Drug conjugates comprising antibodies against claudin 18.2

Abstract

The present invention provides anti-CLDN18.2 antibody-drug conjugates which are effective for treating and/or preventing cancer diseases associated with cells expressing CLDN18.2, including gastric cancer, esophageal cancer, pancreatic cancer, lung cancer, ovarian cancer, colon cancer, hepatic cancer, head-neck cancer, and cancer of the gallbladder and metastases thereof.

1 - 68 . (canceled) 
     
     
         69 . A method of treating a human patient having a cancer expressing a human CLDN18.2 polypeptide comprising administering a conjugate comprising an anti-CLDN18.2 antibody and at least one toxin drug moiety,
 wherein the antibody is covalently attached to the at least one toxin drug moiety via a linker that is cleavable under intracellular conditions, and   wherein the antibody comprises a heavy chain variable region (V H ) comprising a V H  CDR1 of positions 45-52 of SEQ ID NO: 17, a VH CDR2 of positions 70-77 of SEQ ID NO: 17, and a V H  CDR3 of positions 116-126 of SEQ ID NO: 17 and a light chain variable region (V L ) comprising a V L  CDR1 of positions 47-58 of SEQ ID NO: 24, a V L  CDR2 of positions 76-78 of SEQ ID NO: 24, and a V L  CDR3 of positions 115-123 of SEQ ID NO: 24.   
     
     
         70 . The method of  claim 69 , wherein the antibody comprises an antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 32 and an antibody light chain comprising the amino acid sequence of SEQ ID NO: 39. 
     
     
         71 . The method of  claim 69 , wherein the antibody comprises an antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 17 or 51 and an antibody light chain comprising the amino acid sequence of SEQ ID NO: 24. 
     
     
         72 . The method of  claim 69 , wherein the linker is hydrolyzable at a pH of less than 5.5. 
     
     
         73 . The method of  claim 69 , wherein the linker is cleavable by an intracellular protease. 
     
     
         74 . The method of  claim 69 , wherein the linker is a cathepsin-cleavable linker. 
     
     
         75 . The method of  claim 69 , wherein the linker is an N-succinimidyl-4-(2-pyridyldithio)butyrate linker. 
     
     
         76 . The method of  claim 69 , wherein the linker is a valine-citrulline linker. 
     
     
         77 . The method of  claim 69 , wherein the at least one toxin drug moiety is a maytansinoid or an auristatin. 
     
     
         78 . The method of  claim 69 , wherein the at least one toxin drug moiety is a maytansinoid selected from the group consisting of DM1 and DM4. 
     
     
         79 . The method of  claim 69 , wherein the at least one toxin drug moiety is an auristatin selected from the group consisting of monomethyl auristatin E (MMAE) and monomethyl auristatin F (MMAF). 
     
     
         80 . The method of  claim 69 , wherein the at least one toxin drug moiety is DM4 and the linker is an N-succinimidyl-4-(2-pyridyldithio)butyrate linker. 
     
     
         81 . The method of  claim 69 , wherein the at least one toxin drug moiety is MMAE and the linker is a valine-citrulline linker. 
     
     
         82 . The method of  claim 69 , wherein the antibody comprises a human heavy chain constant region selected from the group consisting of IgG1 and IgG3. 
     
     
         83 . The method of  claim 69 , wherein the antibody comprises a human kappa light chain constant region and a human IgG1 heavy chain constant region. 
     
     
         84 . The method of  claim 83 , wherein the human kappa light chain constant region is allotype Km(3) and/or the human IgG1 heavy chain constant region is allotype G1m(3). 
     
     
         85 . The method of  claim 69 , wherein the cancer is an adenocarcinoma. 
     
     
         86 . The method of  claim 69 , wherein the cancer is selected from the group consisting of gastric cancer, esophageal cancer, pancreatic cancer, lung cancer, breast cancer, ovarian cancer, colon cancer, hepatic cancer, head-neck cancer, and cancer of the gallbladder. 
     
     
         87 . The method of  claim 69 , wherein the cancer is selected from the group consisting of a metastasis of gastric cancer, a metastasis of esophageal cancer, a metastasis of pancreatic cancer, a metastasis of lung cancer, a metastasis of breast cancer, a metastasis of ovarian cancer, a metastasis of colon cancer, a metastasis of hepatic cancer, a metastasis of head-neck cancer, and a metastasis of cancer of the gallbladder. 
     
     
         88 . The method of  claim 69 , wherein the cancer is selected from the group consisting of a Krukenberg tumor, peritoneal metastasis, and lymph node metastasis. 
     
     
         89 . The method of  claim 69 , wherein the cancer is selected from the group consisting of cancer of the stomach, cancer of the esophagus, cancer of the eso-gastric junction, and gastroesophageal cancer. 
     
     
         90 . The method of  claim 69 , wherein the cancer is selected from the group consisting of a metastasis of a cancer of the stomach, a metastasis of a cancer of the esophagus, a metastasis of a cancer of the eso-gastric junction, and a metastasis of a gastroesophageal cancer. 
     
     
         91 . The method of  claim 69 , wherein the cancer is gastric cancer. 
     
     
         92 . The method of  claim 69 , wherein the cancer is non small cell lung cancer (NSCLC). 
     
     
         93 . The method of  claim 69 , wherein the cancer is pancreatic cancer.