Chimeric receptor comprising a ligand binding domain and an endodomain comprising a cytokine receptor endodomain and an intracellular T cell signalling domain
The present invention provides a chimeric receptor which comprises: a ligand-binding exodomain; and an endodomain which comprises: (i) a cytokine receptor endodomain; and (ii) an intracellular T cell signalling domain.
1 . A chimeric receptor comprising:
a ligand-binding exodomain that comprises an antigen binding domain of an antibody;
a transmembrane domain; and
an endodomain which comprises:
(i) a cytokine receptor endodomain, wherein the cytokine receptor endodomain comprises or consists of an IL-2 receptor β-chain endodomain; and
(ii) an intracellular T cell signalling domain that includes a CD3 zeta endodomain.
2 . The chimeric receptor according to claim 1 , wherein the antigen binding domain binds to a tumor-secreted factor or a tumor-associated antigen.
3 . The chimeric receptor according to claim 1 , wherein the intracellular T cell signalling domain further includes a CD28 endodomain, an OX40 endodomain, a 4-1BB endodomain, a CD2 endodomain, a CD27 endodomain, an ICOS endodomain, and/or a CD40 endodomain.
4 . A cell which comprises a chimeric receptor according to claim 1 .
5 . A pharmaceutical composition comprising a plurality of cells according to claim 4 .
6 . A method for treating cancer, which comprises the step of administering a pharmaceutical composition according to claim 5 to a subject with cancer, wherein the cells comprise cells from a cell-containing sample isolated from a subject and that comprise the chimeric receptor.
7 . A method according to claim 6 , wherein the sample is a T-cell containing sample.
8 . A method according to claim 6 , wherein the cancer is bladder cancer, breast cancer, colon cancer, endometrial cancer, kidney cancer, leukaemia, lung cancer, melanoma, non-Hodgkin lymphoma, pancreatic cancer, prostate cancer or thyroid cancer.
9 . A chimeric receptor system which comprises first and second chimeric receptors;
wherein the first chimeric receptor comprises a chimeric receptor according to claim 1 , and
wherein the second chimeric receptor comprises a ligand-binding exodomain that comprises an antigen binding domain of an antibody;
a transmembrane domain; and
an endodomain that comprises
(i) a cytokine receptor endodomain that comprises or consists of a type I cytokine receptor common y-chain endodomain; and
(ii) an intracellular T cell signalling domain that includes a CD3 zeta endodomain.
10 . A chimeric receptor system according to claim 9 , wherein the antigen binding domain of the first chimeric receptor and the antigen binding domain of the second chimeric receptor bind to different epitopes of the same antigen.
11 . A cell that comprises a chimeric receptor system according to claim 9 .
12 . A pharmaceutical composition comprising a plurality of cells according to claim 11 .
13 . A method for treating cancer, which comprises the step of administering a pharmaceutical composition according to claim 12 to a subject with cancer, wherein the cells comprise cells from a cell-containing sample isolated from a subject and that comprise the chimeric receptor.
14 . A chimeric receptor system comprising a chimeric receptor according to claim 1 , and an intracellular fusion protein,
wherein the intracellular fusion protein comprises a ZAP70 SH2 domain and a cytokine receptor endodomain
that is complementary to the cytokine receptor endodomain of the chimeric receptor according to claim 1 .
15 . A cell that comprises a chimeric receptor system according to claim 14 .
16 . A pharmaceutical composition comprising a plurality of cells according to claim 15 .
17 . A method for treating cancer, which comprises the step of administering a pharmaceutical composition according to claim 16 to a subject with cancer, wherein the cells comprise cells from a cell-containing sample isolated from a subject and that comprise the chimeric receptor.
18 . A chimeric receptor system comprising a chimeric receptor according to claim 1 , and a transmembrane protein,
wherein the transmembrane protein comprises a type I cytokine receptor common γ-chain endodomain.
19 . A cell that comprises a chimeric receptor system according to claim 18 .
20 . A pharmaceutical composition comprising a plurality of cells according to claim 19 .
21 . A method for treating cancer, which comprises the step of administering a pharmaceutical composition according to claim 20 to a subject with cancer, wherein the cells comprise cells from a cell-containing sample isolated from a subject and that comprise the chimeric receptor.