Anti-claudin 18 antibodies and methods of use thereof

Abstract

Antibodies that specifically bind to the human tight junction molecule CLDN18.2 and have functional properties that make them suitable for use in antibody-based immunotherapies of a disease associated with aberrant expression of CLDN18.2 are disclosed.

1 .- 10 . (canceled) 
     
     
         11 . An anti-CLDN18.2 antibody comprising
 (a) a heavy chain variable region comprising CDR1 comprising the amino acid sequence of SEQ ID NO: 269, CDR2 comprising the amino acid sequence of SEQ ID NO: 270, and CDR3 comprising the amino acid sequence of SEQ ID NO: 271; and   (b) a light chain variable region comprising CDR1 comprising the amino acid sequence of SEQ ID NO: 272, CDR2 comprising the amino acid sequence of SEQ ID NO: 273, and CDR3 comprising the amino acid sequence of SEQ ID NO: 274.   
     
     
         12 . The antibody of  claim 11 , wherein the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 201 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 202. 
     
     
         13 . The antibody of  claim 12 , wherein the antibody is characterized by enhanced ADCC activity relative to the ADCC activity of an antibody comprising the same variable VH and VL regions in combination with a wild-type human IgG1 Fc domain. 
     
     
         14 . The antibody of  claim 11 , wherein the antibody is of the IgG1 isotype and comprises L235V, F243L, R292P, Y300L, and P396L mutations. 
     
     
         15 . The antibody of  claim 11 , wherein the antibody comprises a recombinant heavy chain sequence of SEQ ID NO: 336 and a light chain sequence of SEQ ID NO: 337. 
     
     
         16 . The antibody of  claim 11 , wherein the antibody comprises a recombinant heavy chain sequence of SEQ ID NO: 338 and a light chain sequence of SEQ ID NO: 337. 
     
     
         17 . The antibody of  claim 11 , wherein the antibody does not bind to CLDN18.1. 
     
     
         18 . The antibody of  claim 11 , wherein the antibody is a monoclonal antibody, a recombinant antibody, a chimeric antibody, a humanized antibody, a human antibody, a bispecific antibody, or a multi-specific antibody. 
     
     
         19 . The antibody of  claim 11 , wherein the antibody is a human antibody. 
     
     
         20 . The antibody of  claim 11 , wherein the antibody is of the IgG class. 
     
     
         21 . The antibody of  claim 20 , wherein the antibody has an IgG1, IgG2, IgG3, or IgG4 isotype. 
     
     
         22 . An isolated nucleic acid molecule encoding the antibody of  claim 11 . 
     
     
         23 . A vector comprising the nucleic acid molecule according to  claim 22 . 
     
     
         24 . A host cell comprising the nucleic acid molecule of  claim 22 . 
     
     
         25 . A host cell comprising the vector molecule of  claim 23 . 
     
     
         26 . A method of making the antibody of  claim 11  comprising culturing a host cell according to  claim 25  under suitable conditions for producing the antibody. 
     
     
         27 . The method of  claim 26  further comprising isolating the antibody secreted from the host cell. 
     
     
         28 . A method for treating cancer, comprising administering to a subject in need thereof a composition comprising the antibody of  claim 11 . 
     
     
         29 . The method of  claim 28 , wherein the cancer is a solid tumor cancer associated with cells expressing CLDN18.2. 
     
     
         30 . The method of  claim 28 , wherein the cancer is gastric cancer, pancreatic and esophageal cancer, lung cancer, ovarian cancer, colon cancer, or hepatic cancer.