JPWO2020180664A5 - - Google Patents

Claims (50)

a. a PD-1 ectodomain;
b. a transmembrane domain;
c. a Janus kinase (JAK) binding domain;
d. a PD-1 chimeric cytokine receptor comprising a recruitment domain; 2. The chimeric cytokine receptor of Claim 1, wherein said recruitment domain is a STAT recruitment domain. 3. The chimeric cytokine receptor of claim 1 or 2, wherein said recruitment domain is derived from the receptor, optionally from the cytokine receptor. The chimeric cytokine receptor of any one of claims 1-3, wherein said PD-1 chimeric receptors are clustered. The PD-1 chimeric receptor is dimerized, each monomer comprising:
a. a PD-1 ectodomain;
b. a transmembrane domain;
c. a Janus kinase (JAK) binding domain;
d. The chimeric cytokine receptor of any one of claims 1-3, comprising a recruitment domain and a. 6. The chimeric cytokine receptor of any one of claims 1-5, wherein said PD-1 ectodomain comprises a wild-type PD-1 ectodomain sequence. 6. The chimeric cytokine receptor of any one of claims 1-5, wherein said PD-1 ectodomain comprises a mutation relative to said wild-type PD-1 ectodomain sequence. 8. The chimeric cytokine receptor of claim 7, wherein said PD-1 ectodomain sequence is a high affinity PD-1 ectodomain. 2. The chimeric cytokine receptor of claim 1, wherein said PD-1 ectodomain comprises an amino acid sequence selected from SEQ ID NOs:2-5, 129-130, 132-133, and 168-169. 6. The chimeric cytokine receptor of any one of claims 1-5, wherein said PD-1 ectodomain comprises a PD-1 ligand antigen binding domain. 11. The chimeric cytokine receptor of claim 10, wherein said PD-1 ligand antigen binding domain is a scFv. The chimeric cytokine receptor of any one of claims 10-11, wherein said PD-1 ligand antigen binding domain comprises a PD-L1 antigen binding domain or a PD-L2 antigen binding domain. 13. The chimeric cytokine receptor of any one of claims 1-12, wherein the PD-1 ectodomain is activated when the PD-1 ectodomain binds to PD-L1 , PD-L2 or an anti-PD-1 antibody. Chimeric cytokine receptor. 14. The chimeric cytokine receptor of claim 13 , wherein said anti-PD-1 antibody is nivolumab or pembrolizumab. 15. The chimeric cytokine receptor of any one of claims 1-14 , wherein said JAK binding domain is a JAK1 binding domain , a JAK2 binding domain, a JAK3 binding domain or a TYK-2 binding domain . 16. Any one of claims 1-15, wherein said transmembrane domain and JAK binding domain comprise transmembrane and JAK2 binding domain amino acid sequences selected from SEQ ID NOs: 14-44 and SEQ ID NOs: 134-135 . A chimeric cytokine receptor as described in . 17. The chimeric cytokine receptor of any one of claims 1-16 , wherein said transmembrane domain is from EpoR, GP130, PrlR, GHR, GCSFR, or TPOR/MPLR receptors. The transmembrane domain is
a. TPOR/MPLR receptor,
b. a TPOR/MPLR receptor comprising amino acids 478-582 of the naturally occurring TPOR/MPLR receptor of SEQ ID NO: 131; or
c. a TPOR/MPLR receptor comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 16-44 and SEQ ID NOs: 134-135;
18. The chimeric cytokine receptor of claim 17 , derived from 19. The chimeric cytokine receptor of any one of claims 2-18 , wherein said STAT recruitment domain is derived from a receptor selected from the receptors shown in Table 5. 20. The STAT recruitment domain of any one of claims 2-19 , wherein the STAT recruitment domain comprises one or more amino acid sequences of the receptor sequences of SEQ ID NOs:45-87 and SEQ ID NOs:170-171. Chimeric cytokine receptor. 21. The chimeric cytokine receptor of any one of claims 2-20 , wherein the cytoplasmic domain comprises a STAT recruitment domain from IL7Ra. 22. The chimeric cytokine receptor of claim 21 , wherein IL7Ra is IL7Ra(316-459). 