Innate Immunity Killer Cells Targeting PSMA Positive Tumor Cells
The present disclosure provides an innate immunity cell such as a gamma delta T (gdT) cell, Natural Killer (NK) cell, or macrophage having 2-[3-(1,3-dicarboxypropyl)ureido] pentanedioic acid (DUPA) chemically conjugated to the cell surface. The DUPA-conjugated cells provided herein demonstrate increased cytotoxicity toward cancer cells expressing PSMA. DUPA-conjugated cells can be primary cells or cells of a cell line. Also provided are methods of conjugating DUPA to the surface of NK cells, gamma delta T (gdT) cells, or macrophages and methods of treating cancer using DUPA-conjugated NK cells, gamma delta T (gdT) cells, or macrophages.
1 . A gamma delta T (gdT) cell, Natural Killer (NK) cell, or macrophage comprising 2-[3-(1,3-dicarboxypropyl)ureido]pentanedioic acid (DUPA) conjugated to the cell surface.
2 . A cell according to claim 1 , wherein DUPA is conjugated to the surface of the cell via a linker.
3 . A cell according to claim 2 , wherein the linker comprises a functional group that reacts with lysine.
4 . A cell according to claim 3 , wherein the functional group is N-hydroxysuccinimide (NHS), pentafluorophenyl, or p-nitrophenyl.
5 . A cell according to claim 2 , wherein the linker comprises one or more of (CH 2 ) n -, —(CH 2 CH 2 O) n -, —CH 2 (C═O)—, —(C═O)—, —(C═O)CH 2 CH 2 OCH 2 CH 2 OCH 2 CH 2 —, —(C═O)CH 2 CH 2 O(CH 2 CH 2 O) n CH 2 CH 2 NH—, —(C═O)CH 2 CH 2 (C═O)—, —(C═O)CH 2 CH 2 O(CH 2 CH 2 O) n CH 2 CH 2 NH(C═O)—, an amino acid, a dipeptide, a tripeptide, polyglycine, p-aminobenzyl (PAB), piperazine, piperidine, or a triazole, where n can be, independently, 1-30.
6 . The innate immune system cell of claim 5 , wherein the linker comprises (CH 2 ) n -, —(CH 2 CH 2 O) n -, or —CH 2 (C═O)—.
7 . A cell according to any of claims 1 - 6 , wherein the cell is a gamma delta T (gdT) cell.
8 . The gdT cell of claim 7 , wherein the gdT cell is from a cell line.
9 . The gdT cell of claim 8 , wherein the gdT cell is irradiated.
10 . The gdT cell of claim 7 , wherein the gdT cell is a primary cell.
11 . The gdT cell of claim 10 , wherein the gdT cell is isolated from PBMCs or cord blood.
12 . A population of DUPA-conjugated gamma delta T cells comprising a plurality of cells of claim 7 .
13 . A pharmaceutical composition comprising a population of gamma delta T cells according to claim 12 .
14 . The pharmaceutical composition of claim 13 , wherein the cells are provided in a bag, vial, or tube, wherein the cells are optionally frozen.
15 . A method of treating a subject having a PSMA-positive cancer, comprising administering one or more doses of an effective amount of the population of gamma delta T cells of claim 12 to the subject.
16 . A method according to claim 15 , wherein the PSMA-positive cancer is prostate cancer.
17 . A method according to claim 15 , wherein the population of cells is administered by injection or infusion.
18 . A method according to claim 15 , wherein more than one dose is administered.
19 . A population of DUPA-conjugated gamma delta T cells according to claim 12 for use in a method of treating a subject having a PSMA-positive cancer, wherein the subject is administered one or more doses of an effective amount of the gamma delta T cells.
20 . A population of DUPA-conjugated gamma delta T cells according to claim 19 , wherein the PSMA-positive cancer is prostate cancer.
21 . A population of DUPA-conjugated gamma delta T cells according to claim 19 , wherein the population of cells is administered by injection or infusion.
22 . A population of DUPA-conjugated gamma delta T cells according to claim 19 , wherein the population of cells is administered more than once.
23 . A cell according to any of claims 1 - 6 , wherein the cell is a Natural Killer (NK) cell.
24 . The NK cell of claim 23 , wherein the NK cell is a primary cell.
25 . The NK cell of claim 24 , wherein the NK cell is isolated from PBMCs or cord blood.
26 . The NK cell of claim 23 , wherein the NK cell is from a cell line.
27 . The NK cell of claim 23 , wherein the NK cell is irradiated.
28 . The NK cell of claim 26 , wherein the NK cell is a KHYG cell.
29 . A population of DUPA-conjugated NK cells comprising a plurality of cells of claim 23 .
30 . A pharmaceutical composition comprising a population of NK cells according to claim 29 .
31 . The pharmaceutical composition of claim 30 , wherein the cells are provided in a bag, vial, or tube, wherein the cells are optionally frozen.
32 . A method of treating a subject having a PSMA-positive cancer, comprising administering one or more doses of an effective amount of the population of NK cells of claim 29 or a pharmaceutical composition thereof to the subject.
33 . A method according to claim 32 , wherein the PSMA-positive cancer is prostate cancer.
34 . A method according to claim 32 , wherein the population of cells is administered by injection or infusion.
35 . A method according to claim 32 , wherein more than one dose is administered.
36 . A population of DUPA-conjugated NK cells according to claim 29 for use in a method of treating a subject having a PSMA-positive cancer, wherein the subject is administered one or more doses of an effective amount of the NK cells.
37 . A population of DUPA-conjugated NK cells according to claim 36 , wherein the PSMA-positive cancer is prostate cancer.
38 . A population of DUPA-conjugated gamma delta T cells according to claim 35 , wherein the population of cells is administered by injection or infusion.
39 . A population of DUPA-conjugated gamma delta T cells according to claim 35 , wherein the population of cells is administered more than once.
40 . A cell according to any of claims 1 - 6 , wherein the cell is a macrophage.
41 . The macrophage of claim 40 , wherein the macrophage is from a cell line.
42 . The macrophage of claim 40 , wherein the macrophage is a primary cell.
43 . The macrophage of claim 42 , wherein the macrophage is isolated from PBMCs.
44 . A population of DUPA-conjugated macrophages comprising a plurality of cells of claim 40 .
45 . A pharmaceutical composition comprising a population of macrophages according to claim
44 .
46 . The pharmaceutical composition of claim 45 , wherein the macrophages are provided in a bag, vial, or tube, wherein the cells are optionally frozen.
47 . A method of treating a subject having a PSMA-positive cancer, comprising administering one or more doses of an effective amount of the population of macrophages of claim 44 or a pharmaceutical composition thereof to the subject.
48 . A method according to claim 47 , wherein the PSMA-positive cancer is prostate cancer.
49 . A method according to claim 47 , wherein the population of macrophages is administered by injection or infusion.
50 . A method according to claim 47 , wherein more than one dose is administered.
51 . A population of DUPA-conjugated macrophages according to claim 50 or a pharmaceutical composition thereof, for use in a method of treating a subject having a PSMA-positive cancer, wherein the subject is administered one or more doses of an effective amount of the macrophages.
52 . A population of DUPA-conjugated macrophages or pharmaceutical composition according to claim 51 , wherein the PSMA-positive cancer is prostate cancer.
53 . A population of DUPA-conjugated macrophages or pharmaceutical composition according to claim 51 , wherein the population of macrophages is administered by injection or infusion.
54 . A population of DUPA-conjugated macrophages or pharmaceutical composition according to claim 51 , wherein the population of macrophages is administered more than once.