Chimeric cytokine receptors and encoding nucleic acids
The present invention provides a chimeric cytokine receptor (CCR) comprising: (i) an exodomain which binds to a ligand selected from a tumour secreted factor, a chemokine and a cell-surface antigen; and (ii) a cytokine receptor endodomain.
1. A chimeric transmembrane protein comprising:
(i) a first polypeptide which comprises
(a) a first dimerization domain comprising the dimerization portion of an antibody heavy chain constant domain (C H ) and
(b) a first chain of a cytokine receptor endodomain; and
(ii) a second polypeptide which comprises
(a) a second dimerization domain comprising the dimerization portion of an antibody light chain constant domain (C L ), which dimerizes with the first dimerization domain and
(b) a second chain of the cytokine-receptor endodomain,
wherein one of the first and second chains of the cytokine receptor endodomain comprises an IL-2 receptor β-chain endodomain, an IL-7 receptor α-chain endodomain, or an IL-15 receptor α-chain endodomain, and wherein the other of the first and second chains of the cytokine receptor endodomain comprises a v-chain receptor endodomain that is common to the IL-2, IL-7, and IL-15 receptors; and
wherein the first and second polypeptides spontaneously dimerize.
2. The chimeric transmembrane protein according to claim 1 , wherein:
(i) the first polypeptide comprises
(a) a heavy chain constant domain (C H ) and
(b) a first chain of the cytokine receptor endodomain; and
(ii) the second polypeptide comprises
(a) a light chain constant domain (C L ) and
(b) a second chain of the cytokine-receptor endodomain.
3. The chimeric transmembrane protein according to claim 2 , wherein the first polypeptide comprises an antibody heavy chain variable domain (V H ) and a heavy chain constant domain (C H ); and the second polypeptide comprises an antibody light chain variable domain (V L ) and a light chain constant domain (C L ).
4. A nucleic acid construct which comprises
(i) a first nucleic acid comprising a nucleic acid sequence encoding a first polypeptide which comprises:
(a) an antibody heavy chain constant domain (C H ) and
(b) a first chain of a cytokine receptor endodomain; and
(ii) a second nucleic acid comprising a nucleic acid sequence encoding a second polypeptide which comprises:
(a) an antibody light chain constant domain (C L ) and
(b) a second chain of the cytokine-receptor endodomain,
wherein one of the first and second chains of the cytokine receptor endodomain comprises an IL-2 receptor β-chain endodomain, an IL-7 receptor α-chain endodomain, or an IL-15 receptor α-chain endodomain, and wherein the other of the first and second chains of the cytokine receptor endodomain comprises a v-chain receptor endodomain that is common to the IL-2, IL-7, and IL-15 receptors.
5. The nucleic acid construct according to claim 4 which also comprises a nucleic acid sequence encoding a chimeric antigen receptor (CAR).
6. A vector comprising a nucleic acid construct according to claim 4 .
7. A method for making a cell, which comprises a step of introducing: a nucleic acid that comprises a nucleic acid sequence that encodes the chimeric transmembrane protein of claim 1 an isolated into cell.
8. An isolated cell which comprises a chimeric transmembrane protein according to claim 1 .
9. The cell according to claim 8 , which also comprises a chimeric antigen receptor.
10. A cell which comprises a chimeric transmembrane protein according to claim 2 .
11. A pharmaceutical composition comprising a plurality of cells according to claim 8 .
12. A pharmaceutical composition comprising a plurality of cells according to claim 10 .
13. A kit which comprises:
(i) a first vector comprising a nucleic acid sequence encoding a first polypeptide which comprises
(a) an antibody heavy chain constant domain (CH) and
(b) a first chain of a cytokine receptor endodomain; and
(ii) a second vector comprising a nucleic acid sequence encoding a second polypeptide which comprises
(a) an antibody light chain constant domain (CL) and
(b) a second chain of the cytokine receptor endodomain,
wherein one of the first and second chains of the cytokine receptor endodomain comprises an IL-2 receptor β-chain endodomain, an IL-7 receptor α-chain endodomain, or an IL-15 receptor α-chain endodomain, and wherein the other of the first and second chains of the cytokine receptor endodomain comprises a γ-chain receptor endodomain that is common to the IL-2, IL-7, and IL-15 receptors.
14. The kit according to claim 13 which also comprises a vector comprising a nucleic acid sequence encoding a chimeric antigen receptor.
15. A kit which comprises:
i) a vector comprising a nucleic acid according to claim 4 and
ii) a vector comprising a nucleic acid sequence encoding a chimeric antigen receptor.