21. The chimeric cytokine receptor of any one of claims 2-20 , wherein the cytoplasmic domain comprises a STAT recruitment domain from IL2Rb. 24. The chimeric cytokine receptor of claim 23 , wherein said cytoplasmic domain comprises a STAT recruitment domain comprising IL2Rb(393-433, 518-551) or IL2Rb(339-379, 393-433, 518-551). 23. The chimeric cytokine receptor of any one of claims 1-22 , wherein said cytoplasmic domain comprises STAT recruitment domains from two cytokine receptors. 26. The chimeric cytokine receptor of any one of claims 1-25 , wherein said receptor is constitutively active and further inducible. 2. The chimeric cytokine receptor of claim 1, comprising the amino acid sequence of any one of SEQ ID NOs:88-121, SEQ ID NOs:136-145, SEQ ID NOs:172-205, and SEQ ID NOs:206-213. A polynucleotide encoding any one of the chimeric cytokine receptors of any one of claims 1-25 . An expression vector comprising the polynucleotide of claim 28 . 30. The expression vector of claim 29 , comprising the polynucleotide of claim 28 and a polynucleotide expressing a chimeric antigen receptor (CAR). 30. The expression vector of claim 29 , wherein said CAR binds to any one or more of the targets in Table 11. The expression vector of any one of claims 29-31 , wherein said vector is a lentiviral vector. An engineered immune cell comprising the vector of any one of claims 29-32 . 34. The engineered immune cell of Claim 33 , wherein said immune cell is a T cell. An engineered immune cell expressing at least one chimeric antigen receptor (CAR) and at least one chimeric cytokine receptor according to any one of claims 1-25 . 34. The engineered immune cell of claim 33 , wherein said CAR and said chimeric cytokine receptor are expressed in stoichiometrically equal amounts. 37. The engineered immune cell of any one of claims 33-36 , wherein said immune cell is a T cell. 38. The engineered immune cell of any one of claims 33-37 , wherein said engineered immune cell comprises a CAR, and said CAR binds to any one or more of the targets in Table 11. 39. The engineered immune cell of any one of claims 33-38 , wherein said cell is an allogeneic immune cell. 39. The engineered immune cell of any one of claims 33-38 , wherein said cell is an autoimmune cell. wherein said immune cells are selected from the group consisting of immune cells derived from T cells, dendritic cells, killer dendritic cells, mast cells, NK cells, macrophages, monocytes, B cells, and stem cells, claims 33- 40. The engineered immune cell of any one of paragraphs 40 . A method of preparing an engineered immune cell comprising introducing into the immune cell a polynucleotide according to claim 28 or an expression vector according to any one of claims 29-32 . 43. The method of claim 42 , wherein said immune cells are selected from the group consisting of T cells, dendritic cells, killer dendritic cells, mast cells, NK cells, macrophages, monocytes, B cells, and immune cells derived from stem cells. described method. A pharmaceutical composition comprising the immune cells of any one of claims 33-41 . A kit comprising the immune cells of any one of claims 33-41 or the pharmaceutical composition of claim 44 . 45. The pharmaceutical composition of claim 44 for treating cancer in a subject . 45. The pharmaceutical composition of Claim 44 , wherein said cancer comprises a solid tumor or a liquid tumor . 48. The pharmaceutical composition of any one of claims 46-47 , wherein said subject is treated with an anti-PD-1 antibody. 48. The pharmaceutical composition of claim 47 , wherein said antibody is nivolumab or pembrolizumab. The pharmaceutical composition according to any one of claims 46-47 , wherein said tumor expresses PD-L1 and/or PD-L2.