate of claim 74 , wherein the immunoconjugate further comprises a second (C).
87. The immunoconjugate of claim 86 , wherein the immunoconjugate further comprises a third (C).
88. The immunoconjugate of claim 87 , wherein the immunoconjugate further comprises a fourth (C).
89. The immunoconjugate of claim 74 , wherein the immunoconjugate comprises 1-10 (C).
90. The immunoconjugate of claim 74 , wherein the immunoconjugate comprises 2-6 (C).
91. The immunoconjugate of claim 74 , wherein the immunoconjugate comprises 3-4 (C).
92. A pharmaceutical composition comprising the antibody or antigen binding fragment thereof of claim 1 and a pharmaceutically acceptable carrier.
93. A pharmaceutical composition comprising the immunoconjugate of claim 42 and a pharmaceutically acceptable carrier.
94. The pharmaceutical composition of claim 93 , wherein the immunoconjugates have an average of about 3 to about 4 (C) per (A).
95. A pharmaceutical composition comprising the immunoconjugate of claim 74 and a pharmaceutically acceptable carrier.
96. The pharmaceutical composition of claim 95 , wherein the immunoconjugates have an average of about 3 to about 4 (C) per (A).
97. A diagnostic reagent comprising the antibody or antigen binding fragment thereof of claim 1 and further comprising a label.
98. The diagnostic reagent of claim 97 , wherein the label is selected from the group consisting of a radiolabel fluorophore, a chromophore, an imaging reagent, and a metal ion.
99. A kit comprising the antibody or antigen binding fragment thereof of claim 1 and instructions for administering the antibody or antigen binding fragment.
100. A kit comprising the immunoconjugate of claim 42 and instructions for administering the immunoconjugate.
101. A kit comprising the immunoconjugate of claim 74 and instructions for administering the immunoconjugate.
102. The antibody or antigen binding fragment thereof of claim 1 , wherein the antibody or antigen binding fragment thereof comprises a LC comprising the same amino acid sequence as the amino acid sequence of the LC encoded by the plasmid deposited with the American Type Culture Collection (ATCC) as PTA-10773 or PTA-10774.
103. The immunoconjugate of claim 42 , wherein the antibody or antigen binding fragment thereof comprises a LC comprising the same amino acid sequence as the amino acid sequence of the LC encoded by the plasmid deposited with the ATCC as PTA-10773 or PTA-10774.
104. The immunoconjugate of claim 74 , wherein the antibody or antigen binding fragment thereof comprises a LC comprising the same amino acid sequence as the amino acid sequence of the LC encoded by the plasmid deposited with the ATCC as PTA-10773 or PTA-10774.