B7-DC variants immunogenic compositions and methods of use thereof
Compositions and methods for costimulating 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) are provided. Suitable compositions include variant B7-DC polypeptides, fragments and fusion proteins thereof. Variant B7-DC polypeptides have reduced binding affinity for the inhibitory PD-1 ligand and substantially retain the ability to costimulate T cells. Methods for using variant B7-DC polypeptides to stimulate immune responses in subjects in need thereof are provided.
1. An immunogenic composition for inducing an immune response against a cancer antigen, comprising
(a) an antigen from a tumor cell, and
(b) a variant B7-DC polypeptide,
wherein the variant B7-DC polypeptide is an isolated variant of a wildtype human B7-DC polypeptide comprising an IgV domain of B7-DC comprising an amino acid substitution in the A′, B, C, C′, C″, D, E, F, or G β-strand of the wild-type human B7-DC polypeptide, and has altered affinity for PD-1 compared to the wild-type human B7-DC polypeptide.
2. The immunogenic composition of claim 1 , wherein the variant B7-DC polypeptide is B7-DC fusion protein.
3. The immunogenic composition of claim 1 , wherein the isolated variant B7-DC polypeptide comprises the extracellular domain of human B7-DC.
4. The immunogenic composition of claim 1 , wherein the variant B7-DC polypeptide has decreased binding affinity for PD-1compared to the wild-type B7-DC polypeptide.
5. The immunogenic composition of claim 2 , wherein the variant B7-DC fusion protein comprises a first fusion partner comprising the variant human B7-DC polypeptide of (b), and a second fusion partner, comprising one or more domains of an Ig heavy chain constant region.
6. The immunogenic composition of claim 5 , wherein the second fusion partner of the variant B7-DC fusion protein comprises an amino acid sequence corresponding to the hinge, C H 2 and C H 3 regions of a human immunoglobulin chain.
7. The immunogenic composition of claim 6 , wherein the first fusion partner comprises the extracellular domain of the variant B7-DC, and 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 chain.
8. The immunogenic composition of claim 1 , wherein the antigen is selected from the group consisting of peptides, proteins, polysaccharides, saccharides, lipids, and combinations thereof.
9. The immunogenic composition of claim 1 , wherein the antigen is an epitope of a polypeptide encoded by a nucleic acid.
10. The immunogenic composition of claim 1 , wherein the antigen is selected from the group consisting of alpha-actinin-4, Bcr-Ab1 fusion protein, Casp-8, beta-catenin, cdc27, cdk4, cdkn2a, coa-1, dek-can fusion protein, EF2, ETV6-AML1 fusion protein, LDLR-fucosyltransferase, AS fusion protein, HLA-A2, HLA-A11, hsp70-2, KIAA0205, Mart2, Mum-1,2, and 3, neo-PAP, myosin class I, OS-9, pm1-RARα fusion protein, PTPRK, K-ras, N-ras, Triosephosphate isomeras, Bage-1, Gage 3,4,5,6,7, GnTV, Herv-K -mel, Lage-1, Mage-A1, 2,3,4,6,10,12, Mage-C2, NA-88, NY-Eso-1/Lage-2, SP17, SSX-2, and TRP2-Int 2, MelaA (MART-I), gp100 (Pmel 17), tyrosinase, TRP-1, TRP-2, MAGE -1, MAGE-3, BAGE, GAGE-1, GAGE-2, p15(58), CEA, RAGE, NY-ESO (LAGE), SCP-1, Hom/Mel-40, PRAME, p53, H-Ras, HER-2/neu, BCR-ABL, E2A-PRL, H4-RET, IGH-IGK, MYL-RAR, Epstein Barr virus antigens, EBNA, human papillomavirus (HPV) antigens E6 and E7, TSP-180, MAGE-4, MAGE-5, MAGE-6, p185erbB2, p180erbB-3, c-met, nm-23H1, PSA, TAG-72-4, CA 19-9, CA 72-4, CAM 17.1, NuMa, K-ras, β-Catenin, CDK4, Mum-1, p16, TAGE, PSMA, PSCA, CT7, telomerase, 43-9F, 5T4, 791Tgp72, α-fetoprotein, 13HCG, BCA225, BTAA, CA 125, CA 15-3 (CA 27.29\BCAA), CA 195, CA 242, CA-50, CAM43, CD68\KP1, CO-029, FGF-5, G250, Ga733 (EpCAM), HTgp-175, M344, MA-50, MG7-Ag, MOV18, NB\70K, NY-CO-1, RCAS1, SDCCAG16, TA-90 (Mac-2 binding protein\cyclophilin C -associated protein), TAAL6, TAG72, TLP, and TPS.
11. A method for inducing an immune response to a cancer antigen in a human subject comprising administering to the subject the immunogenic composition of claim 1 .
