COMPOSITIONS AND METHODS FOR CANCER IMMUNOTHERAPY
The present invention includes, among other things, β-1,6-glucan linked to an antibody directed to a cell present in a tumor microenvironment. T regulatory cells can be one type of cell present in the tumor microenvironment. In particular embodiments, the antibody is directed to a surface feature of a T regulatory cell, MDSC, or other immune cell. In certain embodiments, the antibody is directed to T regulatory cells, MDSCs, or other immune cells present in a tumor microenvironment. Compositions including β-1,6-glucan linked to an antibody directed to a T regulatory cell, MDSC, or other immune cell may be useful, e.g., in the treatment of a tumor or cancer in a subject in need thereof. Accordingly, the present invention provides, among other things, methods and compositions for treatment of a tumor or cancer.
1 . A composition comprising β-1,6-glucan linked to an antibody, wherein the antibody is directed to a surface feature of a T regulatory cell.
2 . The composition of claim 1 , wherein the antibody is a monoclonal antibody.
3 . The composition of claim 1 , wherein the antibody is a human antibody.
4 . The composition of claim 1 , wherein the antibody is a humanized antibody.
5 . The composition of claim 1 , wherein the antibody is an antibody fragment.
6 . The composition of claim 1 , wherein the β-1,6-glucan is derived from a fungal glucan.
7 . The composition of claim 1 , wherein the β-1,6-glucan is derived from pustulan.
8 . The composition of claim 1 , wherein the β-1,6-glucan is derived from a fungal glucan via one or more processing steps that include hydrolysis and/or enzymatic digestion.
9 . The composition of claim 1 , wherein the β-1,6-glucan is chemically synthesized.
10 . The composition of claim 1 , wherein the β-1,6-glucan is genetically engineered.
11 . The composition of claim 1 , wherein the β-1,6-glucan is synthesized in a bacteria, yeast, or mammalian cell.
12 . The composition of claim 1 , wherein the β-1,6-glucan is soluble.
13 . The composition of claim 1 , wherein the β-1,6-glucan comprises a structural modification selected from the group consisting of O-acetylation, methylation, alkylation, esterification, alkoylation, sulfation, phosphorylation, lipid conjugation and combinations thereof.
14 . The composition of claim 1 , wherein the β-1,6-glucan has a molecular weight less than 100 kDa.
15 . The composition of claim 1 , wherein the β-1,6-glucan contains fewer than 85 glucose monosaccharide units.
16 . The composition of claim 1 , wherein the β-1,6-glucan contains 85, 84, 83, 82, 81, 80, 79, 78, 77, 76, 75, 74, 73, 72, 71, 70, 69, 68, 67, 66, or 65 glucose monosaccharide units.
17 . The composition of claim 1 , wherein the β-1,6-glucan contains 64, 63, 62, 61, 60, 59, 58, 57, 56, 55, 54, 53, 52, 51, 50, 49, 48, 47, 46, 45, or 44 glucose monosaccharide units.
18 . The composition of claim 1 , wherein the β-1,6-glucan contains 43, 42, 41, 40, 39, 38, 37, 36, 35, 34, 33, 32, 31, 30, 29, 28, 27, 26, 25, 24, or 23 glucose monosaccharide units.
19 . The composition of claim 1 , wherein the β-1,6-glucan contains 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, or 3 glucose monosaccharide units.
20 . The composition of claim 1 , wherein at least 90% of the dry weight of glucan contained in the composition is β-1,6-glucan.
21 . The composition of claim 1 , wherein less than 10% of the dry weight of glucan contained in the composition is β-1-3-glucan.
22 . The composition of claim 1 , wherein the composition is substantially free of β-1-3-glucan.
23 . The composition of claim 1 , wherein the β-1,6-glucan is directly linked to the antibody.
24 . The composition of claim 1 , wherein the β-1,6-glucan is linked to the antibody via a linker molecule.
