Folate Receptor 1 Antibodies and Immunoconjugates and Uses Thereof

Abstract

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 .- 127 . (canceled) 
     
     
         128 . An immunoconjugate comprising the formula (A)-(L)-(C), wherein:
 (A) is an antibody or antigen binding fragment thereof that specifically binds a human folate receptor 1;   (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 heavy chain CDR1 comprising the amino acid sequence of GYFMN (SEQ ID NO:1), a heavy chain CDR2 comprising the amino acid sequence of RIHPYDGDTF (SEQ ID NO:131), and a heavy chain CDR3 comprising the amino acid sequence of YDGSRAMDY (SEQ ID NO:3); and   a light chain CDR1 comprising the amino acid sequence of KASQSVSFAGTSLMH (SEQ ID NO:7), a light chain CDR2 comprising the amino acid sequence of RASNLEA (SEQ ID NO:8), and a light chain CDR3 comprising the amino acid sequence of QQSREYPYT (SEQ ID NO:9).   
     
     
         129 . The immunoconjugate of  claim 128 , wherein (L) is a linker selected from the group consisting of: a non-cleavable linker, a hydrophilic linker, and a dicarboxylic acid based linker. 
     
     
         130 . The immunoconjugate of  claim 128 , wherein the linker is selected from the group consisting of: 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). 
     
     
         131 . The immunoconjugate of  claim 128 , wherein (L) is a cleavable linker. 
     
     
         132 . The immunoconjugate of  claim 131 , wherein the linker is 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); and N-succinimidyl 4-(2-pyridyldithio)-2-sulfobutanoate (sulfo-SPDB). 
     
     
         133 . The immunoconjugate of  claim 128 , wherein the cytotoxic agent is selected from the group consisting of: a maytansinoid, maytansinoid analog, benzodiazepine, taxoid, CC-1065, CC-1065 analog, duocarmycin, duocarmycin analog, calicheamicin, dolastatin, dolastatin analog, auristatin, tomaymycin derivative, and leptomycin derivative or a prodrug of the cytotoxic agent. 
     
     
         134 . The immunoconjugate of  claim 133 , wherein the cytotoxic agent is a maytansinoid. 
     
     
         135 . The immunoconjugate of  claim 134 , wherein the cytotoxic agent is N(2′)-deacetyl-N(2′)-(3-mercapto-1-oxopropyl)-maytansine (DM1) or N(2′)-deacetyl-N(2′)-(4-mercapto-4-methyl-1-oxopentyl)-maytansine (DM4). 
     
     
         136 . The immunoconjugate of  claim 128 , wherein the linker is N-succinimidyl 4-(2-pyridyldithio)-2-sulfobutanoate (sulfo-SPDB) and the cytotoxic agent is N(2′)-deacetyl-N(2′)-(4-mercapto-4-methyl-1-oxopentyl)-maytansine (DM4). 
     
     
         137 . The immunoconjugate of  claim 128 , wherein the antibody or antigen binding fragment thereof comprises a light chain variable domain comprising the amino acid sequence of SEQ ID NO:11. 
     
     
         138 . The immunoconjugate of  claim 137 , wherein (L) is a linker selected from the group consisting of: a non-cleavable linker, a hydrophilic linker, and a dicarboxylic acid based linker. 
     
     
         139 . The immunoconjugate of  claim 137 , wherein the linker is selected from the group consisting of: 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). 
     
     
         140 . The immunoconjugate of  claim 137 , wherein (L) is a cleavable linker. 
     
     
         141 . The immunoconjugate of  claim 140 , wherein the linker is 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); and N-succinimidyl 4-(2-pyridyldithio)-2-sulfobutanoate (sulfo-SPDB). 
     
     
         142 . The immunoconjugate of  claim 137 , wherein the cytotoxic agent is selected from the group consisting of: a maytansinoid, maytansinoid analog, benzodiazepine, taxoid, CC-1065, CC-1065 analog, duocarmycin, duocarmycin analog, calicheamicin, dolastatin, dolastatin analog, auristatin, tomaymycin derivative, and leptomycin derivative or a prodrug of the cytotoxic agent. 
     
     
         143 . The immunoconjugate of  claim 142 , wherein the cytotoxic agent is a maytansinoid. 
     
     
         144 . The immunoconjugate of  claim 143 , wherein the cytotoxic agent is N(2′)-deacetyl-N(2′)-(3-mercapto-1-oxopropyl)-maytansine (DM1) or N(2′)-deacetyl-N(2′)-(4-mercapto-4-methyl-1-oxopentyl)-maytansine (DM4). 
     
     
         145 . The immunoconjugate of  claim 137 , wherein the linker is N-succinimidyl 4-(2-pyridyldithio)-2-sulfobutanoate (sulfo-SPDB) and the cytotoxic agent is N(2′)-deacetyl-N(2′)-(4-mercapto-4-methyl-1-oxopentyl)-maytansine (DM4). 
     