12. The immunogenic composition of claim 1 , wherein the substitution in the variant B7-DC polypeptide of (b) comprises replacing the amino acid residue corresponding to amino acid position 111numbered from the initiation methionine of wild-type human B7-DC (SEQ ID NO:1).
13. The immunogenic composition of claim 12 , wherein the amino acid substitution is with a serine residue.
14. The immunogenic composition of claim 1 , wherein the substitution in the variant B7-DC polypeptide of (b) comprises replacing the amino acid residue corresponding to amino acid position 113numbered from the initiation methionine of wild-type human B7-DC (SEQ ID NO:1).
15. The immunogenic composition of claim 14 , wherein the substitution is with a serine residue.
16. The immunogenic composition of claim 1 , wherein the substitution in the variant B7-DC polypeptide of (b) comprises replacing the amino acid residue corresponding to amino acid position 56 numbered from the initiation methionine of wild-type human B7-DC (SEQ ID NO:1).
17. The immunogenic composition of claim 16 , wherein the substitution is with a serine residue.
18. The immunogenic composition of claim 1 , wherein the substitution in the variant B7-DC polypeptide of (b) comprises replacing the amino acid residue corresponding to amino acid position 67 numbered from the initiation methionine of wild-type human B7-DC (SEQ ID NO:1).
19. The immunogenic composition of claim 18 , wherein the substitution is with a tyrosine.
20. The immunogenic composition of claim 1 , wherein the substitution in the variant B7-DC polypeptide of (b) comprises replacing the amino acid residue corresponding to amino acid position 71 numbered from the initiation methionine of wild-type human B7-DC (SEQ ID NO:1).
21. The immunogenic composition of claim 20 , wherein the substitution is with a serine residue.
22. The immunogenic composition of claim 1 , wherein the substitution in the variant B7-DC polypeptide of (b) comprises replacing the amino acid residue corresponding to amino acid position 101 numbered from the initiation methionine of wild-type human B7-DC (SEQ ID NO:1).
23. The immunogenic composition of claim 22 , wherein the substitution is with a serine residue.
24. The immunogenic composition of claim 1 , wherein the substitution in the variant B7-DC polypeptide of (b) comprises replacing the amino acid residue corresponding to amino acid position 105 numbered from the initiation methionine of wild-type human B7-DC (SEQ ID NO:1).
25. The immunogenic composition of claim 24 , wherein the substitution is with an alanine.
26. The immunogenic composition of claim 1 , wherein the isolated variant B7-DC polypeptide has increased binding affinity for PD-1 compared to wild-type B7-DC polypeptide.
27. An immunogenic composition for inducing an immune response against a soluble antigen, comprising
(a) the soluble antigen, and
(b) a variant B7-DC polypeptide,
wherein the variant B7-DC polypeptide is an isolated variant of a wildtype human B7-DC polypeptide comprising an IgV domain of B7-DC comprising an amino acid substitution in the A′, B, C, C′, C″, D, E, F, or G β-strand of the wild-type human B7-DC polypeptide, and has altered affinity for PD-1 compared to the wild-type human B7-DC polypeptide.
28. The immunogenic composition of claim 27 , wherein the B7-DC polypeptide is a B7-DC fusion protein.
29. The immunogenic composition of claim 27 , wherein the B7-DC polypeptide comprises the extracellular domain of human B7-DC.
30. The immunogenic composition of claim 27 , wherein the B7-DC polypeptide has decreased binding affinity for PD-1compared to the wild-type B7-DC polypeptide.
31. The immunogenic composition of claim 28 , wherein the B7-DC fusion protein comprises
a first fusion partner comprising the human B7-DC polypeptide of (b), and
a second fusion partner, comprising one or more domains of an Ig heavy chain constant region.
32. The immunogenic composition of claim 31 , wherein the second fusion partner of the B7-DC fusion protein comprises an amino acid sequence corresponding to the hinge, C H 2 and C H 3 regions of a human immunoglobulin chain.
33. The immunogenic composition of claim 32 , wherein the first fusion partner comprises the extracellular domain of B7-DC, and 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 chain.
34. The immunogenic composition of claim 27 , wherein the antigen is selected from the group consisting of peptides, proteins, polysaccharides, saccharides, and combinations thereof.
35. The immunogenic composition of claim 27 , wherein the antigen is an epitope of a polypeptide encoded by a nucleic acid.
36. The immunogenic composition of claim 27 , wherein the antigen is derived from a virus, bacterium, parasite, plant, protozoan, fungus, tissue, transformed cell, allergen, environmental antigen, or tumor antigen.
