METHODS AND COMPOSITIONS FOR IMMUNE DIS-INHIBITION
The disclosure provides methods and compositions for immune dis-inhibition. In certain embodiments, the methods comprise administering an effective amount of an agent that decreases the amount of a soluble cytotoxic receptor or inhibits its activity. In certain embodiments, the agent inhibits the proliferation, growth, or survival of cancer cells, decreases the size or a tumor, or inhibits tumor growth.
1 - 16 . (canceled)
17 . A method for decreasing the amount or activity of a soluble cytotoxic receptor in a subject in need thereof, comprising administering an effective amount of an agent to the subject, wherein:
the agent comprises a soluble TNFR antagonist;
the soluble TNFR antagonist is a modified TNF ligand; and
the modified TNF ligand comprises a TNFR-binding portion of TNF alpha coupled to a moiety that sterically inhibits binding of the modified TNF ligand to cell surface TNFR but does not inhibit binding of the modified TNF ligand to soluble TNFR.
18 . The method of claim 17 , wherein administering the agent inhibits the proliferation, growth, or survival of cancer cells in the subject, decreases the size of a tumor in the subject, or inhibits tumor growth in the subject.
19 . The method of claim 17 , wherein the agent decreases the amount or activity of soluble TNFR present in a tumor microenvironment in the subject.
20 - 26 . (canceled)
27 . The method of claim 17 , wherein the TNFR is TNFR1 or TNFR2.
28 - 47 . (canceled)
48 . A method for decreasing the amount or activity of a soluble cytotoxic receptor in a subject in need thereof, comprising administering an effective amount of an agent to the subject, wherein:
the agent comprises a soluble interleukin-2 (IL-2) receptor antagonist; and
the soluble IL-2 receptor antagonist is a modified IL-2 ligand or receptor binding portion thereof coupled to a moiety that sterically inhibits binding of the ligand to cell surface IL-2 receptor.
49 . The method of claim 48 , wherein administering the agent inhibits the proliferation, growth, or survival of cancer cells in the subject, decreases the size of a tumor in the subject, or inhibits tumor growth in the subject.
50 . The method of claim 48 , wherein the agent decreases the amount or activity of soluble IL-2 receptor present in a tumor microenvironment in the subject.
51 - 57 . (canceled)
58 . The method of claim 48 , wherein the IL-2 receptor comprises IL-2 receptor α, IL-2 receptor β, or IL-2 receptor γ.
59 - 61 . (canceled)
62 . The method of claim 17 , wherein the subject has a cancer.
63 . The method of claim 17 , wherein the subject is a human.
64 . The method of claim 17 , wherein administering comprises systemic administration.
65 . The method of claim 64 , wherein the systemic administration comprises intravenous administration.
66 . The method of claim 17 , wherein administering comprises local administration.
67 . The method of claim 66 , wherein the local administration comprises injection into a tumor.
68 . (canceled)
69 . The method of claim 17 , wherein administering the agent does not induce general immunosuppression.
70 - 93 . (canceled)
94 . The method of claim 17 , wherein the agent binds soluble TNFR with at least 5 fold, 10 fold, 20 fold, 50 fold, or 100 fold higher affinity (e.g., lower Kd) than cell surface TNFR.
95 . The method of claim 17 , wherein the agent does not specifically bind cell surface TNFR when administered at a concentration effective for specific binding of the agent to soluble TNFR.
96 . The method of claim 48 , wherein the agent binds soluble IL-2 receptor with at least 5 fold, 10 fold, 20 fold, 50 fold, or 100 fold higher affinity (e.g., lower Kd) than cell surface IL-2 receptor.
97 . The method of claim 48 , wherein the agent does not specifically bind cell surface IL-2 receptor when administered at a concentration effective for specific binding of the agent to soluble IL-2 receptor.
98 - 101 . (canceled)
102 . A method for decreasing the amount or activity of a soluble cytotoxic receptor in a human subject, comprising administering to the subject an inhibitor of a soluble cytotoxic receptor, wherein:
the cytotoxic receptor may exist in either a soluble form or a cell-surface form;
the inhibitor selectively binds the soluble form of the receptor relative to the cell-surface form of the receptor; and either:
binding of the inhibitor to the soluble form of the receptor decreases the activity of the soluble form of the cytotoxic receptor; or
binding of the inhibitor to the soluble form of the receptor decreases the amount of the soluble form of the cytotoxic receptor that is capable of binding a cytotoxic cytokine ligand.
103 . The method of claim 102 , wherein the inhibitor comprises a moiety that sterically inhibits the inhibitor from binding to the cell-surface form of the cytotoxic receptor.
104 . The method of claim 102 , wherein the affinity of the inhibitor for the soluble form of the cytotoxic receptor is greater than 10-fold higher than the affinity of the inhibitor for the cell-surface form of the cytotoxic receptor.
105 . The method of claim 102 , wherein the cytotoxic receptor is a tumor necrosis factor receptor or an interleukin-2 receptor.
106 . The method of claim 102 , wherein:
the inhibitor comprises a moiety that sterically inhibits the inhibitor from binding to the cell-surface form of the cytotoxic receptor;
the affinity of the inhibitor for the soluble form of the cytotoxic receptor is greater than 10-fold higher than the affinity of the inhibitor for the cell-surface form of the cytotoxic receptor; and
the cytotoxic receptor is a tumor necrosis factor receptor or an interleukin-2 receptor.
107 . The method of claim 102 , wherein the inhibitor is selected from antibodies, antibody fragments, peptides, polypeptides, small molecules, or protein display scaffolds.
108 . The method of claim 62 , wherein the cancer is metastatic cancer.