# US 2019/0292533 A1 · Inducible chimeric cytokine receptors > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 2019/0292533 A1 - Document ID: US20190292533A1 - Status: Published application - Kind: A1 - Application number: 16/290,388 - Filed: 2019-03-01 - Published: 2019-09-26 - Earliest claimed: 2018-03-02 - Assignees: Allogene Therapeutics, Inc. - Applicants: Allogene Therapeutics, Inc. - Inventors: Andrew Ross NAGER; Spencer PARK; Javier Fernando CHAPARRO RIGGERS; Regina Junhui LIN; Thomas John VAN BLARCOM - Web page: https://patentgrep.com/patent/US20190292533A1 ## CPC - C12N 9/90: Isomerases (5.) - A61K 35/17: Lymphocytes; B-cells; T-cells; Natural killer cells; Interferon-activated or cytokine-activated lymphocytes (when activated by a specific antigen A61K39/00) - 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 - A61K 40/4204: {Epidermal growth factor receptors [EGFR]} - A61K 40/4217: {Receptors for interleukins [IL]} - A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca - C07K 14/70517: {CD8} - C07K 14/70578: {NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95 (NGF-receptor C07K14/71, TNF-receptor C07K14/7151)} - C07K 14/71: for growth factors; for growth regulators - C07K 14/715: for cytokines; for lymphokines; for interferons - C07K 14/7155: {for interleukins [IL]} - C07K 14/7156: {for interferons [IFN]} - C07K 14/72: for hormones {(for neuromediators C07K14/70571)} - C12N 5/0636: {T lymphocytes} - C12Y 502/01008: Peptidylprolyl isomerase (5.2.1.8), i.e. cyclophilin - A61K 38/00: Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00) - A61K 48/00: Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy - A61K 2239/31: characterized by the route of administration - A61K 2239/38: characterised by the dose, timing or administration schedule - C07K 14/7051: {T-cell receptor (TcR)-CD3 complex} - C07K 2319/02: containing a signal sequence - C07K 2319/03: containing a transmembrane segment - C07K 2319/70: containing domain for protein-protein interaction - C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00) - 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) - 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) - C12Y: ENZYMES ## Abstract The present invention provides inducible chimeric cytokine receptors responsive to a ligand, e.g., a small molecule or protein, uses of such receptors for improving the functional activities of genetically modified immune cells, such as T cells, comprising the inducible chimeric cytokine receptors, and compositions comprising such cells. ## Claims ### Claim 1 An inducible chimeric cytokine receptor comprising: a dimerization domain; a tyrosine kinase activating domain; and a tyrosine effector domain, wherein the tyrosine effector domain comprises at least two STAT-activation domains of, or derived from, two receptors; or wherein the tyrosine effector domain comprises at least one STAT-activation domain of, or derived from, a receptor and a portion of the cytoplasmic tail of, or derived from, at least one receptor tyrosine kinase (RTK). ### Claim 2 (depends on 1) The inducible chimeric cytokine receptor of claim 1, wherein the tyrosine kinase activating domain comprises a Janus Kinase (JAK)-binding domain of, or derived from, a protein. ### Claim 3 (depends on 1) The inducible chimeric cytokine receptor of claim 1, wherein the tyrosine kinase activating domain comprises a tyrosine kinase domain of, or derived from, a receptor tyrosine kinase (RTK). ### Claim 4 (depends on 1) The inducible chimeric cytokine receptor of claim 1, wherein the tyrosine kinase activating domain comprises a transmembrane domain. ### Claim at position 5 5-7. (canceled) ### Claim 8 (depends on 1) The inducible chimeric cytokine receptor of claim 1, wherein the dimerization domain binds to a ligand AP1903, AP20187, dimeric FK506, or a dimeric FK506-like analog. ### Claim 9 (depends on 1) The