Signalling system

Abstract

The present invention provides a chimeric antigen receptor (CAR) signalling system comprising; (i) a receptor component comprising an antigen binding domain, a transmembrane domain and a first binding domain; and (ii) an intracellular signalling component comprising a signalling domain and a second binding domain which specifically binds the first binding domain of the receptor component; wherein, binding of the first and second binding domains is disrupted by the presence of an agent, such that in the absence of the agent the receptor component and the signalling component heterodimerize and binding of the antigen binding domain to antigen results in signalling through the signalling domain, whereas in the presence of the agent the receptor component and the signalling component do not heterodimerize and binding of the antigen binding domain to antigen does not result in signalling through the signalling domain.

1 . A chimeric antigen receptor (CAR) system comprising;
 (i) a receptor component comprising an antigen binding domain, a transmembrane domain and a first binding domain; and   (ii) an intracellular signalling component comprising a signalling domain and a second binding domain which specifically binds the first binding domain of the receptor component;   
       wherein, binding of the first and second binding domains is disruptable by the presence of an agent, such that in the absence of the agent the receptor component and the intracellular signalling component heterodimerize and binding of the antigen binding domain to antigen results in signalling through the signalling domain, whereas in the presence of the agent the receptor component and the intracellular signalling component do not heterodimerize and binding of the antigen binding domain to antigen does not result in signalling through the signalling domain. 
     
     
         2 - 3 . (canceled) 
     
     
         4 . The CAR system according to  claim 1  wherein the first binding domain comprises Tet Repressor Protein (TetR) or a variant thereof and the second binding domain comprises Transcription inducing peptide (TiP) or a variant thereof;
 or wherein the first binding domain comprises TiP or a variant thereof and the second binding domain comprises TetR or a variant thereof; 
 and the agent is tetracycline, doxycycline or minocycline or an analogue thereof . 
 
     
     
         5 - 10 . (canceled) 
     
     
         11 . The CAR system according to  claim 1 , wherein the signalling domain of the intracellular signalling component comprises a single endodomain selected from CD3 zeta endodomain, CD28 endodomain, 41 BB endodomain and OX40 endodomain. 
     
     
         12 . The CAR system according to  claim 1 , wherein the signalling domain of the intracellular signalling component comprises at least one of CD3 zeta endodomain, CD28 endodomain, 41 BB endodomain and OX40 endodomain. 
     
     
         13 - 18 . (canceled) 
     
     
         19 . A nucleic acid comprising a nucleotide sequence encoding a CAR system according to  claim 1 , wherein the receptor component and intracellular signalling component are co-expressed, joined by a self-cleaving peptide which is cleaved between the receptor component and the intracellular signalling component after translation. 
     
     
         20 . A vector comprising a nucleic acid according to  claim 19 . 
     
     
         21 . (canceled) 
     
     
         22 . A T cell or NK cell which expresses a CAR system according to  claim 1 . 
     
     
         23 . (canceled) 
     
     
         24 . A pharmaceutical composition comprising a plurality of T cells or NK cells according to  claim 22 . 
     
     
         25 . (canceled) 
     
     
         26 . A method for treating a disease, which comprises the step of administering a pharmaceutical composition according to  claim 24  to a subject. 
     
     
         27 . A method for treating a disease, which comprises the following steps:
 (i) isolating a T cell or NK cell containing sample;   (ii) transducing or transfecting the T or NK cells with a nucleic acid sequence according to  claim 19  or a vector comprising the nucleic acid; and   (iii) administering the T cells or NK cells from (ii) to a subject.   
     
     
         28 . A method according to  claim 26 , which involves monitoring toxic activity in the subject and comprises the step of administering an agent for use in the CAR system to the subject to reduce adverse toxic effects. 
     
     
         29 . A method according to  claim 27 , which involves monitoring the progression of disease and/or monitoring toxic activity in the subject and comprises the step of administering an agent for use in the CAR system to the subject to provide acceptable levels of disease progression and/or toxic activity. 
     
     
         30 . The method according to  claim 26 , wherein the disease is cancer. 
     
     
         31 - 32 . (canceled) 
     
     
         33 . A method for making a T cell or NK cell, which comprises the step of introducing a nucleic acid according to  claim 19  or a vector comprising the nucleic acid into a T cell or NK cell. 
     
     
         34 . (canceled) 
     
     
         35 . A method for inhibiting the CAR system according to  claim 1  in a subject which comprises a T or NK cell which expresses the CAR signaling system, which method comprises the step of administering the agent to the subject.