CHIMERIC CYTOKINE RECEPTOR, WHICH COMPRISES A TRUNCATED IL2RBETA AND IL2RGAMMA
The present invention provides a chimeric cytokine receptor comprising a cytokine receptor endodomain which comprises a first chain and a second chain, wherein both the first and second chain of the cytokine-receptor endodomain are truncated. The invention also provides cells comprising such a chimeric cytokine receptor, optionally in combination with a chimeric antigen receptor (CAR) and their use in the treatment of diseases such as autoimmune diseases and cancer.
1 . A chimeric cytokine receptor, which comprises two polypeptides:
(i) a first polypeptide which comprises:
(a) a first dimerization domain; and
(b) a truncated IL2 receptor β-chain endodomain which comprises the sequence shown as SEQ ID No. 2 with a C-terminal truncation of between about 10 and about 70 amino acids; and
(ii) a second polypeptide which comprises:
(a) a second dimerization domain which dimerises with the first dimerization domain; and
(b) a truncated common γ-chain endodomain which comprises the sequence shown as SEQ ID No. 1 with a C-terminal truncation of between about 10 and about 30 amino acids.
2 . A chimeric cytokine receptor according to claim 1 , wherein the truncated IL2 receptor β-chain endodomain of the first polypeptide has the sequence shown as SEQ ID No. 58.
3 . A chimeric cytokine receptor according to claim 1 , wherein the truncated common γ-chain endodomain of the second polypeptide has the sequence shown as SEQ ID No. 62.
4 . A chimeric cytokine receptor according to claim 1 , wherein the first and second dimerization domains dimerise spontaneously.
5 . A chimeric cytokine receptor according to claim 1 , where the first and second dimerization domains dimerise in the presence of a chemical inducer of dimerization (CID) or the presence of a ligand.
6 . A chimeric cytokine receptor according to claim 4 wherein:
the first dimerization domain comprises a heavy chain constant domain (CH) and the second dimerization domain comprises a light chain constant domain (CL); or
the first dimerization domain comprises a light chain constant domain (CL) and the second dimerization domain comprises a heavy chain constant domain (CH).
7 . A chimeric cytokine receptor according to claim 5 which comprises two polypeptides:
(i) a first polypeptide which comprises:
(a) a first antigen-binding domain which binds a first epitope of the ligand; and
(b) a truncated IL2 receptor β-chain endodomain which comprises the sequence shown as SEQ ID No. 2 with a C-terminal truncation of between about 10 and about 70 amino acids; and
(ii) a second polypeptide which comprises:
(a) a second antigen-binding domain which binds a second epitope of the ligand; and
(b) a truncated common γ-chain endodomain which comprises the sequence shown as SEQ ID No. 1 with a C-terminal truncation of between about 10 and about 30 amino acids.
8 - 12 . (canceled)
13 . A cell which comprises a chimeric cytokine receptor according to claim 1 .
14 . A cell according to claim 13 , which also comprises a chimeric antigen receptor.
15 . A nucleic acid construct encoding a chimeric cytokine receptor according to claim 1 which comprises a first nucleic acid sequence encoding the first polypeptide; and a second nucleic acid sequence encoding the second polypeptide.
16 . A nucleic acid construct according to claim 15 which also encodes a chimeric antigen receptor (CAR).
17 . A nucleic acid construct according to claim 15 which comprises an MND promoter.
18 . A vector comprising a nucleic acid construct according to claim 15 .
19 . A vector according to claim 18 which is a lentiviral vector.
20 - 21 . (canceled)
22 . A method for making a cell according to claim 13 , which comprises the step of introducing introducing into a cell:
i) a first nucleic acid sequence encoding a first polypeptide which comprises:
(a) a first dimerization domain; and
(b) a truncated IL2 receptor β-chain endodomain which comprises the sequence shown as SEQ ID No. 2 with a C-terminal truncation of between about 10 and about 70 amino acids; and
(ii) a second nucleotide sequence encoding a second polypeptide which comprises:
(c) a second dimerization domain which dimerises with the first dimerization domain;
(d) and a truncated common γ-chain endodomain which comprises the sequence shown as SEQ ID No. 1 with a C-terminal truncation of between about 10 and about 30 amino acids.
23 . (canceled)
24 . A pharmaceutical composition comprising a plurality of cells according to claim 13 .
25 . A method for treating a disease, which comprises the step of administering a pharmaceutical composition according to claim 24 to a subject.
26 - 30 . (canceled)