inducible chimeric cytokine receptor of claim 1, herein the dimerization domain comprises an FKBP polypeptide. ### Claim 10 (depends on 9) The inducible chimeric cytokine receptor of claim 9, wherein the FKBP polypeptide is an FKBP12 polypeptide. ### Claim 11 (depends on 10) The inducible chimeric cytokine receptor of claim 10, wherein the FKBP12 polypeptide contains the amino acid substitution F36V (SEQ ID NO: 218). ### Claim 12 (depends on 1) The inducible chimeric cytokine receptor of claim 1, wherein the dimerization domain comprises an amino acid sequence selected from the group consisting of: (i) a FKBP polypeptide containing one or more amino acid substitutions, (ii) two or three tandem repeats of an unmodified FKBP polypeptide, and (iii) two or three tandem repeats of a FKBP polypeptide containing one or more amino acid substitutions. ### Claim 13 (depends on 1) The inducible chimeric cytokine receptor of claim 1, wherein the dimerization domain comprises a dimerization domain sequence selected from SEQ ID NOs: 69-87. ### Claim 14 (depends on 1) The inducible chimeric cytokine receptor of claim 1, wherein the dimerization domain comprises an FKBP dimerization domain sequence selected from SEQ ID NOs. 69-73. ### Claim 15 (depends on 1) The inducible chimeric cytokine receptor of claim 1, wherein the dimerization domain comprises an amino acid sequence of, or derived from, a polypeptide selected from the group consisting of: FKBP12, FKBP12(F36V), an extracellular domain of OX-40, and an extracellular domain of a TNFR2 superfamily receptors. ### Claim 16 (depends on 15) The inducible chimeric cytokine receptor of claim 15, wherein the TNFR2 superfamily receptor is BCMA, TACI, or BAFFR. ### Claim at position 15 17-18. (canceled) ### Claim 19 (depends on 1) The inducible chimeric cytokine receptor of claim 1, wherein the dimerization domain comprises an amino acid sequence of, or derived from, a protein selected from the group consisting of: FKBP, cyclophilin, steroid binding protein, estrogen binding protein, glucocorticoid binding protein, vitamin D binding protein, tetracycline binding protein, extracellular domain of a cytokine receptor, a receptor tyrosine kinase, a TNFR-family receptor, and an immune co-receptor. ### Claim 20 (depends on 19) The inducible chimeric cytokine receptor of claim 19, wherein the immune co-receptor is selected from the group consisting of: erythropoietin receptor, prolactin receptor, growth hormone receptor, thrombopoietin receptor, granulocyte colony-stimulating factor receptor, GP130, common gamma chain receptor, common beta chain receptor, IFN alpha receptor, IFN gamma receptor, IFN lambda receptor, IL2/IL15 receptor, IL3 receptor, IL4 receptor, IL5 receptor, IL7 receptor, IL9 receptor, IL10 receptor, IL12 receptor, IL13 receptor, IL20 receptor, IL21 receptor, IL22 receptor, IL23 receptor, IL27 receptor, TSLP Receptor, G-CSF receptor, GM-CSF receptor, CNTF receptor, OSM receptor, LIF receptor, CT-1 receptor, TGFBR1/ALKL5, TGFBR2, EGFR/HER1, ERBB2/HER2, ERBB3/HER3, ERRB4/HER4, INSR, IGF-1R, IRR, PDGFRA, PDGFRB, CSF-1R, KIT/SCFR, FLK2/FLT3, VEGFR1, VEGFR2, VEGFR3, FGFR-1, FGFR-2, FGFR-3, FGFR-4, CCK4, TRKA, TRKB, TRKC, MET, RON, EPHA1, EPHA2, EPHA3, EPHA4, EPHA5, EPHA6, EPHA7, EPHA8, EPHB1, EPHB2, EPHB3, EPHB4, EPHB5, EPHB6, AXL, MER, TYRO3, TIE, TEK, RYK, DDR1, DDR2, RET, ROS, LTK, ALK, ROR1, ROR2, MUSK, AATYK, AATYK2, AATYK3, RTK106, TNFR1, Fas, TRAILR1, TRAILR2, NGFR, DR3, DR6, EDAR, TNFR2, LTbR, OX40, CD40, CD27, CD30, 4-1BB, RANK, Fn14, TACI, BAFFR, HVEM, BCMA, GITR, TROY, RELT, XEDAR, TRAILR3, TRAILR4, OPG, DcR3, PD-1, CD80, CD86, ICOS-L, ICOS, CTLA-4, BTLA, CD160, LAG3, and TIM3. ### Claim 21 (depends on 2) The inducible chimeric cytokine receptor of claim 2, wherein the protein is a receptor. ### Claim 22 (depends on 21) The inducible chimeric cytokine receptor of claim 21, wherein the receptor