37. The immunogenic composition of claim 27 , wherein the antigen is selected from the group consisting of alpha-actinin-4, Bcr-Ab1 fusion protein, Casp-8, beta-catenin, cdc27, cdk4, cdkn2a, coa-1, dek-can fusion protein, EF2, ETV6-AML1 fusion protein, LDLR-fucosyltransferase, AS fusion protein, HLA-A2, HLA-A11, hsp70-2, KIAA0205, Mart2, Mum-1,2, and 3, neo-PAP, myosin class I, OS-9, pm1-RARα fusion protein, PTPRK, K-ras, N-ras, Triosephosphate isomeras, Bage-1, Gage 3,4,5,6,7, GnTV, Herv-K-mel, Lage-1, Mage-A1, 2,3,4,6,10,12, Mage-C2, NA-88, NY-Eso-1/Lage-2, SP17, SSX-2, and TRP2-Int 2, MelaA (MART-I), gp100 (Pmel 17), tyrosinase, TRP-1, TRP-2, MACE -1, MAGE-3, BAGE, GAGE-1, GAGE-2, p15(58), CEA, RAGE, NY-ESO (LAGE), SCP-1, Hom/Mel-40, PRAME, p53, H-Ras, HER-2/neu, BCR-ABL, E2A-PRL, H4-RET, IGH-IGK, MYL-RAR, Epstein Barr virus antigens, EBNA, human papillomavirus (HPV) antigens E6 and E7, TSP-180, MAGE-4, MAGE-5, MAGE-6, p185erbB2, p180erbB-3, c-met, nm-23H1, PSA, TAG-72-4, CA 19-9, CA 72-4, CAM 17.1, NuMa, K-ras, β-Catenin, CDK4, Mum-1, p16, TAGE, PSMA, PSCA, CT7, telomerase, 43-9F, 5T4, 791Tgp72, α-fetoprotein, 13HCG, BCA225, BTAA, CA 125, CA 15-3 (CA 27.29\BCAA), CA 195, CA 242, CA-50, CAM43, CD68\KP1, CO-029, FGF-5, G250, Ga733 (EpCAM), HTgp-175, M344, MA-50, MG7-Ag, MOV18, NB\70K, NY-CO-1, RCAS1, SDCCAG16, TA-90 (Mac-2 binding protein\cyclophilin C -associated protein), TAAL6, TAG72, TLP, and TPS.
38. The immunogenic composition of claim 27 , wherein the substitution in the variant B7-DC polypeptide of (b) comprises replacing the amino acid residue corresponding to amino acid position 111 numbered from the initiation methionine of wild-type human B7-DC (SEQ ID NO:1).
39. The immunogenic composition of claim 38 , wherein the amino acid substitution is with a serine residue.
40. The immunogenic composition of claim 27 , wherein the substitution in the variant B7-DC polypeptide of (b) comprises replacing the amino acid residue corresponding to amino acid position 113 numbered from the initiation methionine of wild-type human B7-DC (SEQ ID NO:1).
41. The immunogenic composition of claim 40 , wherein the substitution is with a serine residue.
42. The immunogenic composition of claim 27 , wherein the substitution in the variant B7-DC polypeptide of (b) comprises replacing the amino acid residue corresponding to amino acid position 56 numbered from the initiation methionine of wild-type human B7-DC (SEQ ID NO:1).
43. The immunogenic composition of claim 42 , wherein the substitution is with a serine residue.
44. The immunogenic composition of claim 27 , wherein the substitution in the variant B7-DC polypeptide of (b) comprises replacing the amino acid residue corresponding to amino acid position 67 numbered from the initiation methionine of wild-type human B7-DC (SEQ ID NO:1).
45. The immunogenic composition of claim 44 , wherein the substitution is with a tyrosine.
46. The immunogenic composition of claim 27 , wherein the substitution in the variant B7-DC polypeptide of (b) comprises replacing the amino acid residue corresponding to amino acid position 71 numbered from the initiation methionine of wild-type human B7-DC (SEQ ID NO:1).
47. The immunogenic composition of claim 46 , wherein the substitution is with a serine residue.
48. The immunogenic composition of claim 27 , wherein the substitution in the variant B7-DC polypeptide of (b) comprises replacing the amino acid residue corresponding to amino acid position 101 numbered from the initiation methionine of wild-type human B7-DC (SEQ ID NO:1).
49. The immunogenic composition of claim 48 , wherein the substitution is with a serine residue.
50. The immunogenic composition of claim 27 , wherein the substitution in the variant B7-DC polypeptide of (b) comprises replacing the amino acid residue corresponding to amino acid position 105 numbered from the initiation methionine of wild-type human B7-DC (SEQ ID NO:1).
51. The immunogenic composition of claim 50 , wherein the substitution is with an alanine.
52. The immunogenic composition of claim 27 , wherein the isolated variant B7-DC polypeptide has increased binding affinity for PD-1 compared to wild-type B7-DC polypeptide.
53. A method for inducing an immune response to a soluble antigen in a human subject comprising administering to the subject the immunogenic composition of claim 27 .