Peptide mimotopes of claudin 18.2 and uses thereof

Abstract

The present invention provides molecules that mimic antigenic determinants of the integral transmembrane protein claudin 18.2 (CLDN18.2). These molecules compete with CLDN18.2 for binding to a CLDN18.2 binding domain, e.g. a CLDN18.2 binding domain of an antibody, and are capable of detecting antibodies against CLDN18.2. The mimotopes of the invention may be used to generate or inhibit immune responses in animals and preferably humans. Furthermore, they can be used for purposes of detecting agents comprising a CLDN18.2 binding domain in biological samples as well as for purifying agents comprising a CLDN18.2 binding domain.

1 - 63 . (canceled) 
     
     
         64 . A method for treating a patient affected from a cancer characterized by cancer cells expressing CLDN18.2 comprising a step of administering to the patient a cell comprising a chimeric antigen receptor (CAR), the CAR comprising a single-chain variable fragment (scFV) fused to a CD3-zeta transmembrane and endodomain,
 wherein said scFV comprises a heavy chain variable region (VH) and a light chain variable region (VL), each comprising a set of three complementarity-determining regions (CDR1, CDR2, and CDR3),   wherein the VH CDR1, CDR2, and CDR3 have the amino acid sequences of positions 45-52, positions 70-77, and positions 116-126 of SEQ ID NO: 12, respectively, and   wherein the VL CDR1, CDR2, and CDR3 have the amino acid sequences of positions 47-58, positions 76-78, and positions 115-123 of SEQ ID NO: 13, respectively.   
     
     
         65 . (canceled) 
     
     
         66 . (canceled) 
     
     
         67 . (canceled) 
     
     
         68 . The method of  claim 64 , wherein the cell is an immune effector cell. 
     
     
         69 . The method of  claim 64 , wherein the cell is a T cell. 
     
     
         70 . The method of  claim 64 , wherein the VH comprises an amino acid sequence represented by SEQ ID NO: 2 and the VL comprises an amino acid sequence represented by SEQ ID NO: 3. 
     
     
         71 . The method of  claim 70 , wherein the scFV further comprises a peptide linker connecting the VH and VL, wherein the peptide linker comprises the amino acid sequence (GGGGS)3, VE(GGSGGS)2GGVD, (GGGGS)4, (GGGGS)5, or GGGGS(GGS)3GGGS. 
     
     
         72 . The method of  claim 71 , wherein the cell is an immune effector cell. 
     
     
         73 . The method of  claim 71 , wherein the cell is a T cell. 
     
     
         74 . The method of  claim 64 , wherein the cancer comprises a primary tumor. 
     
     
         75 . The method of  claim 64 , wherein the cancer is gastric cancer, esophageal cancer, pancreatic cancer, lung cancer, ovarian cancer, colon cancer, hepatic cancer, head-neck cancer, or cancers of the gallbladder 
     
     
         76 . The method of  claim 64 , wherein the chimeric antigen receptor is expressed on the surface of the cell. 
     
     
         77 . The method of  claim 64 , wherein the CD3-zeta endodomain transmits an activation signal in response to recognition by the scFv of claudin 18.2 (CLDN18.2) on a target cell and the T cell mediates killing of the target cell that expresses CLDN18.2. 
     
     
         78 . A method for treating a patient affected from a cancer characterized by cancer cells expressing CLDN18.2 comprising a step of administering to the patient an immune effector cell comprising a chimeric antigen receptor (CAR), the CAR comprising a single-chain variable fragment (scFV) fused to a CD3-zeta transmembrane and endodomain,
 wherein said scFV comprises a heavy chain variable region (VH) and a light chain variable region (VL), each comprising a set of three complementarity-determining regions (CDR1, CDR2, and CDR3),   wherein the VH CDR1, CDR2, and CDR3 have the amino acid sequences of positions 45-52, positions 70-77, and positions 116-126 of SEQ ID NO: 12, respectively, and   wherein the VL CDR1, CDR2, and CDR3 have the amino acid sequences of positions 47-58, positions 76-78, and positions 115-123 of SEQ ID NO: 13, respectively; and   wherein the CAR is expressed on the cell surface of said immune effector cell.   
     
     
         79 . The method of  claim 78 , wherein the VH comprises an amino acid sequence represented by SEQ ID NO: 2 and the VL comprises an amino acid sequence represented by SEQ ID NO: 3. 
     
     
         80 . The method of  claim 79 , wherein the scFV further comprises a peptide linker connecting the VH and VL, wherein the peptide linker comprises the amino acid sequence (GGGGS)3, VE(GGSGGS)2GGVD, (GGGGS)4, (GGGGS)5, or GGGGS(GGS)3GGGS. 
     
     
         81 . The method of  claim 78 , wherein the immune effector cell is a T cell. 
     
     
         82 . The method of  claim 78 , wherein the cancer comprises a primary tumor. 
     
     
         83 . The method of  claim 78 , wherein the cancer is gastric cancer, esophageal cancer, pancreatic cancer, lung cancer, ovarian cancer, colon cancer, hepatic cancer, head-neck cancer, or cancers of the gallbladder. 
     
     
         84 . The method of  claim 78 , wherein the CD3-zeta endodomain transmits an activation signal in response to recognition by the scFv of claudin 18.2 (CLDN18.2) on a target cell and the T cell mediates killing of the target cell that expresses CLDN18.2.