Cell

Abstract

The present invention provides a cell which co-expresses a first chimeric antigen receptor (CAR) and second CAR at the cell surface, each CAR comprising: (i) an antigen-binding domain; (ii) a spacer (iii) a trans-membrane domain; and (iv) an endodomain wherein the antigen binding domains of the first and second CARs bind to different antigens, wherein the spacer of the first CAR is different to the spacer of the second CAR and wherein one of the first or second CARs is an activating CAR comprising an activating endodomain and the other CAR is an inhibitory CAR comprising a ligation-off inhibitory endodomain.

1 . A T cell which co-expresses a first chimeric antigen receptor (CAR) and second CAR at the cell surface, each CAR comprising:
 (i) an antigen-binding domain;   (ii) a spacer   (iii) a trans-membrane domain; and   (iv) an endodomain   wherein the antigen binding domains of the first and second CARs bind to different antigens, wherein the spacer of the first CAR is different to the spacer of the second CAR and wherein one of the first or second CARs is an activating CAR comprising an activating endodomain and the other CAR is an inhibitory CAR comprising a ligation-off inhibitory endodomain.   
     
     
         2 - 7 . (canceled) 
     
     
         8 . A nucleic acid sequence encoding both the first and second chimeric antigen receptors (CARs) as defined in  claim 1 . 
     
     
         9 . A nucleic acid sequence according to  claim 8 , which has the following structure:
 AgB1-spacer1-TM1-endo1-coexpr-AbB2-spacer2-TM2-endo2   in which   AgB1 is a nucleic acid sequence encoding the antigen-binding domain of the first CAR;   spacer 1 is a nucleic acid sequence encoding the spacer of the first CAR;   TM1 is a nucleic acid sequence encoding the transmembrane domain of the first CAR;   endo 1 is a nucleic acid sequence encoding the endodomain of the first CAR;   coexpr is a nucleic acid sequence enabling co-expression of both CARs   AgB2 is a nucleic acid sequence encoding the antigen-binding domain of the second CAR;   spacer 2 is a nucleic acid sequence encoding the spacer of the second CAR;   TM2 is a nucleic acid sequence encoding the transmembrane domain of the second CAR;   endo 2 is a nucleic acid sequence encoding the endodomain of the second CAR;   which nucleic acid sequence, when expressed in a T cell, encodes a polypeptide which is cleaved at the cleavage site such that the first and second CARs are co-expressed at the T cell surface.   
     
     
         10 - 14 . (canceled) 
     
     
         15 . A vector comprising a nucleic acid sequence according to  claim 8 . 
     
     
         16 - 18 . (canceled) 
     
     
         19 . A pharmaceutical composition comprising a plurality of T cells according to  claim 1 . 
     
     
         20 . A method for treating and/or preventing a disease, which comprises the step of administering a pharmaceutical composition according to  claim 19  to a subject. 
     
     
         21 . (canceled) 
     
     
         22 . A method according to  claim 20 , wherein the disease is a cancer. 
     
     
         23 - 24 . (canceled) 
     
     
         25 . A natural killer (NK) cell which co-expresses a first chimeric antigen receptor (CAR) and second CAR at the cell surface, each CAR comprising:
 (i) an antigen-binding domain;   (ii) a spacer   (iii) a trans-membrane domain; and   (iv) an endodomain   wherein the antigen binding domains of the first and second CARs bind to different antigens, wherein the spacer of the first CAR is different to the spacer of the second CAR and wherein one of the first or second CARs is an activating CAR comprising an activating endodomain and the other CAR is an inhibitory CAR comprising a ligation-off inhibitory endodomain.   
     
     
         26 . (canceled)