COMBINATION CANCER THERAPY WITH ANTI-CANCER AGENTS AND ANTIBODIES TARGETING A COMPLEX COMPRISING NON-CLASSICAL HLA-I AND NEOANTIGEN
Disclosed herein are methods and compositions for targeting a complex comprising a non-classical HLA-I and a neoantigen in cancer characterized by expression of CD94/NKG2A inhibitory receptor. Further disclosed herein are methods and compositions for combination cancer therapy.
1 . A method of treating cancer characterized by expression of CD94/NKG2A inhibitory receptor in an individual in need thereof, comprising administering to the individual an antibody that selectively binds to a complex comprising an HLA-E and a neoantigen.
2 . The method of claim 1 , further comprising administering an additional anti-cancer agent.
3 . The method of claim 1 , further comprising assaying for expression of CD94/NKG2A inhibitory receptor in the individual.
4 . The method of claim 1 , wherein the cancer is characterized by the overexpression of the CD94/NKG2A inhibitory receptor.
5 . The method of claim 1 , wherein the antibody does not have a binding affinity to (i) the HLA-E alone; or (ii) the neoantigen alone.
6 . The method of claim 1 , wherein the neoantigen comprises, consists essentially of, or consists of a sequence VMAPRTLFL.
7 . The method of claim 1 , wherein the HLA-E is HLA-E*0101 or HLA-E*0103.
8 . The method of claim 7 , wherein the antibody selectively binds to the complex comprising:
(a) the HLA-E*0101 and the neoantigen;
(b) the HLA-E*0103 and the neoantigen; or
(c) the HLA-E*0101 and the neoantigen, and the HLA-E*0103 and the neoantigen.
9 . The method of claim 1 , wherein the complex comprises the HLA-E and VMAPRTLFL.
10 . The method of claim 1 , wherein the antibody is a murine antibody, a chimeric antibody, a camelid antibody, a humanized antibody, or a human antibody.
11 . The method of claim 1 , wherein the antibody is a TCR-like antibody.
12 . The method of claim 1 , wherein the antibody is a single domain antibody.
13 . The method of claim 12 , wherein the single domain antibody is a camelid single domain antibody.
14 . The method of claim 1 , wherein the antibody is a multispecific antibody.
15 . The method of claim 1 , wherein the antibody is a multifunctional antibody.
16 . The method of claim 1 , wherein the selective binding of the antibody to the complex comprising the HLA-E and the neoantigen inhibits the binding of the complex to the CD94/NKG2A inhibitory receptor.
17 . The method of claim 16 , wherein the inhibition in binding of the complex to the CD94/NKG2A inhibitory receptor induces activation of natural killer (NK) cells.
18 . The method of claim 16 , wherein the inhibition in binding of the complex to the CD94/NKG2A inhibitory receptor induces activation of CD8+ T cells.
19 . The method of claim 16 , wherein the inhibition in binding of the complex to the CD94/NKG2A inhibitory receptor induces cell death of a cell expressing the HLA-E and the neoantigen.
20 . The method of claim 19 , wherein the cell is a cancer cell.
21 . The method of claim 2 , wherein the additional anti-cancer agent comprises CD20 inhibitor, HER-2 inhibitor, CD52 inhibitor, EGFR inhibitor, VEGF inhibitor, CCR4 inhibitor, PD-L1 inhibitor, SLAMF7 inhibitor, CD38 inhibitor, GD2 inhibitor, PTK-7 inhibitor, P-cadherin inhibitor, MCSF inhibitor, IDO1 inhibitor, CCR2 inhibitor, CXCR4 inhibitor, PD-1 inhibitor, CTLA-4 inhibitor, OX40 agonist, 4-1BB agonist, androgen receptor inhibitor, tyrosine kinase inhibitor, PARP inhibitor, chimeric antigen receptor T cells (CAR-T cells), oncolytic virus, and any combination thereof.
22 . The method of claim 2 , wherein the additional anti-cancer agent comprises Rituximab, Trastuzumab, Alemutuzumab, Cetixumab, Bevacizumab, Panitumumab, Obinutuzumab, Mogamulizumab, Necitumumab, Atezolizumab, Elotuzumab, Daratumumab, Dinutuximab, and any combination thereof.