is a hormone receptor. ### Claim 23 (depends on 2) The inducible chimeric cytokine receptor of claim 2, wherein the protein is selected from the group consisting of EPOR, GP130, PRLR, GHR, GCSFR, and TPOR/MPLR. ### Claim 24 (depends on 3) The inducible chimeric cytokine receptor of claim 3, wherein the RTK is selected from the group consisting of: EGFR/HER1, ERBB2/HER2, ERBB3/HER3, ERRB4/HER4, INSR, IGF-1R, IRR, PDGFRA, PDGFRB, CSF-1R, KIT/SCFR, FLK2/FLT3, VEGFR1, VEGFR2, VEGFR3, FGFR-1, FGFR-2, FGFR-3, FGFR-4, CCK4, TRKA, TRKB, TRKC, MET, RON, EPHA1, EPHA2, EPHA3, EPHA4, EPHA5, EPHA6, EPHA7, EPHA8, EPHB1, EPHB2, EPHB3, EPHB4, EPHB5, EPHB6, AXL, MER, TYRO3, TIE, TEK, RYK, DDR1, DDR2, RET, ROS, LTK, ALK, ROR1, ROR2, MUSK, AATYK, AATYK2, AATYK3, and RTK106. ### Claim 25 (depends on 24) The inducible chimeric cytokine receptor of claim 24, wherein the RTK is EGFR. ### Claim 26 (depends on 1) The inducible chimeric cytokine receptor of claim 1, wherein the tyrosine kinase activating domain comprises a tyrosine kinase activating domain sequence selected from SEQ ID NOs.: 88-133. ### Claim 27 (depends on 4) The inducible chimeric cytokine receptor of claim 4, wherein the transmembrane domain comprises a transmembrane domain of, or derived from, a protein selected from the group consisting of: EPOR, GP130, PRLR, GHR, GCSFR, PD-1, and TPOR/MPLR. ### Claim 28 (depends on 4) The inducible chimeric cytokine receptor of claim 4, wherein the transmembrane domain comprises a transmembrane domain derived from TPOR/MPLR. ### Claim 29 (depends on 4) The inducible chimeric cytokine receptor of claim 4, wherein the transmembrane domain is derived from amino acids 478-582 of the naturally occurring TPOR/MPLR sequence of SEQ ID No.: 64. ### Claim 30 (depends on 4) The inducible chimeric cytokine receptor of claim 4, wherein the transmembrane domain comprises a deletion variant of the amino acid region 478-582 of the naturally occurring TPOR/MPLR sequence of SEQ ID No.: 64. ### Claim 31 (depends on 30) The inducible chimeric cytokine receptor of claim 30, wherein the deletion variant comprises a deletion of 1 to 18 amino acids from the region 478-582 of the naturally occurring TPOR/MPLR sequence of SEQ ID No.: 64. ### Claim 32 (depends on 30) The inducible chimeric cytokine receptor of claim 30, wherein the deletion variant comprises a deletion of 1 to 18 amino acids from the region 489-510 of the naturally occurring TPOR/MPLR sequence of SEQ ID No.: 64. ### Claim 33 (depends on 4) The inducible chimeric cytokine receptor of claim 4, wherein the transmembrane domain comprises an insertion variant of the amino acid region 478-582 of the naturally occurring TPOR/MPLR sequence of SEQ ID No.: 64. ### Claim 34 (depends on 33) The inducible chimeric cytokine receptor of claim 33, wherein the insertion variant comprises an insertion of 1 to 8 amino acids in the region 478-582 of the naturally occurring TPOR/MPLR sequence of SEQ ID No.: 64. ### Claim 35 (depends on 33) The inducible chimeric cytokine receptor of claim 33, wherein the insertion variant comprises an insertion of 1 to 8 amino acids in the region 489-510 of the naturally occurring TPOR/MPLR sequence of SEQ ID No.: 64. ### Claim 36 (depends on 33) The inducible chimeric cytokine receptor of claim 33, wherein the amino acids inserted in the insertion variant are selected from the group consisting of: leucine, valine, and isoleucine. ### Claim 37 (canceled) ### Claim 38 (depends on 1) The inducible chimeric cytokine receptor of claim 1, wherein at least one of the two receptors is a hormone receptor. ### Claim 39 (depends on 1) The inducible chimeric cytokine receptor of claim 1, wherein at least one of the two receptors is a cytokine receptor. ### Claim 40 (depends on 1) The inducible chimeric cytokine receptor of claim 1, wherein the two receptors are selected from the group consisting of: