JP-2025514373-A5 -

Dates

Publication Date

20260511

Application Date

20230428

Description

In summary, these data demonstrate that P2RY2 expression on cancer cells inhibits both T cell activation and T cell-mediated cytotoxicity, and that the modulation of P2RY2 activity can be used to regulate T cell activity in immunotherapy. The present invention includes, for example, the following embodiments: [1] A P2Y purine receptor 2 (P2RY2) activity regulator for use in T cell immunotherapy. [2] The P2RY2 activity modifier for use according to [1], wherein the T cell immunotherapy is adoptive T cell immunotherapy, preferably tumor-infiltrating lymphocyte (TIL) therapy and/or engineered T cell immunotherapy, particularly chimeric antigen receptor (CAR) and/or recombinant T cell receptor immunotherapy. [3] The P2RY2 modulator is a P2RY2 activity-reducing compound, preferably the P2RY2 activity-reducing compound increases T cell anticancer activity in vitro and/or in vivo. [4] A P2RY2 activity modifier for use according to any one of [1] to [3], wherein the T cell immunotherapy is cancer T cell immunotherapy, and preferably further comprises at least one of administering an immune checkpoint inhibitor, administering a cytokine, administering a T cell engager, and preferably identifying the subject as suitable for T cell immunotherapy according to the method of [13] or [14]. [5] A P2RY2 activity modifier for use according to [3] or [4], wherein the P2RY2 activity-reducing compound is a direct P2RY2 activity-reducing compound that specifically binds to P2RY2 and inhibits P2RY2, and the direct P2RY2 activity-reducing compound is a small molecule inhibitor, an inhibitor polypeptide, an inhibitor polynucleotide, or a non-polynucleotide inhibitor polymer. [6] A P2RY2 activity regulator for use according to [5], wherein the small molecule inhibitor is AR-C 118925XX (CAS number: 216657-60-2), the inhibitor polypeptide is selected from a list consisting of antibodies, aptamers, antikalin, and designed ankyrin repeat protein (DARPin), and/or the inhibitor polynucleotide is a polynucleotide aptamer. [7] The P2RY2 activity-reducing compound is an indirect P2RY2 activity-reducing compound that reduces the amount of P2RY2 in target cells, wherein the indirect P2RY2 activity-reducing compound is selected from a list consisting of shRNA, siRNA, miRNA agents, antisense oligonucleotides, ribozymes, and CRISPR/Cas oligonucleotides, preferably pairs of CRISPR/Cas oligonucleotides, to be a P2RY2 activity modifier for use as described in [3] or [4]. [8] The P2RY2 activity modifier for use according to any one of [1] to [7], wherein the P2RY2 activity modifier is administered locally, preferably within the tumor. [9] A P2RY2 activity regulator for use according to any one of [1] to [3], wherein the P2RY2 regulator is a P2RY2 activity increasing compound, and the T cell immunotherapy is T cell immunotherapy for autoimmune diseases. [10] The P2RY2 activity-enhancing compound is a direct P2RY2 activity-enhancing compound that binds to P2RY2 and activates the activity of P2RY2, wherein the P2RY2 activity-enhancing compound is a small molecule activator, an activator polypeptide, an activator polynucleotide, or a non-polynucleotide activator polymer; preferably, the small molecule activator is a nucleotide or a derivative thereof, preferably ATP or UTP or a derivative thereof, more preferably MRS P2RY2 activity modifiers for use as described in [9], which are 2768 (uridine-5'-tetraphosphate δ-phenyl ester, CAS number: 1047980-83-5), uridine-5'-(γ-thio)-triphosphate (CAS number: 1266569-94-1), 4-thiouridine-5'-O-(β,γ-difluoromethylene)triphosphate (CAS number: 1657025-60-9), denufosol (CAS number: 211448-85-0), or diquafosol (CAS number: 59985-21-6). [11] The P2RY2 activator is an indirect P2RY2 activator that increases the amount of P2RY2 in target cells, and the indirect P2RY2 activator is (i) Polypeptides containing P2RY2 polypeptide, (ii) Polynucleotides encoding polypeptides containing the P2RY2 polypeptide, (iii) A vector containing polynucleotides (ii), (iv) Host cells containing the polynucleotides of (ii) and/or the vector of (iii), or (v) Any combination of (i) to (iv) The P2RY2 activity modifier for use as described in [9]. [12] Host cells for use in T-cell immunotherapy, comprising a polynucleotide encoding a P2RY2 activity regulator as specified in any of [5] to [11], and/or a P2RY2 activity regulator as specified in any of [5] to [11]. [13] A method for identifying subjects suitable for T-cell immunotherapy, (A) A step of determining the activity (amount) of P2RY2 in the sample of the subject, (B) A step of comparing the quantity determined in step (B) with a reference, and (C) A step to identify subjects suitable for T-cell immunotherapy based on the comparison in step (C). A method comprising, preferably, the reference being derived from (i) a subject or group of subjects known to be suitable for immunotherapy, or (ii) a subject or group of subjects known to be unsuitable for immunotherapy. [14] The method according to