Chimeric antigen receptors and uses thereof

Abstract

The present invention relates to chimeric antigen receptors (CARs) directed to cells expressing a dysfunctional or non-functional P2X purinoceptor 7 receptor. Further provided are methods of targeting neoplastic cells and tumours expressing a dysfunctional or non-functional P2X purinoceptor 7 receptor and methods of treating and preventing cancer is a subject.

We claim: 
     
         1 . A chimeric antigen receptor comprising an antigen-recognition domain and a signalling domain, wherein the antigen-recognition domain recognises a dysfunctional P2X 7  receptor. 
     
     
         2 . The chimeric antigen receptor according to  claim 1 , wherein the antigen-recognition domain recognises an epitope associated with an adenosine triphosphate (ATP)-binding site of the dysfunctional P2X 7  receptor. 
     
     
         3 . The chimeric antigen receptor according to  claim 1 , wherein the dysfunctional P2X 7  receptor has a reduced capacity to bind ATP compared to an ATP-binding capacity of a wild-type (functional) P2X 7  receptor. 
     
     
         4 . The chimeric antigen receptor according to  claim 1 , wherein the dysfunctional P2X 7  receptor has a conformational change that renders the receptor dysfunctional. 
     
     
         5 . The chimeric antigen receptor according to  claim 4 , wherein the conformational change is a change of an amino acid from a trans-conformation to a cis-conformation. 
     
     
         6 . The chimeric antigen receptor according to  claim 5 , wherein the amino acid that has changed from a trans-conformation to a cis-conformation is proline at amino acid position 210 of the dysfunctional P2X 7  receptor. 
     
     
         7 . The chimeric antigen receptor according to  claim 1 , wherein the antigen-recognition domain recognises an epitope that includes proline at amino acid position 210 of the dysfunctional P2X 7  receptor. 
     
     
         8 . The chimeric antigen receptor according to  claim 1 , wherein the antigen-recognition domain recognises an epitope that includes one or more amino acid residues spanning from glycine at amino acid position 200 to cysteine at amino acid position 216 of the dysfunctional P2X 7  receptor. 
     
     
         9 - 15 . (canceled) 
     
     
         16 . The chimeric antigen receptor according to  claim 1 , wherein the signalling domain comprises a portion derived from an activation receptor and/or a co-stimulatory receptor. 
     
     
         17 . The chimeric antigen receptor according to  claim 16 , wherein the activation receptor is a member of the CD3 co-receptor complex and/or an Fc receptor. 
     
     
         18 - 22 . (canceled) 
     
     
         23 . The chimeric antigen receptor according to  claim 16 , wherein the co-stimulatory receptor is selected from the group consisting of CD27, CD28, CD30, CD40, DAP10, OX40, 4-1BB (CD137) and ICOS. 
     
     
         24 . A nucleic acid molecule comprising a nucleotide sequence encoding the chimeric antigen receptor according to  claim 1 . 
     
     
         25 - 31 . (canceled) 
     
     
         32 . A genetically modified cell, the cell comprising the chimeric antigen receptor of  claim 1  or a nucleic acid molecule comprising a nucleotide sequence encoding such a chimeric antigen receptor. 
     
     
         33 - 43 . (canceled) 
     
     
         44 . The genetically modified cell according to  claim 32 , wherein the cell is a leukocyte, a Peripheral Blood Mononuclear Cell (PBMC), a lymphocyte, a T cell, a CD4+ T cell, a CD8+ T cell, a natural killer cell or a natural killer T cell. 
     
     
         45 - 51 . (canceled) 
     
     
         52 . A method of killing a cell expressing a dysfunctional P2X 7  receptor, the method including exposing the cell expressing a dysfunctional P2X 7  receptor to a genetically modified cell having a chimeric antigen receptor, wherein the chimeric antigen receptor is directed against the dysfunctional P2X 7  receptor. 
     
     
         53 - 58 . (canceled) 
     
     
         59 . A method of killing a cell expressing a dysfunctional P2X 7  receptor, the method including exposing the cell expressing a dysfunctional P2X 7  receptor to a genetically modified cell comprising the chimeric antigen receptor according to  claim 1 . 
     
     
         60 - 62 . (canceled) 
     
     
         63 . The method according to  claim 59 , wherein the cell expressing a dysfunctional P2X 7  receptor is a cancer cell. 
     
     
         64 . The method according to  claim 63 , wherein the cancer cell is selected from one or more of; brain cancer, oesophageal cancer, mouth cancer, tongue cancer, thyroid cancer, lung cancer, stomach cancer, pancreatic cancer, kidney cancer, colon cancer, rectal cancer, prostate cancer, bladder cancer, cervical cancer, epithelial cell cancers, skin cancer, leukaemia, lymphoma, myeloma, breast cancer, ovarian cancer, endometrial cancer and testicular cancer. 
     
     
         65 - 74 . (canceled) 
     
     
         75 . A pharmaceutical composition comprising a genetically modified cell according to  claim 32  and a pharmaceutically acceptable carrier. 
     
     
         76 - 82 . (canceled)