Novel anti-claudin antibodies and methods of use

Abstract

Provided herein are novel anti-CLDN antibodies and antibody drug conjugates (ADC), including derivatives thereof, and methods of using the same to treat proliferative disorders.

1 .- 23 . (canceled) 
     
     
         24 . A method of treating ovarian cancer comprising administering to a subject in need thereof an antibody drug conjugate comprising a monoclonal antibody conjugated, linked, or otherwise associated with a cytotoxic agent, wherein the monoclonal antibody binds to a human CLDN6 protein; and
 wherein the monoclonal antibody comprises three complementarity determining regions of a light chain variable region comprising an amino acid sequence set forth as SEQ ID NO: 73, and three complementarity determining regions of a heavy chain variable region comprising an amino acid sequence set forth as SEQ ID NO: 87.   
     
     
         25 .- 32 . (canceled) 
     
     
         33 . The method of  claim 24 , wherein the monoclonal antibody is an internalizing antibody. 
     
     
         34 . The method of  claim 24 , wherein the monoclonal antibody is selected from the group consisting of a chimeric antibody, humanized antibody, and CDR grafted antibody. 
     
     
         35 . The antibody of  claim 24 , wherein the monoclonal antibody comprises:
 (a) residues 24-34 of SEQ ID NO: 73 for CDR-L1, residues 50-56 of SEQ ID NO: 73 for CDR-L2, residues 89-97 of SEQ ID NO: 73 for CDR-L3, residues 31-35 of SEQ ID NO: 87 for CDR-H1, residues 50-65 of SEQ ID NO: 87 for CDR-H2 and residues 95-102 of SEQ ID NO: 87 for CDR-H3, wherein the residues are numbered according to Kabat;   (b) residues 24-34 of SEQ ID NO: 73 for CDR-L1, residues 50-56 of SEQ ID NO: 73 for CDR-L2, residues 89-97 of SEQ ID NO: 73 for CDR-L3, residues 26-32 of SEQ ID NO: 87 for CDR-H1, residues 52-56 of SEQ ID NO: 87 for CDR-H2 and residues 95-102 of SEQ ID NO: 87 for CDR-H3, wherein the residues are numbered according to Chothia; or   (c) residues 30-36 of SEQ ID NO: 73 for CDR-L1, residues 46-55 of SEQ ID NO: 73 for CDR-L2, residues 89-96 of SEQ ID NO: 73 for CDR-L3, residues 30-35 of SEQ ID NO: 87 for CDR-H1, residues 47-58 of SEQ ID NO: 87 for CDR-H2 and residues 93-101 of SEQ ID NO: 87 for CDR-H3, wherein the residues are numbered according to MacCallum.   
     
     
         36 . The method of  claim 24 , wherein the monoclonal antibody comprises a light chain variable region comprising an amino acid sequence set forth as SEQ ID NO: 73 and a heavy chain variable region comprising an amino acid sequence set forth as SEQ ID NO: 87. 
     
     
         37 . The method of  claim 36 , wherein the monoclonal antibody is an IgG1 antibody comprising:
 (i) a cysteine residue at heavy chain position 220 and a deletion of a cysteine residue at light chain position 214, (ii) a cysteine residue at heavy chain position 220 and a substitution of a cysteine residue at light chain position 214, (iii) a cysteine residue at light chain position 214 and a deletion of a cysteine residue at heavy chain position 220, or (iv) a cysteine residue at light chain position 214 and a substitution of a cysteine residue at heavy chain position 220; and   wherein the engineered antibody comprises native cysteine residues at heavy chain positions 226 and 229.   
     
     
         38 . The method of  claim 37 , wherein the monoclonal antibody comprises a cysteine residue at light chain position 214. 
     
     
         39 . The method of  claim 24 , wherein the cytotoxic agent is a pyrrolobenzodiazepine, an auristatin, a maytansinoid, a calicheamicin, or a radioisotope. 
     
     
         40 . The method of  claim 24 , wherein the cytotoxic agent is a pyrrolobenzodiazepine. 
     
     
         41 . The method of  claim 24 , wherein the antibody drug conjugate comprises the formula M-[L-D]n wherein:
 M comprises the monoclonal antibody;   L comprises an optional linker;   D comprises a drug, which is the cytotoxic agent; and   n is an integer from 1 to 20.   
     
     
         42 . The method of  claim 24 , wherein the monoclonal antibody is conjugated to the cytotoxic agent via a linker. 
     
     
         43 . The method of  claim 42 , wherein the linker comprises a cleavable linker. 
     
     
         44 . The method of  claim 24 , wherein the antibody drug conjugate has a drug loading of 2. 
     
     
         45 . The method of  claim 24 , wherein the monoclonal antibody comprises a light chain variable region comprising an amino acid sequence set forth as SEQ ID NO: 73 and a heavy chain variable region comprising an amino acid sequence set forth as SEQ ID NO: 87, and
 wherein the cytotoxic agent is a pyrrolobenzodiazepine.   
     
     
         46 . The method of  claim 24 , wherein the cancer is refractory, relapsed, or resistant to a platinum based agent. 
     
     
         47 . A method of treating ovarian cancer comprising administering to a subject in need thereof an antibody drug conjugate comprising a monoclonal antibody conjugated, linked, or otherwise associated with a cytotoxic agent,
 wherein the monoclonal antibody binds to a human CLDN6 protein and comprises a light chain variable region comprising an amino acid sequence set forth as SEQ ID NO: 73 and a heavy chain variable region comprising an amino acid sequence set forth as SEQ ID NO: 87;   wherein the cytotoxic agent is a pyrrolobenzodiazepine; and   wherein the antibody drug conjugate has a drug loading of 2.   
     
     
         48 . A method of treating cancer comprising administering to a subject in need thereof an antibody drug conjugate comprising a monoclonal antibody conjugated, linked, or otherwise associated with a cytotoxic agent,
 wherein the monoclonal antibody comprises three complementarity determining regions of a light chain variable region comprising an amino acid sequence set forth as SEQ ID NO: 73 and three complementarity determining regions of a heavy chain variable region comprising an amino acid sequence set forth as SEQ ID NO: 87.   
     
     
         49 . The method of  claim 48 , wherein the monoclonal antibody comprises a light chain variable region comprising an amino acid sequence set forth as SEQ ID NO: 73 and a heavy chain variable region comprising an amino acid sequence set forth as SEQ ID NO: 87, and
 wherein the cytotoxic agent is a pyrrolobenzodiazepine.   
     
     
         50 . The method of  claim 49 , wherein the cancer is lung adenocarcinoma. 
     
     
         51 . The method of  claim 49 , wherein the cancer is endometrial cancer.