IPC분류정보
| 국가/구분 |
United States(US) Patent
등록
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| 국제특허분류(IPC7판) |
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| 출원번호 |
US-0413990
(2012-03-07)
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| 등록번호 |
US-8445447
(2013-05-21)
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발명자
/ 주소 |
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| 출원인 / 주소 |
- The Johns Hopkins University
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| 대리인 / 주소 |
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| 인용정보 |
피인용 횟수 :
0 인용 특허 :
58 |
초록
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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
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.
대표청구항
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1. A method for inducing an immune response to an antigen in a human subject comprising administering to the subject (a) an antigen, and(b) a fusion protein comprising a first fusion partner comprising a variant B7-DC polypeptide fused (i) directly to a second polypeptide or,(ii) fused to a linker p
1. A method for inducing an immune response to an antigen in a human subject comprising administering to the subject (a) an antigen, and(b) a fusion protein comprising a first fusion partner comprising a variant B7-DC polypeptide fused (i) directly to a second polypeptide or,(ii) fused to a linker peptide sequence that is fused to the second 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 method of claim 1, wherein (a) is administered to the subject prior to (b). 3. The method of claim 1, wherein (b) is administered to the subject prior to (a). 4. The method of claim 1, wherein (a) and (b) are co-administered to the subject in an immunogenic composition. 5. The method of claim 4, wherein the immunogenic composition further comprises an adjuvant. 6. The method of claim 4, wherein the immunogenic composition further comprises a targeting molecule. 7. The method of claim 1, wherein the subject has cancer. 8. The method of claim 1, wherein the antigen is a soluble antigen. 9. The method of claim 1, wherein the antigen is a tumor antigen. 10. The method of claim 1, wherein the immune response is an increase antigen-specific proliferation of T cells, enhanced cytokine production by T cells, stimulation of differentiation, stimulation of an effector function of T cells, or increased survival of T cells in the subject compared to administering (a) alone. 11. A method for treating cancer in a human subject comprising administering to the subject (a) an antigen, and(b) a fusion protein comprising a first fusion partner comprising a variant B7-DC polypeptide fused (i) directly to a second polypeptide or,(ii) fused to a linker peptide sequence that is fused to the second 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,wherein (a) and (b) are administered to the subject in an effective amount to reduce a symptom of the cancer. 12. The method of claim 11, wherein (a) is administered to the subject prior to (b). 13. The method of claim 11, wherein (b) is administered to the subject prior to (a). 14. The method of claim 11, wherein (a) and (b) are co-administered to the subject in an immunogenic composition. 15. The method of claim 14, wherein the immunogenic composition further comprises an adjuvant. 16. The method of claim 14, wherein the immunogenic composition further comprises a targeting molecule. 17. The method of claim 11, wherein the antigen is a soluble antigen. 18. The method of claim 11, wherein the antigen is a tumor antigen. 19. The method of claim 11 further comprising administering the subject a chemotherapeutic agent, a hormonal agent, a second immunostimulatory agent, or radiation therapy. 20. A method for increasing antigen-specific proliferation of T cells in a human subject comprising administering to the subject (a) an antigen, and(b) a fusion protein comprising a first fusion partner comprising a variant B7-DC polypeptide fused (i) directly to a second polypeptide or,(ii) fused to a linker peptide sequence that is fused to the second 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,wherein (b) is administered in an effective amount to increase proliferation of T cells specific to the antigen in the subject compared to administrating the subject (a) alone. 21. A method for enhancing production of a cytokine by T cells in a human subject comprising administering to the subject (a) an antigen, and(b) a fusion protein comprising a first fusion partner comprising a variant B7-DC polypeptide fused (i) directly to a second polypeptide or,(ii) fused to a linker peptide sequence that is fused to the second 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,wherein (b) is administered in an effective amount to enhance production of the cytokine by T cells in the subject compared to administrating the subject (a) alone. 22. The method of claim 21, wherein the cytokine is selected from the group consisting of Il-2, IL-4, IL-5, IL-6, IL-10, IL-13, and IFN-γ. 23. A method for increasing differentiation of T cells in a human subject comprising administering to the subject (a) an antigen, and(b) a fusion protein comprising a first fusion partner comprising a variant B7-DC polypeptide fused (i) directly to a second polypeptide or,(ii) fused to a linker peptide sequence that is fused to the second 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,wherein (b) is administered in an effective amount to increase differentiation of T cells in the subject compared to administrating the subject (a) alone. 24. A method for increasing an effector function of T cells in a human subject comprising administering to the subject (a) an antigen, and(b) a fusion protein comprising a first fusion partner comprising a variant B7-DC polypeptide fused (i) directly to a second polypeptide or,(ii) fused to a linker peptide sequence that is fused to the second 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,wherein (b) is administered in an effective amount to increase the effector function of T cells in the subject compared to administrating the subject (a) alone. 25. A method for increasing survival of T cells in a human subject comprising administering to the subject (a) an antigen, and(b) a fusion protein comprising a first fusion partner comprising a variant B7-DC polypeptide fused (i) directly to a second polypeptide or,(ii) fused to a linker peptide sequence that is fused to the second 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′, 13, 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,wherein (b) is administered in an effective amount to increase survival of T cells in the subject compared to administrating the subject (a) alone.
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