23 . The method of claim 2 , wherein the antibody and the additional anti-cancer agent are administered concurrently.
24 . The method of claim 2 , wherein the antibody and the additional anti-cancer agent are administered sequentially.
25 . The method of claim 2 , wherein the antibody is administered prior to the additional anti-cancer agent.
26 . The method of claim 2 , wherein the antibody is administered after the additional anti-cancer agent.
27 . The method of claim 2 , wherein the antibody and the additional anti-cancer agent are administered in a unified dosage form.
28 . The method of claim 2 , wherein the antibody and the additional anti-cancer agent are administered in a separate dosage form.
29 . The method of claim 2 , wherein the antibody and the additional anti-cancer agent are administered continuously for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 14, 15, 28, 30 or more days.
30 . The method of claim 2 , wherein the antibody and the additional anti-cancer agent are administered at predetermined time intervals for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 14, 15, 28, 30 or more days.
31 . The method of claim 2 , wherein the antibody and the additional anti-cancer agent are administered intermittently for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 14, 15, 28, 30 or more days.
32 . The method of claim 2 , wherein the antibody and the additional anti-cancer agent are administered in 1 dose, 2 doses, 3 doses, 4 doses, 5 doses, 6 doses or more.
33 . The method of claim 2 , wherein the antibody and the additional anti-cancer agent are administered at a therapeutically effective amount.
34 . The method of claim 1 , wherein the cancer is breast cancer, kidney cancer, lung cancer, ovarian cancer, or colorectal cancer.
35 . The method of claim 1 , wherein the cancer is a B-cell malignancy.
36 . A method of treating cancer in an individual in need thereof, comprising administering to the individual:
(a) an antibody that selectively binds to a complex comprising a HLA-E and a neoantigen, and
(b) an additional anti-cancer agent.
37 . The method of claim 36 , wherein the antibody does not have a binding affinity to (i) the HLA-E alone; or (ii) the neoantigen alone.
38 . The method of claim 36 , wherein the neoantigen comprises, consists essentially of, or consists of a sequence VMAPRTLFL.
39 . The method of claim 36 , wherein the HLA-E is HLA-E*0101 or HLA-E*0103.
40 . The method of claim 39 , wherein the antibody selectively binds to the complex comprising:
(a) the HLA-E*0101 and the neoantigen;
(b) the HLA-E*0103 and the neoantigen; or
(c) the HLA-E*0101 and the neoantigen, and the HLA-E*0103 and the neoantigen.
41 . The method of claim 36 , wherein the complex comprises the HLA-E and VMAPRTLFL.
42 . The method of claim 36 , wherein the antibody is a murine antibody, a chimeric antibody, a camelid antibody, a humanized antibody, or a human antibody.
43 . The method of claim 36 , wherein the antibody is a TCR-like antibody.
44 . The method of claim 36 , wherein the antibody is a single domain antibody.
45 . The method of claim 44 , wherein the single domain antibody is a camelid single domain antibody.
46 . The method of claim 36 , wherein the antibody is a multispecific antibody.
47 . The method of claim 36 , wherein the antibody is a multifunctional antibody.
48 . The method of claim 36 , wherein the selective binding of the antibody to the complex comprising the HLA-E and the neoantigen inhibits the binding of the complex to a CD94/NKG2A inhibitory receptor.
49 . The method of claim 48 , wherein the inhibition in binding of the complex to the CD94/NKG2A inhibitory receptor induces activation of natural killer (NK) cells.
50 . The method of claim 48 , wherein the inhibition in binding of the complex to the CD94/NKG2A inhibitory receptor induces activation of CD8+ T cells.
51 . The method of claim 48 , wherein the inhibition in binding of the complex to the CD94/NKG2A inhibitory receptor induces cell death of a cell expressing the HLA-E and the neoantigen.
52 . The method of claim 51 , wherein the cell is a cancer cell.
53 . The method of claim 36 , wherein the additional anti-cancer agent comprises CD20 inhibitor, HER-2 inhibitor, CD52 inhibitor, EGFR inhibitor, VEGF inhibitor, CCR4 inhibitor, PD-L1 inhibitor, SLAMF7 inhibitor, CD38 inhibitor, GD2 inhibitor, PTK-7 inhibitor, P-cadherin inhibitor, MCSF inhibitor, IDO1 inhibitor, CCR2 inhibitor, CXCR4 inhibitor, PD-1 inhibitor, CTLA-4 inhibitor, OX40 agonist, 4-1BB agonist, androgen receptor inhibitor, tyrosine kinase inhibitor, PARP inhibitor, chimeric antigen receptor T cells (CAR-T cells), oncolytic virus, and any combination thereof.
