CHIMERIC CYTOKINE RECEPTOR
The present invention provides a chimeric cytokine receptor (CCR) which comprises two polypeptides: (i) a first polypeptide which comprises: (a) an ectodomain which comprises a first dimerization domain; (b) an interleukin-18 receptor 1 (IL18R1) endodomain; and (ii) a second polypeptide which comprises: (a) an ectodomain which comprises a second dimerization domain; (b) an interleukin-18 receptor accessory protein (IL18RAP) endodomain. The first polypeptide and the second polypeptide spontaneously dimerise causing IL18-type signalling to occurs through the IL18R1 and IL18RAP endodomains. The invention also provides a cell comprising such a CCR and optionally a chimeric antigen receptor (CAR) and the use of such a cell in the treatment of e.g. cancer or an autoimmune disease.
1 . A chimeric cytokine receptor (CCR) which comprises two polypeptides:
(i) a first polypeptide which comprises:
(a) an ectodomain which comprises a first dimerization domain;
(b) an interleukin-18 receptor 1 (IL18R1) endodomain; and
(ii) a second polypeptide which comprises:
(a) an ectodomain which comprises a second dimerization domain which spontaneously dimerises with the first dimerization domain;
(b) an interleukin-18 receptor accessory protein (IL18RAP) endodomain;
wherein one of the first and second dimerization domains comprises a heavy chain constant domain (CH) and the other comprises a light chain constant domain (CL).
2 - 6 . (canceled)
7 . A cell which comprises a chimeric cytokine receptor according to claim 1 .
8 . A cell according to claim 7 , which also comprises a chimeric antigen receptor.
9 . A nucleic acid construct encoding a chimeric cytokine receptor (CCR) according to claim 1 , which nucleic acid construct comprises a first nucleic acid sequence encoding the first polypeptide and a second nucleic acid sequence encoding the second polypeptide.
10 . (canceled)
11 . A nucleic acid construct according to claim 9 which also comprises a nucleic acid sequence which encodes a chimeric antigen receptor.
12 . A vector comprising a nucleic acid construct according to claim 9 .
13 . A kit which comprises:
i) a vector comprising a nucleic acid sequence encoding a first polypeptide which comprises:
(a) an ectodomain which comprises a first dimerization domain;
(b) an interleukin-18 receptor 1 (IL18R1) endodomain; and
ii) a vector comprising a nucleic acid sequence encoding a second polypeptide which comprises:
(a) an ectodomain which comprises a second dimerization domain which spontaneously dimerises with the first dimerization domain;
(b) an interleukin-18 receptor accessory protein (IL18RAP) endodomain, wherein one of the first and second dimerization domains comprises a heavy chain contact domain (CH) and the other comprises a light chain contact domain (CL).
14 . (canceled)
15 . A method for making a cell which expresses a chimeric cytokine receptor (CCR), which method comprises the step of introducing: a nucleic acid construct according to claim 9 , into a cell ex vivo.
16 . A pharmaceutical composition comprising a plurality of cells according to claim 7 .
17 . (canceled)
18 . A method for treating cancer or an autoimmune disease which comprises the step of administering a pharmaceutical composition according to claim 16 to a subject.
19 . (canceled)
20 . A vector comprising a nucleic acid construct according to claim 11 .
21 . A method for making a cell which co-expresses a chimeric cytokine receptor (CCR) and a chimeric antigen receptor (CAR), which comprises the step of introducing a nucleic acid construct according to claim 11 into a cell.
22 . A pharmaceutical composition comprising a plurality of cells according to claim 8 .
23 . A method for treating cancer or an autoimmune disease which comprises the step of administering a pharmaceutical composition according to claim 22 to a subject.