PD-1 ANTAGONISTS AND METHODS OF USE THEREOF
Compositions and methods for enhancing and/or prolonging the activation of T cells (i.e., increasing antigen-specific proliferation of T cells, enhancing cytokine production by T cells, stimulating differentiation ad effector functions of T cells and/or promoting T cell survival) or overcoming T cell exhaustion and/or anergy are provided. Suitable compositions include PD-1 receptor antagonists that bind to and block the endogenous PD-1 receptor without triggering inhibitory signals from PD-1, or bind to and block PD-1 receptor ligands and preventing them from interacting with PD-1 receptors. Methods for using the PD-1 receptor antagonists to enhance immune responses in subjects in need thereof are provided.
1 . A method of modulating an immune response comprising administering an effective amount a PD-1 antagonist to induce, augment, or enhance an immune response against a tumor, wherein the dose of the molecule, the timing of administration of the molecule and/or the affinity of the molecule allows for intermittent access of a ligand to the PD-1 receptor.
2 . The method of claim 1 wherein the PD-1 antagonist inhibits or reduces binding of endogenous PD-L1 to PD-1.
3 . The method of claim 1 wherein the PD-1 antagonist inhibits or reduces binding of endogenous PD-L2 to PD-1.
4 . The method of claim 1 wherein the PD-1 antagonist binds to PD-1.
5 . The method of claim 1 wherein the PD-1 antagonist is selected from the group consisting of PD-1, PD-L1, PD-L2, B7.1, and fragments thereof.
6 . The method of claim 1 wherein the molecule binds to PD-1 or a ligand thereof for three months or less after in vivo administration.
7 . The method of claim 1 wherein more than one PD-1 antagonist is administered.
8 . The method of claim 1 , wherein the tumor is from a cancer selected from the group consisting of: bladder, brain, breast, cervical, colo-rectal, esophageal, kidney, liver, lung, nasopharangeal, pancreatic, prostate, skin, stomach, uterine, ovarian, testicular and hematologic.
9 . The method of claim 1 further comprising administering a tumor antigen in combination with the PD-1 antagonist to enhance an immune response against the tumor.
10 . The method of claim 1 , wherein the PD-1 antagonist is a fusion protein of a PD-1 ligand.
11 . The method of claim 10 , wherein the fusion protein comprises the extracellular domain of PD-L2 or a fragment thereof capable of binding to PD-1.
12 . The method of claim 11 wherein the fusion protein has an amino acid sequence according to SEQ ID NO:57.
13 . The method of claim 1 , further comprising administering with the PD-1 antagonist an additional active agent selected from the group consisting of immunomodulators, agents that deplete or inhibit the function of Tregs, and costimulatory molecules.
14 . The method of claim 17 , wherein the additional active agent is an agent that depletes or inhibits the function of CD4+CD25+ Tregs.
15 . The method of claim 17 , wherein the agent that depletes or inhibits the function of CD4+CD25+ Tregs is cyclophosphamide.
16 . The method of claim 1 for enhancing antigen presenting cell function comprising contacting APCs with a PD-1 antagonist in an amount effective to inhibit, reduce, or block PD-1 signal transduction in the APCs or enhance clearance of diseased.
17 . A composition comprising an effective amount of a PD-1 receptor antagonist to bind to a ligand of a PD-1 receptor in vivo and reduce or inhibit PD-1 receptor signal transduction.
18 . The composition of claim 17 wherein the PD-1 antagonist comprises a B7-DC polypeptide or fragment thereof that binds B7-H1 polypeptide and inhibits or reduces binding of the B7-H1 polypeptide to the PD-1 receptor.
19 . The composition of claim 18 wherein the fragment comprises the extracellular domain of B7-DC or fragment thereof that binds B7-H1 or the extracellular domain of B7-H1 or fragment thereof that binds B7-DC.
20 . The composition of claim 17 wherein the PD-1 antagonist comprises a fusion protein.
21 . The composition of claim 20 wherein the fusion proteins binds the PD-1 receptor without triggering signal transduction through the PD-1 receptor.
22 . The composition of claim 17 wherein the PD-1 receptor antagonist comprises a B7-H1 polypeptide that binds to B7-DC polypeptide and inhibits or reduces binding of the B7-DC polypeptide to PD-1 receptors.
23 . The composition of claim 22 wherein the PD-1 receptor antagonist comprises a fusion protein.
24 . A composition comprising an effective amount of a polypeptide to bind PD-1 in vivo without triggering signal transduction through PD-1.
25 . The composition of claim 24 wherein the polypeptide comprises a B7-DC or B7-H1 polypeptide modified so that it binds to PD-1 without triggering signal transduction.
26 . The composition of claim 24 wherein the polypeptide comprises a variant extracellular domain of B7-DC or B7-H1 modified so that the polypeptide binds to PD-1 without triggering signal transduction through PD-1.
27 . A fusion polypeptide comprising:
a) a first fusion partner, and
b) a second fusion partner,
wherein the first fusion partner comprises a variant extracellular domain or fragment thereof of a ligand of PD-1 modified to bind PD-1 without triggering signal transduction through PD-1 and wherein the first fusion partner is fused directly to the second fusion partner, or optionally, is fused to a linker sequence that is fused to the second fusion partner.
28 . The fusion polypeptide of claim 27 wherein the second fusion partner comprises one or more domains of an Ig heavy chain constant region.
29 . The fusion polypeptide of claim 28 wherein the second polypeptide comprises an amino acid sequence corresponding to the hinge, C H 2 and C H 3 regions of a human immunoglobulin Cγ1 chain.
30 . The fusion polypeptide of claim 27 , wherein the first polypeptide comprises the extracellular domain of B7-DC or B7-H1 modified to bind PD-1 without triggering signal transduction through PD-1.