Chimeric antigen receptor signalling system comprising heterodimerization domains

1. A chimeric antigen-receptor (CAR) signalling system comprising;

(i) a targeting component comprising an antigen-binding domain, a transmembrane domain and a first heterodimerization domain; and

(ii) a soluble intracellular signalling component that localizes to the cytoplasm when expressed in a cell, comprising a signalling domain and a second heterodimerization domain;

wherein the targeting component and the intracellular signalling component are separate molecules; and

wherein spontaneous heterodimerization between the first and second heterodimerization domains causes the targeting component and signalling component to form a functional CAR complex.

2. The CAR signalling system according to claim 1 , wherein the first and second heterodimerization domains comprise leucine zipper domains.

3. The CAR signalling system according to claim 1 , wherein the first and second heterodimerization domains comprise DDD1 and AD1 domains.

4. The CAR signalling system according to claim 1 , wherein the first and second heterodimerization domains comprise Barnase and Barstar domains.

5. The CAR signalling system according to claim 1 , wherein the first and second heterodimerization domains comprise human pancreatic RNAse and S-peptide domains.

6. A cell which comprises a CAR signalling system according to claim 1 .

7. The cell according to claim 6 , which is a T cell or NK cell.

8. A pharmaceutical composition comprising a plurality of cells according to claim 6 .

9. A method for treating or preventing a disease, comprising the step of administering a pharmaceutical composition comprising a plurality of T cells or NK cells which comprise a CAR signalling system according to claim 1 to a subject.

10. The method according to claim 9 , comprising the steps of:

(i) isolation of a T cell or NK cell containing sample from a subject;

(ii) transduction or transfection of the T cells or NK cells with a nucleic acid construct or a vector comprising a nucleic acid construct encoding a CAR signaling system, wherein the chimeric antigen-receptor (CAR) signalling system comprises (a) a targeting component comprising an antigen-binding domain, a transmembrane domain and a first heterodimerization domain and (b) a soluble intracellular signalling component that localizes to the cytoplasm when expressed in a cell, comprising a signalling domain and a second heterodimerization domain, wherein the targeting component and the intracellular signalling component are separate molecules; and spontaneous heterodimerization between the first and second heterodimerization domains causes the targeting component and signalling component to form a functional CAR complex, and wherein the nucleic acid construct comprises the following structure

A-X B

in which A is a nucleic acid sequences encoding a targeting component and B is a nucleic acid sequence encoding a signalling component, and X is a nucleic acid sequence which encodes a cleavage site, such that A is cleaved from B after translation; and

(iii) administering the T cells or NK cells from (ii) in a pharmaceutical composition to the subject.

11. The method according to claim 9 , wherein the disease is cancer.