1. WO2020222007 - CHIMERIC PROTEIN COMPRISING A CASPASE 1 DOMAIN
ISR/WOSA/A17(2)(a)
1. A chimeric protein having the formula:
Ht1-Ht2-Casp1
Caspl is a caspase 1 domain;
Ht1 is a first heterodimerization domain; and
Ht2 is a second heterodimerization domain.
2. A chimeric protein according to claim 1 , wherein one heterodimerization domain comprises an FK506-binding protein (FKBP) and the other heterodimerization domain comprises an FRB domain of mTOR.
3. A chimeric protein according to claim 2, wherein Ht1 comprises FRB and Ht2 comprises FKBP.
4. A chimeric protein according to claim 2 or 3 wherein Ht1 from one chimeric protein molecule dimerises with Ht2 from another chimeric protein molecule is the presence of rapamycin or a rapamycin analog.
5. A nucleic acid sequence which encodes a chimeric protein according to any preceding claim.
6. A nucleic acid construct which comprises a nucleic acid sequence according to claim 5 and a nucleic acid sequence encoding a T-cell receptor (TCR) or chimeric antigen receptor (CAR).
7. A vector which comprises a nucleic acid sequence according to claim 5 or a nucleic acid construct according to claim 6.
8. A kit of vectors which comprises first vector comprising a nucleic acid sequence according to claim 5 and a second vector comprising a nucleic acid sequence which encodes a chimeric antigen receptor or a T-cell receptor.
9. A cell which expresses a chimeric protein according to any of claims 1 to 4.
10. A cell according to claim 9, which is a haematopoietic stem cell, a lymphocyte or a T cell.
11. A method for making a cell according to claim 9 which comprises the step of transducing or transfecting a cell with a vector according to claim 7 or a kit of vectors according to claim 8.
12. A method for deleting a cell according to claim 9 or 10, which comprises the step of exposing the cells to a chemical inducer of dimerization (CID)
13. A method according to claim 12, wherein the CID is rapamycin or a rapamycin analog.
14. A chemical inducer of dimerization (CID) for use in deleting a cell according to claim 9 or 10 in vivo.
15. A method for treating a disease in a subject, which comprises the step of administering a cell according to claim 9 or 10 to the subject.
16 A method according to claim 14 which comprises the following steps:
(i) transducing or transfecting a sample of cells isolated from a subject with a vector according to claim 7 or a kit of vectors according to claim 8, and
(ii) administering the transduced/transfected cells to a patient.
17. A method according to claim 16 for treating cancer.
18. A cell according to claim 9 or 10 for use in a method for treating a disease in a subject
19. A method for preventing and/or treating a pathological immune reaction in a subject caused by administration of a cell according to any of claims claim 9 or 10 to the subject, which comprises the step of administering a chemical inducer of dimerization (CID) to the subject.
20. A method according to claim 19, wherein the pathological immune reaction is selected from the following group: graft-versus-host disease; on-target, off-tumour toxicity; immune activation syndrome; and lymphoproliferative disorders.
21. A chemical inducer of dimerization (CID) for use in preventing and/or treating a pathological immune reaction in a subject caused by administration of a cell according to claim 9 or 10 to the subject.
22. A method for treating a disease in a subject according to claim 15, which comprises the following steps:
(i) administering a cell according to claim 9 or 10 to the subject;
(ii) monitoring the subject for the development of a pathological immune reaction; and
(iii) administering chemical inducer of dimerization (CID) to the subject if the subject shows signs of developing or having developed a pathological immune reaction.