     
         146 . The immunoconjugate of  claim 128 , wherein the antibody or antigen binding fragment thereof comprises a light chain comprising the amino acid sequence of SEQ ID NO:13. 
     
     
         147 . The immunoconjugate of  claim 146 , wherein (L) is a linker selected from the group consisting of: a non-cleavable linker, a hydrophilic linker, and a dicarboxylic acid based linker. 
     
     
         148 . The immunoconjugate of  claim 146 , wherein the linker is selected from the group consisting of: 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). 
     
     
         149 . The immunoconjugate of  claim 146 , wherein (L) is a cleavable linker. 
     
     
         150 . The immunoconjugate of  claim 149 , wherein the linker is 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); and N-succinimidyl 4-(2-pyridyldithio)-2-sulfobutanoate (sulfo-SPDB). 
     
     
         151 . The immunoconjugate of  claim 146 , wherein the cytotoxic agent is selected from the group consisting of: a maytansinoid, maytansinoid analog, benzodiazepine, taxoid, CC-1065, CC-1065 analog, duocarmycin, duocarmycin analog, calicheamicin, dolastatin, dolastatin analog, auristatin, tomaymycin derivative, and leptomycin derivative or a prodrug of the cytotoxic agent. 
     
     
         152 . The immunoconjugate of  claim 151 , wherein the cytotoxic agent is a maytansinoid. 
     
     
         153 . The immunoconjugate of  claim 152 , wherein the cytotoxic agent is N(2′)-deacetyl-N(2′)-(3-mercapto-1-oxopropyl)-maytansine (DM1) or N(2′)-deacetyl-N(2′)-(4-mercapto-4-methyl-1-oxopentyl)-maytansine (DM4). 
     
     
         154 . The immunoconjugate of  claim 146 , wherein the linker is N-succinimidyl 4-(2-pyridyldithio)-2-sulfobutanoate (sulfo-SPDB) and the cytotoxic agent is N(2′)-deacetyl-N(2′)-(4-mercapto-4-methyl-1-oxopentyl)-maytansine (DM4). 
     
     
         155 . The immunoconjugate of  claim 128 , wherein the antibody or antigen binding fragment thereof is a full length antibody. 
     
     
         156 . The immunoconjugate of  claim 128 , wherein the antibody or antigen binding fragment thereof is an antigen binding fragment, wherein the antigen binding fragment comprises a Fab, a Fab′, a F(ab′)2, a single chain Fv (scFv), a disulfide linked Fv, an IgG-CH2, a F(ab′)3, a tetrabody, a triabody, a diabody, a (scFv)2, or a scFv-Fc. 
     
     
         157 . The immunoconjugate of  claim 128 , wherein the antibody binds to human FOLR1 with a Kd of 1.0 nM or better. 
     
     
         158 . The immunoconjugate of  claim 128 , wherein the antibody binds to human FOLR1 with a Kd of about 0.06 nM to about 1.0 nM. 
     
     
         159 . The immunoconjugate of  claim 128 , further comprising 2-6 (C). 
     
     
         160 . The immunoconjugate of  claim 128 , wherein the antibody or antigen binding fragment further comprises a second and third (C). 
     
     
         161 . A pharmaceutical composition comprising the immunoconjugate of  claim 129  and a pharmaceutically acceptable carrier, wherein the immunoconjugates have an average of 3 to 4 (C) per (A). 
     
     
         162 . A pharmaceutical composition comprising immunoconjugates, wherein the immunoconjugates comprise the formula (A)-(L)-(C), wherein:
 (A) is an antibody or antigen binding fragment thereof that specifically binds a human folate receptor 1;   (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 HC CDR1 comprising the amino acid sequence of GYFMN (SEQ ID NO:1), 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   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), and wherein the immunoconjugates have an average of 3 to 4 (C) per (A).   
     
     
         163 . A method for the treatment of cancer comprising administering the immunoconjugate of  claim 128  to a subject in need thereof. 
     
     
         164 . A method for the treatment of cancer comprising administering the pharmaceutical composition of  claim 161  to a subject in need thereof. 
     
     
         165 . The method of  claim 164 , wherein the cancer is selected from the group consisting of: ovarian cancer, brain cancer, breast cancer, uterine cancer, pancreatic cancer, renal cancer, cancer of the peritoneum, endometrial cancer, and lung cancer. 
     
     
         166 . The method of  claim 165 , wherein the cancer is endometrial cancer. 
     
     
         167 . The method of  claim 165 , wherein the cancer is ovarian cancer. 
     
     
         168 . The method of  claim 165 , wherein the cancer is cancer of the peritoneum.