25 . The composition of claim 1 , wherein the β-1,6-glucan is linked to the antibody via amide, aldehyde, urethane, imine or disulfide formation between the respective molecules, or between a linker molecule and the respective molecules.
26 . A method of treating cancer, said method comprising administering to a subject in need thereof a composition comprising β-1,6-glucan linked to an antibody, wherein the antibody is directed to a surface feature of a T regulatory cell.
27 . The method of claim 26 , wherein the antibody is a monoclonal antibody.
28 . The method of claim 26 , wherein the antibody is a human antibody.
29 . The method of claim 26 , wherein the antibody is a humanized antibody.
30 . The method of claim 26 , wherein the antibody is an antibody fragment.
31 . The method of claim 26 , wherein the β-1,6-glucan is derived from a fungal glucan.
32 . The method of claim 26 , wherein the β-1,6-glucan is derived from pustulan.
33 . The method of claim 26 , wherein the β-1,6-glucan is derived from a fungal glucan via one or more processing steps that include hydrolysis and/or enzymatic digestion.
34 . The method of claim 26 , wherein the β-1,6-glucan is chemically synthesized.
35 . The method of claim 26 , wherein the β-1,6-glucan is genetically engineered.
36 . The method of claim 26 , wherein the β-1,6-glucan is synthesized in a bacteria, yeast, or mammalian cell.
37 . The method of claim 26 , wherein the β-1,6-glucan is soluble.
38 . The method of claim 26 , wherein the β-1,6-glucan comprises a structural modification selected from the group consisting of O-acetylation, methylation, alkylation, esterification, alkoylation, sulfation, phosphorylation, lipid conjugation and combinations thereof.
39 . The method of claim 26 , wherein the β-1,6-glucan has a molecular weight less than 100 kDa.
40 . The method of claim 26 , wherein the β-1,6-glucan contains fewer than 85 glucose monosaccharide units.
41 . The method of claim 26 , wherein the β-1,6-glucan contains 85, 84, 83, 82, 81, 80, 79, 78, 77, 76, 75, 74, 73, 72, 71, 70, 69, 68, 67, 66, or 65 glucose monosaccharide units.
42 . The method of claim 26 , wherein the β-1,6-glucan contains 64, 63, 62, 61, 60, 59, 58, 57, 56, 55, 54, 53, 52, 51, 50, 49, 48, 47, 46, 45, or 44 glucose monosaccharide units.
43 . The method of claim 26 , wherein the β-1,6-glucan contains 43, 42, 41, 40, 39, 38, 37, 36, 35, 34, 33, 32, 31, 30, 29, 28, 27, 26, 25, 24, or 23 glucose monosaccharide units.
44 . The method of claim 26 , wherein the β-1,6-glucan contains 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, or 3 glucose monosaccharide units.
45 . The method of claim 26 , wherein at least 90% of the dry weight of glucan contained in the composition is β-1,6-glucan.
46 . The method of claim 26 , wherein less than 10% of the dry weight of glucan contained in the composition is β-1-3-glucan.
47 . The method of claim 26 , wherein the composition is substantially free of β-1-3-glucan.
48 . The method of claim 26 , wherein the β-1,6-glucan is directly linked to antibody.
49 . The method of claim 26 , wherein the β-1,6-glucan is linked to the antibody via a linker molecule.
50 . The method of claim 26 , wherein the β-1,6-glucan is linked to the targeting moiety via amide, urethane, imine or disulfide formation between the respective molecules, or between a linker molecule and the respective molecules.
51 . A method of modulating an immune response, said method comprising administering to a subject in need thereof a composition comprising β-1,6-glucan linked to an antibody, wherein the antibody is directed to a surface feature of a T regulatory cell.
52 . The method of claim 51 , wherein the antibody is a monoclonal antibody.
53 . The method of claim 51 , wherein the antibody is a human antibody.
54 . The method of claim 51 , wherein the antibody is a humanized antibody.
55 . The method of claim 51 , wherein the antibody is an antibody fragment.
