Methods and compositions for the inhibition of transplant rejection
View Patent ↗Methods for modulating immune responses in a subject are provided. A preferred embodiment provides methods and compositions for reducing or inhibiting transplant rejection in a subject, preferably a human subject. Transplant rejection can be inhibited or reduced in a subject by administering an effective amount of B7-H4 polypeptide, fragments or fusions thereof to inhibit or reduce the biological activity of an immune cell or to reduce the amounts of proinflammatory molecules at a site of transplant. Th1, Th17 and Th22 cells are exemplary T cells that can be targeted for inhibition by B7-H4 polypeptides, fusion proteins or fragments thereof to inhibit or reduce inflammation.
1. A method for inhibiting or reducing rejection of a tissue or organ transplant in a human subject,
comprising administering to the subject two or more pharmaceutical dosage units, each dosage unit comprising
a dose of 3 mg/kg to 25 mg/kg of a fusion protein comprising a B7-H4 polypeptide comprising the IgV domain of SEQ ID NO:63 or SEQ ID NO:64 fused to a second polypeptide or fused to a linker peptide fused to a second polypeptide,
wherein at least two of the dosage units are administered at least two days apart and within two weeks,
to increase the ratio of regulatory T cells (Tregs) relative to total CD4+ cells in the subject and reduce rejection of the tissue or organ transplant in the subject for at least a week post administration.
2. A method for inhibiting or reducing rejection of a tissue or organ transplant in a human subject,
comprising administering to the subject two or more pharmaceutical dosage units, each dosage unit comprising
a dose of 3 mg/kg to 25 mg/kg of a fusion protein comprising a B7-H4 polypeptide comprising the IgV domain of SEQ ID NO:63 or SEQ ID NO:64 fused to a second polypeptide or fused to a linker peptide fused to a second polypeptide comprising
the hinge, C H 2 and C H 3 regions of an immunoglobulin,
wherein at least two of the dosage units are administered at least two days apart and within two weeks,
to increase the ratio of regulatory T cells (Tregs) relative to total CD4+ cells in the subject and reduce rejection of the tissue or organ transplant in the subject for at least a week post administration.
3. The method of claim 1 , wherein the pharmaceutical dosage unit further comprises a second therapeutic agent.
4. The method of claim 3 wherein the second therapeutic agent is selected from the group consisting of glucocorticoid fluticasone, salmeterol; antibodies to IL-12, IL-6, IFN-γ, IL-23, IL-22, IL-21 and IL-4; vitamin D3, CTLA-4-Ig, belatacept, dexamethasone, and combinations thereof.
5. The method of claim 1 wherein the transplant is an allogeneic transplant.
6. The method of claim 1 , wherein the transplant is a skin graft, a tissue transplant, an organ transplant, or a bone marrow transplant.
7. A method for treating one or more symptoms of graft versus host disease (GVHD) in a human subject,
comprising administering to the subject two or more pharmaceutical dosage units, each dosage unit comprising
a dose of 3 mg/kg to 25 mg/kg of a fusion protein comprising a B7-H4 polypeptide comprising the IgV domain of SEQ ID NO:63 or SEQ ID NO:64 fused to a second polypeptide or fused to a linker peptide fused to a second polypeptide,
wherein at least two of the dosage units are administered at least two days apart and within two weeks,
to increase the ratio of regulatory T cells (Tregs) relative to total CD4+ cells in the subject and reduce one or more symptoms of GVHD in the subject for at least a week post administration.
8. A method for treating one or more symptoms of graft versus host disease (GVHD) in a human subject,
comprising administering to the subject two or more pharmaceutical dosage units, each dosage unit comprising
a dose of 3 mg/kg to 25 mg/kg of a fusion protein comprising a B7-H4 polypeptide comprising the IgV domain of SEQ ID NO:63 or SEQ ID NO:64 fused to a second polypeptide or fused to a linker peptide fused to a second polypeptide,
wherein the second polypeptide comprises the hinge, C H 2 and C H 3 regions of an immunoglobulin,
wherein at least two of the dosage units are administered at least two days apart and within two weeks,
to increase the ratio of regulatory T cells (Tregs) relative to total CD4+ cells in the subject and reduce one or more symptoms of GVHD in the subject for at least a week post administration.
9. A method for inhibiting or reducing rejection of a tissue or organ transplant in a human subject comprising administering to the subject two or more pharmaceutical dosage units, each dosage unit comprising a dose of 3 mg/kg to 25 mg/kg of a fusion protein comprising a B7-H4 polypeptide comprising the IgV domain of B7-H4 fused to a second polypeptide or fused to a linker peptide fused to a second polypeptide,
wherein at least two of the dosage units are administered at least two days apart and within two weeks,
to increase the ratio of regulatory T cells (Tregs) relative to total CD4+ cells in the subject and reduce rejection of tissue or organ transplant in the subject for at least a week post administration.
