METHODS FOR SELECTIVE IN VIVO EXPANSION OF GAMMA DELTA T-CELL POPULATIONS AND COMPOSITIONS THEREOF
The present invention relates to methods for the selective in vivo activation, expansion and/or maintenance of γδ T-cell population(s), compositions and admixtures thereof and methods for using the same as a therapeutic. Methods and compositions of the disclosure are useful in the treatment of various cancers, infectious diseases, and immune disorders.
1 . An in vivo method for activating, expanding, and/or maintaining a population of γδ T cells in a subject, the method comprising administering to the subject an effective amount of one or more agents which selectively expand δ1 T cells, δ2 T cells, or δ3 T cells, or a combination thereof, wherein the one or more agents that selectively expand δ1 T cells bind to an activating epitope specific of a δ1 TCR;
the one or more agents that selectively expand δ2 T cells bind to an activating epitope specific of a δ2 TCR; and
the one or more agents that selectively expand δ3 T cells bind to an activating epitope specific of a δ3 TCR,
thereby activating, expanding and/or maintaining the population of γδ T cells in the subject.
2 . The method of claim 1 , wherein the method comprises administering to the subject an effective amount of one or more agents that selectively expand δ1 T cells.
3 . The method of claim 2 , wherein the agent that selectively expands δ1 T-cells is selected from an agent which binds to the same epitope as an antibody selected from TS-1 and TS8.2.
4 . The method of claim 2 , wherein the agent that selectively expands δ1 T-cells is selected from an agent that does not compete with TS-1, TS8.2, or R9.12.
5 . The method of claim 2 , wherein the agent that selectively expands 81 T-cells is selected from an agent which specifically binds to an epitope comprising a 81 variable region.
6 . The method of claim 2 , wherein the agent that selectively expands 81 T-cells binds to an epitope comprising residues Arg71, Asp72 and Lys120 of the M variable region.
7 . The method of claim 2 , wherein the agent that selectively expands 81 T-cells has reduced binding to a mutant M TCR polypeptide comprising a mutation at K120 of delta J1 and delta J2.
8 . The method of claim 2 , wherein the agents that selectively expand δ1 T-cells are agents that bind a δ1 TCR Bin 1 δ1 epitope, Bin 1b δ1 epitope, Bin 2 δ1 epitope, Bin 2b δ1 epitope, Bin 2c δ1 epitope, Bin 3 δ1 epitope, Bin 4 δ1 epitope, Bin 5 δ1 epitope, Bin 6 δ1 epitope, Bin 7 δ1 epitope, Bin 8 δ1 epitope, or a Bin 9 δ1 epitope of a human δ1 TCR.
9 . The method of claim 2 , wherein the agent that selectively expands δ1 T-cells is selected from an agent which binds to the same, or essentially the same, epitope as, or competes with, an antibody selected from the group consisting of 61-05, δ1-08, δ1-18, 81-22, δ1-23, δ1-26, δ1-35, δ1-37, δ1-39, δ1-113, δ1-143, δ1-149, δ1-155, δ1-182, δ1-183, δ1-191, δ1-192, δ1-195, δ1-197, δ1-199, δ1-201, 61-203, δ1-239, δ1-253, δ1-257, δ1-278, δ1-282, and δ1-285.
10 . The method of claim 2 , wherein the agent that selectively expands δ1 T-cells is an antibody selected from the group consisting of 61-05, δ1-08, δ1-18, 81-22, δ1-23, δ1-26, δ1-35, δ1-37, 61-39, δ1-113, δ1-143, δ1-149, δ1-155, δ1-182, δ1-183, δ1-191, δ1-192, δ1-195, δ1-197, δ1-199, δ1-201, 61-203, δ1-239, δ1-253, δ1-257, δ1-278, δ1-282, and δ1-285.
11 . The method of claim 2 , wherein the agent that selectively expands δ1 T-cells selectively expands δ1 T cells and δ3 T cells.
12 . The method of claim 2 , wherein the agent that selectively expands M T cells comprises the CDRs of antibody M-35 or δ1-08, or binds the same epitope as antibody δ1-08 or δ1-35.
13 . The method of claim 2 , wherein the agent that selectively expands M T cells comprises the CDRs of antibody δ1-35.
14 . The method of claim 2 , wherein the agent that selectively expands δ1 T cells selectively expands δ1, δ3, δ4, and δ5 γδ T cells.
15 . The method of claim 1 , wherein the method comprises administering to the subject an effective amount of one or more agents that selectively expand δ2 T cells.
16 . The method of claim 15 , wherein the agent that selectively expands δ2 T-cells is selected from an agent which binds to the same epitope as an antibody selected from 15D and B6.
17 . The method of claim 15 , wherein the agent that selectively expands δ2 T-cells is selected from an agent which specifically binds to an epitope comprising a δ2 variable region.
18 . The method of claim 15 , wherein the agent that selectively expands δ2 T-cells has reduced binding to a mutant δ2 TCR polypeptide comprising a mutation at G35 of the δ2 variable region.
19 . The method of claim 15 , wherein the agent that selectively expands δ2 T-cells binds a δ2 TCR Bin 1 δ2 epitope, Bin 2 δ2 epitope, Bin 3 δ2 epitope, or Bin 4 δ2 epitope of a human δ2 TCR.
20 . The method of claim 15 , wherein the agent that selectively expands δ2 T-cells is an agent that binds to the same, or essentially the same, epitope as, or competes with, an antibody selected from the group consisting of δ2-14, δ2-17, δ2-22, δ2-30, δ2-31, δ2-32, δ2-33, δ2-35, δ2-36, and δ2-37.