56 . The method of claim 51 , wherein the β-1,6-glucan is derived from a fungal glucan.
57 . The method of claim 51 , wherein the β-1,6-glucan is derived from pustulan.
58 . The method of claim 51 , wherein the β-1,6-glucan is derived from a fungal glucan via one or more processing steps that include hydrolysis and/or enzymatic digestion.
59 . The method of claim 51 , wherein the β-1,6-glucan is chemically synthesized.
60 . The method of claim 51 , wherein the β-1,6-glucan is genetically engineered.
61 . The method of claim 51 , wherein the β-1,6-glucan is synthesized in a bacteria, yeast, or mammalian cell.
62 . The method of claim 51 , wherein the β-1,6-glucan is soluble.
63 . The method of claim 51 , wherein the β-1,6-glucan comprises a structural modification selected from the group consisting of O-acetylation, methylation, alkylation, esterification, alkoylation, sulfation, phosphorylation, lipid conjugation and combinations thereof.
64 . The method of claim 51 , wherein the β-1,6-glucan has a molecular weight less than 100 kDa.
65 . The method of claim 51 , wherein the β-1,6-glucan contains fewer than 85 glucose monosaccharide units.
66 . The method of claim 51 , wherein the β-1,6-glucan contains 85, 84, 83, 82, 81, 80, 79, 78, 77, 76, 75, 74, 73, 72, 71, 70, 69, 68, 67, 66, or 65 glucose monosaccharide units.
67 . The method of claim 51 , wherein the β-1,6-glucan contains 64, 63, 62, 61, 60, 59, 58, 57, 56, 55, 54, 53, 52, 51, 50, 49, 48, 47, 46, 45, or 44 glucose monosaccharide units.
68 . The method of claim 51 , wherein the β-1,6-glucan contains 43, 42, 41, 40, 39, 38, 37, 36, 35, 34, 33, 32, 31, 30, 29, 28, 27, 26, 25, 24, or 23 glucose monosaccharide units.
69 . The method of claim 51 , wherein the β-1,6-glucan contains 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, or 3 glucose monosaccharide units.
70 . The method of claim 51 , wherein at least 90% of the dry weight of glucan contained in the composition is β-1,6-glucan.
71 . The method of claim 51 , wherein less than 10% of the dry weight of glucan contained in the composition is β-1-3-glucan.
72 . The method of claim 51 , wherein the composition is substantially free of β-1-3-glucan.
73 . The method of claim 51 , wherein the β-1,6-glucan is directly linked to antibody.
74 . The method of claim 51 , wherein the β-1,6-glucan is linked to the antibody via a linker molecule.
75 . The method of claim 51 , wherein the β-1,6-glucan is linked to the antibody via amide, urethane, imine or disulfide formation between the respective molecules, or between a linker molecule and the respective molecules.
76 . A composition comprising β-1,6-glucan linked to an antagonistic anti-PD1 antibody.
77 . A composition comprising β-1,6-glucan linked to an antagonistic anti-CTLA-4 antibody.
78 . A composition comprising β-1,6-glucan linked to an antagonistic anti-TIM-3 antibody.
79 . A composition comprising β-1,6-glucan linked to an antagonistic anti-LAG-3 antibody.
80 . A composition comprising β-1,6-glucan linked to an antagonistic anti-ICOS antibody.
81 . A composition comprising β-1,6-glucan linked to an antagonistic anti-TIGIT antibody.
82 . A composition comprising β-1,6-glucan linked to an agonistic anti-GITR antibody.
83 . A composition comprising β-1,6-glucan linked to an agonistic anti-OX-40 antibody.
84 . A composition comprising β-1,6-glucan linked to an agonistic anti-CD40 antibody.
85 . A composition comprising β-1,6-glucan linked to pembrolizumab.
86 . A composition comprising β-1,6-glucan linked to nivolumab.
87 . A composition comprising β-1,6-glucan linked to ipilimumab.
88 . A composition comprising β-1,6-glucan linked to MK-4166.