10. The method of claim 2 , wherein the immunoglobulin is a human IgG1.
11. A method for inhibiting or reducing rejection of a tissue or organ transplant in a human subject,
comprising administering to the subject two or more pharmaceutical dosage units, each dosage unit comprising
a dose of 3 mg/kg to 25 mg/kg of a fusion protein comprising the amino acid sequence of SEQ ID NO:130
wherein at least two of the dosage units are administered at least two days apart and within two weeks,
to increase the ratio of regulatory T cells (Tregs) relative to total CD4+ cells in the subject and reduce rejection of tissue or organ transplant in the subject for at least a week post administration.
12. The method of claim 8 , wherein the immunoglobulin is a human IgG1.
13. The method of claim 8 , wherein the second polypeptide comprises the hinge, C H 2 and C H 3 regions of an immunoglobulin.
14. The method of claim 13 , wherein the immunoglobulin is a human IgG1.
15. A method for treating one or more symptoms of graft versus host disease (GVHD) in a human subject,
comprising administering to the subject two or more pharmaceutical dosage units, each dosage unit comprising 3 mg/kg to 25 mg/kg of a fusion protein comprising the amino acid sequence of SEQ ID NO:130
wherein at least two of the dosage units are administered at least two days apart and within two weeks,
to increase the ratio of regulatory T cells (Tregs) relative to total CD4+ cells in the subject and reduce one or more symptoms of GVHD in the subject for at least a week post administration.
16. A method for treating one or more symptoms of graft versus host disease (GVHD) in a human subject comprising administering to the subject two or more pharmaceutical dosage units, each dosage unit comprising a dose of 3 mg/kg to 25 mg/kg of a fusion protein comprising a B7-H4 polypeptide comprising the IgV domain of B7-H4 fused to a second polypeptide or fused to a linker peptide fused to a second polypeptide,
wherein at least two of the dosage units are administered at least two days apart and within two weeks,
to increase the ratio of regulatory T cells (Tregs) relative to total CD4+ cells in the subject and reduce one or more symptoms of graft versus host disease (GVHD) in the subject for at least a week post administration.
17. The method of claim 1 , wherein at least three of the dosage units are administered at least two days apart and within two weeks.
18. The method of claim 1 , wherein at least two of the dosage units are administered at least two days apart and within one week.
19. The method of claim 1 , wherein at least three of the dosage units are administered at least two days apart and within one week.
20. The method of claim 9 , wherein at least three of the dosage units are administered at least two days apart and within two weeks.
21. The method of claim 9 , wherein at least two of the dosage units are administered at least two days apart and within one week.
22. The method of claim 9 , wherein at least three of the dosage units are administered at least two days apart and within one week.
23. The method of claim 11 , wherein at least three of the dosage units are administered at least two days apart and within two weeks.
24. The method of claim 11 , wherein at least two of the dosage units are administered at least two days apart and within one week.
25. The method of claim 11 , wherein at least three of the dosage units are administered at least two days apart and within one week.
26. The method of claim 15 , wherein at least three of the dosage units are administered at least two days apart and within two weeks.
27. The method of claim 15 , wherein at least two of the dosage units are administered at least two days apart and within one week.
28. The method of claim 15 , wherein at least three of the dosage units are administered at least two days apart and within one week.
29. The method of claim 1 , wherein the administration is effective to reduce rejection of the tissue or organ transplant in the subject for at least 10 days post administration.
30. The method of claim 1 , wherein the administration is effective to reduce rejection of the tissue or organ transplant in the subject for at least two weeks post administration.
31. The method of claim 1 , wherein the administration is effective to reduce rejection of the tissue or organ transplant in the subject for at least three weeks post administration.
32. The method of claim 7 , wherein the administration is effective to reduce one or more symptoms of GVHD in the subject for at least 10 days post administration.
33. The method of claim 7 , wherein the administration is effective to reduce one or more symptoms of GVHD in the subject for at least two weeks post administration.
34. The method of claim 7 , wherein the administration is effective to reduce one or more symptoms of GVHD in the subject for at least three weeks post administration.
35. The method of claim 11 , wherein the administration is effective to reduce rejection of the tissue or organ transplant in the subject for at least 10 days post administration.
36. The method of claim 11 , wherein the administration is effective to reduce rejection of the tissue or organ transplant in the subject for at least two weeks post administration.
37. The method of claim 11 , wherein the administration is effective to reduce rejection of the tissue or organ transplant in the subject for at least three weeks post administration.
38. The method of claim 15 , wherein the administration is effective to reduce one or more symptoms of GVHD in the subject for at least 10 days post administration.
39. The method of claim 15 , wherein the administration is effective to reduce one or more symptoms of GVHD in the subject for at least two weeks post administration.
40. The method of claim 15 , wherein the administration is effective to reduce one or more symptoms of GVHD in the subject for at least three weeks post administration.