BLNK, IL2RG, EGFR, EpoR, GHR, IFNAR1, IFNAR2, IFNAR1/2, IFNLR1, IL10R1, IL12Rb1, IL12Rb2, IL21R, IL2Rb, IL2small, IL7R, IL7Ra, IL9R, IL15R, and IL21R. ### Claim 41 (depends on 1) The inducible chimeric cytokine receptor of claim 1, wherein the tyrosine kinase activating domain comprises a transmembrane domain and a Janus Kinase (JAK)-binding domain and the tyrosine effector domain comprises at least two STAT-activation domains of, or derived from, two receptors. ### Claim 42 (depends on 41) The inducible chimeric cytokine receptor of claim 41, wherein the dimerization domain comprises an FKBP polypeptide; the transmembrane domain comprises a transmembrane domain of, or derived from, a protein selected from the group consisting of: EPOR, GP130, PRLR, GHR, GCSFR, PD-1, and TPOR; the JAK-binding domain comprises a JAK-binding domain of, or derived from, a protein selected from the group consisting of: EPOR, GP130, PRLR, GHR, GCSFR, and TPOR; and the tyrosine effector domain comprises at least two STAT-activation domains of, or derived from, two receptors selected from the group consisting of: BLNK, IL2RG, EGFR, EpoR, GHR, IFNAR1, IFNAR2, IFNAR1/2, IFNLR1, IL10R1, IL12Rb1, IL12Rb2, IL21R, IL2Rb, IL2small, IL7R, IL7Ra, IL9R, IL15R, and IL21R. ### Claim 43 (canceled) ### Claim 44 (depends on 1) The inducible chimeric cytokine receptor of claim 1, wherein the tyrosine effector domain comprises a tyrosine effector domain sequence selected from SEQ ID NOs: 134-176. ### Claim 45 (depends on 1) The inducible chimeric cytokine receptor of claim 1, wherein the dimerization domain is located at the N-terminus of the inducible chimeric cytokine receptor. ### Claim 46 (depends on 1) The inducible chimeric cytokine receptor of claim 1, wherein the dimerization domain is located at the C-terminus of the inducible chimeric cytokine receptor. ### Claim 47 (depends on 1) The inducible chimeric cytokine receptor of claim 1, wherein the inducible chimeric cytokine receptor comprises a membrane-targeting motif. ### Claim 48 (depends on 47) The inducible chimeric cytokine receptor of claim 47, wherein the membrane-targeting motif comprises a myristoylation motif. ### Claim 49 (depends on 1) The inducible chimeric cytokine receptor of claim 1, wherein the receptor is myristoylated. ### Claim 50 (depends on 1) The inducible chimeric cytokine receptor of claim 1, comprising a sequence selected from SEQ ID NOs: 14-19, 46-57, 187-215, 238-243, 270-281, or 283-311. ### Claim 51 (depends on 1) A polynucleotide comprising a nucleic acid sequence encoding the inducible chimeric cytokine receptor of claim 1. ### Claim 52 (depends on 51) An expression vector comprising the polynucleotide of claim 51. ### Claim 53 (depends on 1) An engineered immune cell comprising at least one inducible chimeric cytokine receptor of claim 1. ### Claim 54 (depends on 1, 53) The engineered immune cell of claim 53, wherein the cell comprises at least two inducible chimeric cytokine receptors of claim 1. ### Claim 55 (depends on 1, 53) The engineered immune cell of claim 53, wherein the cell comprises at least three or four inducible chimeric cytokine receptors of claim 1. ### Claim 56 (depends on 53) The engineered immune cell of claim 53, wherein, when more than one inducible chimeric cytokine receptor is present, the dimerization domain, the tyrosine kinase activating domain, and the tyrosine effector domain of each receptor can be the same or different. ### Claim 57 (depends on 53) The engineered immune cell of claim 53, wherein the cell comprises a chimeric antigen receptor (CAR). ### Claim 58 (depends on 53) The engineered immune cell of claim 53, wherein the immune cell is selected from the group consisting of: T cell, dendritic cell, killer dendritic cell, mast cell, NK-cell, macrophage, monocyte, B-cell and an immune cell derived from a stem cell. ### Claim 59 (depends on 53) The engineered immune