Cell
There is provided an effector immune cell which expresses a cell surface receptor or receptor complex which specifically binds an antigen recognition receptor of a target immune cell; which effector immune cell is engineered such that when a synapse is formed between the effector immune cell and the target immune cell, the capacity of the effector immune cell to kill the target immune cell is greater than the capacity of the target immune cell to kill the effector immune cell. There is also provided the use of such a cell in methods for treating cancer, preventing allograft rejection and GVHD.
1 . An effector immune cell which expresses a cell surface receptor or receptor complex which specifically binds an antigen recognition receptor of a target immune cell; which effector immune cell is engineered to be resistant to one or more calcineurin inhibitors.
2 - 3 . (canceled)
4 . An effector immune cell according to claim 3 , which expresses:
calcineurin A comprising mutations T351E and L354A with reference to the sequence shown as SEQ ID No. 65;
calcineurin A comprising mutations V314R and Y341F and with reference to the sequence shown as SEQ ID No. 65; or
calcineurin B comprising mutation L124T and K-125-LA-Ins with reference to the sequence shown as SEQ ID No. 66.
5 - 6 . (canceled)
7 . An effector immune cell which expresses a cell surface receptor or receptor complex which specifically binds an antigen recognition receptor of a target immune cell; which effector immune cell is engineered to express or overexpress PD-L1 or PD-L2 or a fusion protein comprising the extracellular domain of PD-L1 or PD-L2.
8 - 9 . (canceled)
10 . An effector immune cell according to claim 7 , which is engineered to express a fusion protein comprising the extracellular domain of PD-L1 or PD-L2 and a membrane localisation domain.
11 . An effector immune cell according to claim 7 , which is engineered to express a fusion protein comprising the extracellular domain of PD-L1 or PD-L2 and a co-stimulatory endodomain.
12 - 16 . (canceled)
17 . An effector immune cell according to claim 1 , which expresses a cell surface receptor complex which comprises: an MHC class I polypeptide; an MHC class II polypeptide; or β-2 microglobulin, linked to an intracellular signalling domain.
18 - 24 . (canceled)
25 . A nucleic acid construct which comprises:
(i) a first nucleic acid sequence which encodes a cell surface receptor or part of a cell surface receptor complex which specifically binds an antigen recognition receptor of a target immune cell; and
(ii) a second nucleic acid sequence which, when expressed in a cell, confers on that cell resistance to one or more calcineurin inhibitors.
26 . A vector comprising a nucleic acid construct according to claim 25 .
27 . A kit of vectors comprising:
(i) a first vector comprising a first nucleic acid sequence which encodes a cell surface receptor or part of a cell surface receptor complex which specifically binds an antigen recognition receptor of a target immune cell; and
(ii) a second vector comprising a second nucleic acid sequence which, when expressed in a cell, confers on that cell resistance to one or more calcineurin inhibitors.
28 . A pharmaceutical composition comprising a plurality of effector immune cells according to claim 1 .
29 . (canceled)
30 . A method for treating a disease, which comprises the step of administering a pharmaceutical composition according to claim 28 to a subject.
31 . A method according to claim 30 , which comprises the following steps:
(i) administering a pharmaceutical composition to a subject, which pharmaceutical composition comprises a plurality of effector immune cells which express a cell surface receptor or receptor complex which specifically binds an antigen recognition receptor of a target immune cell, and which are engineered to be resistant to one or more calcineurin inhibitors; and
(ii) administering a calcineurin inhibitor to the subject.
32 . (canceled)
33 . A method according to claim 30 , wherein the disease is cancer.
34 . A method for making an effector immune cell according to claim 1 , which comprises the step of introducing into the cell:
(i) a first nucleic acid sequence which encodes a cell surface receptor or part of a cell surface receptor complex which specifically binds an antigen recognition receptor of a target immune cell, and
(ii) a second nucleic acid sequence which, when expressed in a cell, confers on that cell resistance to one or more calcineurin.
35 - 39 . (canceled)
40 . A method for making an effector immune cell according to claim 7 , which comprises the step of introducing into the cell:
(i) a first nucleic acid sequence which encodes a cell surface receptor or part of a cell surface receptor complex which specifically binds an antigen recognition receptor of a target immune cell; and
(ii) a second nucleic acid sequence which encodes PD-L1 or PD-L2 or a fusion protein comprising the extracellular domain of PD-L1 or PD-L2.