# US 10,478,457 B2 · Chimeric protein > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 10,478,457 B2 - Document ID: US10478457B2 - Status: Granted - Kind: B2 - Application number: 16/113,098 - Filed: 2018-08-27 - Published: 2019-01-17 - Granted: 2019-11-19 - Earliest claimed: 2015-02-24 - Assignees: UCL Business PLC - Applicants: Ucl Business PLC - Inventors: Martin Pulé; Ryan Trowbridge; Edward Hodgkin - Web page: https://patentgrep.com/patent/US10478457B2 ## CPC - A61K 31/436: the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin - A61K 40/11: T-cells, e.g. tumour infiltrating lymphocytes [TIL] or regulatory T [Treg] cells; Lymphokine-activated killer [LAK] cells - A61K 40/31: Chimeric antigen receptors [CAR] - A61K 40/42: Cancer antigens - A61P 35/00: Antineoplastic agents - A61P 37/00: Drugs for immunological or allergic disorders - A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection - A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 - C07K 14/705: Receptors; Cell surface antigens; Cell surface determinants {(tumour specific antigens C07K14/4748)} - C12N 9/1205: {Phosphotransferases with an alcohol group as acceptor (2.7.1), e.g. protein kinases} - C12N 9/6472: {Cysteine endopeptidases (3.4.22)} - C12N 15/62: DNA sequences coding for fusion proteins - C12Y 304/22062: Caspase-9 (3.4.22.62) - A61K 2035/124: {the cells being hematopoietic, bone marrow derived or blood cells} - C07K 2319/70: containing domain for protein-protein interaction - Y02A 50/30: Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS - C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00) - C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00) - C12Y: ENZYMES - Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE ## Abstract The present invention provides a chimeric protein having the formula: Casp-Ht1-Ht2 wherein Casp is a caspase domain; Ht1 is a first heterodimerization domain; and Ht2 is a second heterodimerization domain and wherein, in the presence of a chemical inducer of dimerization (CID), an identical pair of the chimeric proteins interact such that Ht1 from one chimeric protein heterodimerizes with Ht2 from the other chimeric protein, causing homodimerization of the two caspase domains. The invention also provides a cell comprising such a protein and its use in adoptive cell therapy. ## Claims ### Claim 1 A chimeric protein having the formula: Ht1-Ht2-Casp, wherein Casp is a caspase domain; Ht1 is a first heterodimerization domain; and Ht2 is a second heterodimerization domain; wherein one heterodimerization domain comprises an FK506-binding protein (FKBP) and the other heterodimerization domain comprises an FRB domain of mTOR; and wherein, in the presence of rapamycin or a rapamycin analog, an identical pair of the chimeric proteins interact such that Ht1 from one chimeric protein heterodimerizes with Ht2 from the other chimeric protein, causing homodimerization of the two caspase domains. ### Claim 2 (depends on 1) The chimeric protein according to claim 1, wherein Ht1 comprises FRB and Ht2 comprises FKBP. ### Claim 3 A nucleic acid comprising a nucleotide sequence which encodes a chimeric protein having the formula: Ht1-Ht2-Casp, wherein Casp is a caspase domain; Ht1 is a first heterodimerization domain; and Ht2 is a second heterodimerization domain; wherein one heterodimerization domain comprises an FK506-binding protein (FKBP) and the other heterodimerization domain comprises an FRB domain of mTOR. ### Claim 4 (depends on 3) The nucleic acid construct which comprises one or more nucleic acid(s) according to claim 3 and a nucleic acid that comprises a nucleotide sequence encoding a T-cell receptor (TCR) or chimeric antigen receptor (CAR). ### Claim 5 (depends on 3) A vector which comprises a nucleic acid according to claim 3. ### Claim 6 (depends on 1) A cell which expresses a chimeric protein according to claim 1. ### Claim 7 (depends on 6) The cell according to claim 6, which is a haematopoietic stem cell, a lymphocyte or a T cell. ### Claim 8 (depends on 5) A method for making a cell which expresses a chimeric protein, the method comprising the step of transducing or transfecting a cell with a vector according to claim 5. ### Claim 9 (depends on 6) A method for deleting a cell according to claim 6, which comprises the step of exposing the cells to a rapamycin or a rapamycin analog. ### Claim 10 (depends on 6) A method for preventing and/or treating a pathological immune reaction in a subject caused by administration of a cell according to claim 6 to the subject, which comprises the step of administering rapamycin or a rapamycin analog to the subject. ### Claim 11 (depends on 10) The method according to claim 10, 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. ### Claim 12 (depends on 4) A vector which comprises a nucleic acid construct according to claim 4. ### Claim 13 (depends on 12) A method for making a cell which expresses a chimeric protein, the method comprising transducing or transfecting a cell with a vector according to claim 12.