cell of claim 53, wherein the immune cell is a T cell. ### Claim 60 (depends on 53) A method of modulating an engineered immune cell in a subject, the method comprising administering a ligand to a subject that has previously been administered an engineered immune cell of claim 53, wherein the ligand binds to the dimerization domain of the inducible chimeric cytokine receptor. ### Claim 61 (canceled) ### Claim 62 (depends on 51) A method of preparing an engineered immune cell, the method comprising introducing a polynucleotide of claim 51 into an immune cell. ### Claim at position 60 63-70. (canceled) ### Claim 71 (depends on 53) The engineered immune cell of claim 53, wherein the engineered immune cell exhibits improved persistence upon contact with a ligand that binds to the dimerization domain relative to persistence of an immune cell that does not express the inducible chimeric cytokine receptor. ### Claim 72 (depends on 53) The engineered immune cell of claim 53, wherein the engineered immune cell exhibits increased activation of STAT upon contact with a ligand that binds to the dimerization domain relative to activation of STAT exhibited by an immune cell that does not express the inducible chimeric cytokine receptor. ### Claim 73 (depends on 72) The engineered immune cell of claim 72, wherein the STAT is STAT1, STAT2, STAT3, STAT4, STAT5, STAT6, or combinations thereof. ### Claim 74 (depends on 72) The engineered immune cell of claim 72, wherein the activation of STAT by the engineered immune cell, upon contact with a ligand that binds to the dimerization domain, increases with the dose of the ligand compared to activation of STAT shown by the immune cell that does not express the inducible chimeric cytokine receptor. ### Claim 75 (depends on 53) The engineered immune cell of claim 53, wherein the engineered immune cell exhibits increased cytotoxicity upon contact with a ligand that binds to the dimerization domain compared to cytotoxicity exhibited by an isolated immune cell that does not express the inducible chimeric cytokine receptor. ### Claim 76 (depends on 53) The engineered immune cell of claim 53, wherein the engineered immune cell expands upon contact with a ligand that binds to the dimerization domain compared to an immune cell that does not express the inducible chimeric cytokine receptor. ### Claim 77 (depends on 53) The engineered immune cell of claim 53, wherein the level of cell markers for stem cell memory (Tscm) and/or central memory (Tcm) on the engineered immune cell are increased or maintained upon contact with a ligand that binds to the dimerization domain compared to the level of these markers on an immune cell that does not express the inducible chimeric cytokine receptor. ### Claim 78 (canceled) ### Claim 79 (depends on 53) A method of generating an engineered immune cell of claim 53, wherein the method comprises the steps of: (a) providing an immune cell; (b) introducing into the immune cell a polynucleotide that encodes a chimeric antigen receptor (CAR) comprising an extracellular ligand-binding domain, a transmembrane domain, and an intracellular signaling domain; and (c) introducing into the immune cell a polynucleotide that encodes the inducible chimeric cytokine receptor. ### Claim at position 70 80-87. (canceled) ### Claim 88 (depends on 53) A pharmaceutical composition comprising the engineered immune cell of claim 53. ### Claim 89 (depends on 88) A method for treating a disorder in a subject, wherein the method comprises administering the pharmaceutical composition of claim 88 to the subject. ### Claim at position 73 90-106. (canceled) ### Claim 107 (depends on 53) The engineered immune cell of claim 53, wherein the cell is an autologous T cell. ### Claim 108 (depends on 53) The engineered immune cell of claim 53, wherein the cell is an allogeneic T cell. ### Claim at position 76 109-110. (canceled)