21 . The method of claim 15 , wherein the agent that selectively expands 82 T-cells is an antibody selected from the group consisting of δ2-14, δ2-17, δ2-22, δ2-30, δ2-31, δ2-32, δ2-33, δ2-35, δ2-36, and δ2-37.
22 . The method of claim 15 , wherein the agent that selectively expands δ2 T-cells comprises the CDRs of antibody δ2-37 or binds the same epitope as antibody δ2-37.
23 . The method of claim 1 , wherein the method comprises administering to the subject an effective amount of one or more agents that selectively expand δ3 T cells.
24 . The method of claim 23 , wherein the agent that selectively expands δ3 T-cells is selected from an agent which binds to the same, or essentially the same, epitope as, or competes with, an antibody selected from the group consisting of δ3-08, δ3-20, δ3-23, δ3-31, δ3-42, δ3-47 and δ3-58.
25 . The method of claim 23 , wherein the agent that selectively expands 83 T-cells is an antibody selected from the group consisting of δ3-08, δ3-20, δ3-23, δ3-31, δ3-42, δ3-47 and δ3-58.
26 . The method of claim 23 , wherein the agent that selectively expands δ3 T-cells comprises the CDRs of antibody δ3-23 or binds the same epitope as antibody δ3-23.
27 . The method of claim 1 , wherein the method comprises administering to the patient a population of engineered and/or non-engineered γδ T cells.
28 . The method of claim 27 , wherein the method comprises administering the population of engineered and/or non-engineered γδ T cells before administering the one or more agents which selectively expand δ1 T cells, δ2 T cells, or δ3 T cells.
29 . The method of claim 27 , wherein the administered population of engineered and/or non-engineered γδ T cells is a population of cells that are autologous to the subject.
30 . The method of claim 27 , wherein the administered population of engineered and/or non-engineered γδ T cells is a population of cells that are allogeneic to the subject.
31 . The method of claim 27 , wherein the administered population of engineered and/or non-engineered γδ T cells is a population comprising at least 60% δ1 γδ T cells, and the method comprises administering the γδ T cells and sequentially or simultaneously administering the one or more agents which selectively expand δ1 T cells wherein the administered population of engineered and/or non-engineered γδ T cells is a population comprising at least 60% δ2 γδ T cells, and the method comprises administering the γδ T cells and sequentially or simultaneously administering the one or more agents which selectively expand δ2 T cells; or
wherein the administered population of engineered and/or non-engineered γδ T cells is a population comprising at least 60% δ3 γδ T cells, and the method comprises administering the γδ T cells and sequentially or simultaneously administering the one or more agents which selectively expand δ3 T cells.
32 . (canceled)
33 . (canceled)
34 . The method of claim 1 , wherein the method comprises administering an aminophosphonate or a prenyl-phosphate.
35 . The method of claim 34 , wherein the method comprises administering an aminophosphonate and the aminophosphonate is selected from the group consisting of zoledronate, pamidronic acid, alendronic acid, risedronic acid, ibandronic acid, and incadronic acid, or a salt thereof, and/or a hydrate thereof.
36 . The method of claim 1 , wherein the agent that selectively expands δ1 T cells, δ2 T cells, or δ3 T cells, or a combination thereof is multivalent, preferably wherein the multivalent agent comprises at least two antigen-binding-sites that specifically bind the same antigen, or wherein the multivalent agent comprises at least two antigen-binding sites that specifically bind the same epitope of the same antigen.
37 . The method of claim 36 , wherein the agent that selectively expands δ1 T cells, δ2 T cells, or δ3 T cells, or a combination thereof is, or is at least, bivalent, trivalent, or tetravalent.
38 . The method of claim 1 , wherein the method comprises simultaneously or sequentially administering a cytokine to the subject.
39 . The method of claim 38 , wherein the method comprises administering engineered γδ T cells to the subject, wherein the engineered γδ T cells comprise a transgene that encodes a secreted cytokine.
40 . The method of claim 38 , wherein the cytokine is a common gamma chain cytokine, or a cytokine selected from the group consisting of IL-2, IL-15 and IL-4, preferably wherein the cytokine is IL-2, IL-15, and/or IL-4.
41 . The method of claim 1 , wherein the method comprises administering a lymphodepletion protocol to the subject before administering γδ T cells.
42 . The method of claim 1 , wherein the method comprises repeatedly administering the one or more agents which selectively expand δ1 T cells, δ2 T cells, and/or δ3 T cells.
43 . The method of claim 1 , wherein the method comprises expanding or maintaining a population of administered γδ T cells in the subject.
44 . The method of claim 1 , wherein the method comprises expanding or maintaining a population of endogenous γδ T cells in the subject.
45 . The method of claim 1 , wherein the method comprises expanding a population of endogenous and/or administered γδ T cells in the subject by at least 10% over the amount of γδ T cells in a subject that has not been administered the one or more agents which selectively expand δ1 T cells, δ2 T cells, and/or δ3 T cells.
46 . The method of claim 1 , wherein the method comprises maintaining a larger population of endogenous and/or administered γδ T cells in the subject by at least 10% over the number of γδ T cells in a subject that has not been administered the one or more agents which selectively expand δ1 T cells, δ2 T cells, and/or δ3 T cells.
47 . A method of treating a cancer, infectious disease, inflammatory disease, or an autoimmune disease in a subject in need thereof by performing the method according to claim 1 .
48 . A use of an agent that selectively expands δ1 T cells, β2 T cells, or δ3 T cells in the manufacture of a medicament for the in vivo expansion of γδ T cells in a subject in need thereof.
49 . The use of claim 48 , wherein the in vivo expansion of γδ T cells in a subject comprises treating a cancer, infectious disease, inflammatory disease, or an autoimmune disease in the subject.
50 . The method of claim 27 , wherein the engineered γδ T cells are engineered to stably express one or more tumor recognition moieties.