54 . The method of claim 36 , wherein the additional anti-cancer agent comprises Rituximab, Trastuzumab, Alemutuzumab, Cetixumab, Bevacizumab, Panitumumab, Obinutuzumab, Mogamulizumab, Necitumumab, Atezolizumab, Elotuzumab, Daratumumab, Dinutuximab, and any combination thereof.
55 . The method of claim 36 , wherein the antibody and the additional anti-cancer agent are administered concurrently.
56 . The method of claim 36 , wherein the antibody and the additional anti-cancer agent are administered sequentially.
57 . The method of claim 36 , wherein the antibody is administered prior to the additional anti-cancer agent.
58 . The method of claim 36 , wherein the antibody is administered after the additional anti-cancer agent.
59 . The method of claim 36 , wherein the antibody and the additional anti-cancer agent are administered in a unified dosage form.
60 . The method of claim 36 , wherein the antibody and the additional anti-cancer agent are administered in a separate dosage form.
61 . The method of claim 36 , wherein the antibody and the additional anti-cancer agent are administered continuously for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 14, 15, 28, 30 or more days.
62 . The method of claim 36 , wherein the antibody and the additional anti-cancer agent are administered at predetermined time intervals for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 14, 15, 28, 30 or more days.
63 . The method of claim 36 , wherein the antibody and the additional anti-cancer agent are administered intermittently for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 14, 15, 28, 30 or more days.
64 . The method of claim 36 , wherein the antibody and the additional anti-cancer agent are administered in 1 dose, 2 doses, 3 doses, 4 doses, 5 doses, 6 doses or more.
65 . The method of claim 36 , wherein the antibody and the additional anti-cancer agent are administered at a therapeutically effective amount.
66 . The method of claim 36 , wherein the cancer is characterized by expression of the CD94/NKG2A inhibitory receptor.
67 . The method of claim 36 , wherein the cancer is characterized by overexpression of the CD94/NKG2A inhibitory receptor.
68 . The method of claim 66 , further comprising assaying for expression of the CD94/NKG2A inhibitory receptor in the individual.
69 . The method of claim 36 , wherein the cancer is breast cancer, kidney cancer, lung cancer, ovarian cancer, or colorectal cancer.
70 . The method of claim 36 , wherein the cancer is a B-cell malignancy.
71 . A method of inducing cell death of a cancer cell in a tumor microenvironment characterized by expression of CD94/NKG2A inhibitory receptor in an individual in need thereof, comprising administering to the individual an antibody that selectively binds to a complex comprising an HLA-E and a neoantigen, wherein the complex is expressed by the cancer cell.
72 . The method of claim 71 , further comprising administering an additional anti-cancer agent.
73 . The method of claim 71 , further comprising assaying for expression of the CD94/NKG2A inhibitory receptor in the individual.
74 . The method of claim 71 , wherein the tumor microenvironment is characterized by the overexpression of the CD94/NKG2A inhibitory receptor.
75 . The method of claim 71 , wherein the antibody does not have a binding affinity to (i) the HLA-E alone; or (ii) the neoantigen alone.
76 . The method of claim 71 , wherein the neoantigen comprises, consists essentially of, or consists of a sequence VMAPRTLFL.
77 . The method of claim 71 , wherein the HLA-E is HLA-E*0101 or HLA-E*0103.
78 . The method of claim 77 , wherein the antibody selectively binds to the complex comprising:
(a) the HLA-E*0101 and the neoantigen;
(b) the HLA-E*0103 and the neoantigen; or
(c) the HLA-E*0101 and the neoantigen, and the HLA-E*0103 and the neoantigen.
79 . The method of claim 71 , wherein the complex comprises the HLA-E and VMAPRTLFL.
80 . The method of claim 71 , wherein the antibody is a murine antibody, a chimeric antibody, a camelid antibody, a humanized antibody, or a human antibody.
81 . The method of claim 71 , wherein the antibody is a TCR-like antibody.
82 . The method of claim 71 , wherein the antibody is a single domain antibody.
83 . The method of claim 82 , wherein the single domain antibody is a camelid single domain antibody.
84 . The method of claim 71 , wherein the antibody is a multispecific antibody.
85 . The method of claim 71 , wherein the antibody is a multifunctional antibody.
86 . The method of claim 71 , wherein the selective binding of the antibody to the complex comprising the HLA-E and the neoantigen inhibits the binding of the complex to the CD94/NKG2A inhibitory receptor.
87 . The method of claim 86 , wherein the inhibition in binding of the complex to the CD94/NKG2A inhibitory receptor induces activation of natural killer (NK) cells.
88 . The method of claim 86 , wherein the inhibition in binding of the complex to the CD94/NKG2A inhibitory receptor induces activation of CD8+ T cells.
89 . The method of claim 72 , wherein the additional anti-cancer agent comprises CD20 inhibitor, HER-2 inhibitor, CD52 inhibitor, EGFR inhibitor, VEGF inhibitor, CCR4 inhibitor, PD-L1 inhibitor, SLAMF7 inhibitor, CD38 inhibitor, GD2 inhibitor, PTK-7 inhibitor, P-cadherin inhibitor, MCSF inhibitor, IDO1 inhibitor, CCR2 inhibitor, CXCR4 inhibitor, PD-1 inhibitor, CTLA-4 inhibitor, OX40 agonist, 4-1BB agonist, androgen receptor inhibitor, tyrosine kinase inhibitor, PARP inhibitor, chimeric antigen receptor T cells (CAR-T cells), oncolytic virus, and any combination thereof.
90 . The method of claim 72 , wherein the additional anti-cancer agent comprises Rituximab, Trastuzumab, Alemutuzumab, Cetixumab, Bevacizumab, Panitumumab, Obinutuzumab, Mogamulizumab, Necitumumab, Atezolizumab, Elotuzumab, Daratumumab, Dinutuximab, and any combination thereof.
91 . The method of claim 72 , wherein the antibody and the additional anti-cancer agent are administered concurrently.
92 . The method of claim 72 , wherein the antibody and the additional anti-cancer agent are administered sequentially.
93 . The method of claim 72 , wherein the antibody is administered prior to the additional anti-cancer agent.
94 . The method of claim 72 , wherein the antibody is administered after the additional anti-cancer agent.
95 . The method of claim 72 , wherein the antibody and the additional anti-cancer agent are administered in a unified dosage form.
96 . The method of claim 72 , wherein the antibody and the additional anti-cancer agent are administered in a separate dosage form.
97 . The method of claim 72 , wherein the antibody and the additional anti-cancer agent are administered continuously for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 14, 15, 28, 30 or more days.
98 . The method of claim 72 , wherein the antibody and the additional anti-cancer agent are administered at predetermined time intervals for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 14, 15, 28, 30 or more days.
99 . The method of claim 72 , wherein the antibody and the additional anti-cancer agent are administered intermittently for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 14, 15, 28, 30 or more days.
100 . The method of claim 72 , wherein the antibody and the additional anti-cancer agent are administered in 1 dose, 2 doses, 3 doses, 4 doses, 5 doses, 6 doses or more.
101 . The method of claim 72 , wherein the antibody and the additional anti-cancer agent are administered at a therapeutically effective amount.
102 . The method of claim 71 , wherein the cancer cell is a breast cancer cell, a kidney cancer cell, a lung cancer cell, an ovarian cancer cell, or a colorectal cancer cell.
103 . The method of claim 71 , wherein the cancer cell is a malignant B cell.
104 . A pharmaceutical composition comprising:
(a) an antibody that selectively binds to a complex comprising a HLA-E and a neoantigen;
(b) an additional anti-cancer agent; and
(c) a pharmaceutically acceptable carrier or excipient.
105 . The pharmaceutical composition of claim 104 for use in treating a cancer.
106 . The pharmaceutical composition of claim 104 for use in treating a cancer characterized by expression of CD94/NKG2A inhibitory receptor.
107 . The pharmaceutical composition of claim 104 for use in treating a cancer characterized by overexpression of CD94/NKG2A inhibitory receptor.