Use of lymphotoxin-β receptor blocking agents for the treatment of antibody mediated immunological diseases
View Patent ↗Compositions and methods comprising “lymphotoxin-β receptor blocking agents” which block lymphotoxin-β receptor signaling and are useful for altering immunological diseases, and particularly antibody mediated immune responses.
1. A method for inhibiting a humoral immune response in a human comprising administering to the human mammal a pharmaceutical composition comprising an effective amount of a soluble human lymphotoxin-beta receptor (LTβR) fused to one or more heterologous protein domains, wherein the soluble human LTβR comprises at least one ligand binding domain that can selectively bind to a human surface LT ligand, and a pharmaceutically acceptable carrier, such that a humoral immune response is inhibited.
2. The method according to claim 1 , wherein the ligand binding domain comprises SEQ ID NO: 1, or a functional fragment thereof encoding an LTβR ligand binding domain.
3. The method according to claim 1 , wherein the heterologous protein domain is selected from the group consisting of immunoglobulins, serum albumin, lipoproteins, apolipoproteins, and transferrin.
4. The method according to claim 1 , wherein the heterologous protein domain comprises a human immunoglobulin Fc domain.
5. A method for inhibiting a humoral immune response by inhibiting LT-β receptor signaling without inhibiting TNF-R signaling in a human subject comprising administering to a human subject a pharmaceutical composition comprising an amount of a soluble human lymphotoxin-β receptor (LTβR) fused to one or more heterologous protein domains, wherein the soluble human LTβR comprises at least one ligand binding domain that can selectively bind to a human surface LT ligand, and a pharmaceutically acceptable carrier, such that a humoral immune response is inhibited by inhibiting human LT-β receptor signaling without inhibiting TNF-R signaling.
6. The method according to claim 5 , wherein the ligand binding domain comprises SEQ ID NO: 1, or a functional fragment thereof encoding an LTβR ligand binding domain.
7. The method according to claim 5 , wherein the heterologous protein domain is selected from the group consisting of immunoglobulins, serum albumin, lipoproteins, apolipoproteins, and transferrin.
8. The method according to claim 5 , wherein the heterologous protein domain comprises a human immunoglobulin Fc domain.
9. A method for disrupting the association of immune complexes and B cell follicles in a human subject comprising administering to the human subject a pharmaceutical composition comprising an amount of a soluble human lymphotoxin-βreceptor (LTβR) fused to one or more heterologous protein domains, wherein the soluble human LTβR comprises at least one ligand binding domain that can selectively bind to a human surface LT ligand, and pharmaceutically acceptable carrier, such that the association of immune complexes and B cell follicles is disrupted.
10. The method according to claim 9 , wherein the ligand binding domain comprises SEQ ID NO: 1, or a functional fragment thereof encoding an LTβR ligand binding domain.
11. The method according claim 9 , wherein the heterologous protein domain is selected from the group consisting of immunoglobulins, serum albumin, lipoproteins, apolipoproteins and transferfin.
12. The method according to claim 9 , wherein the heterologous protein domain comprises a human immunoglobulin Fc domain.
13. A method of treating an antibody-mediated autoimmune disorder in a human subject suffering from an autoimmune disorder, comprising administering to the human subject a pharmaceutical composition comprising an effective amount of a soluble human lymphotoxin-β receptor (LTβ R) fused to one or more heterologous protein domains, wherein the soluble human LTβR comprises at least one ligand binding domain that can selectively bind to a human surface LT ligand, and a pharmaceutically acceptable carrier, such that the antibody-mediated autoimmune disorder is treated.
14. The method of claim 13 , wherein the autoimmune disorder is selected from the group consisting of Myasthenia gravis, autoimmune hemolytic anemia, idiopathic thrombocytopenia purpura (ITP), systemic lupus erythematosus (SLE), Wegener's granulomatosis, poly-arteritis nodosa, and rapidly progressive crescentic glomerulonephritis.
15. The method of claim 13 , wherein the autoimmune disorder is a chronic inflammatory disease.
16. The method of claim 15 , wherein the chronic inflammatory disease is Chagas' disease or Grave's disease.
17. The method according to claim 13 , wherein the ligand binding domain comprises SEQ ID NO: 1, or a functional fragment thereof encoding an LTβR ligand binding domain.
18. The method according to claim 13 , wherein the heterologous protein domain is selected from the group consisting of immunoglobulins, serum albumin, lipoproteins, apolipoproteins, and transferrin.
19. The method according to claim 13 , wherein the heterologous protein domain comprises a human immunoglobulin Fc domain.
20. A method of inhibiting a humoral response in a human subject suffering from a hypersensitivity response, comprising administering to the human subject a pharmaceutical composition comprising an effective amount of a soluble human lymphotoxin-β receptor (LTβR) fused to one or more heterologous protein domains, wherein the soluble human LTβR comprises at least one ligand binding domain that can selectively bind to a human surface LT ligand, and a pharmaceutically acceptable carrier, such that a humoral response is inhibited.
21. The method according to claim 20 , wherein the ligand binding domain comprises SEQ ID NO: 1, or a functional fragment thereof encoding an LTβR ligand binding domain.
22. The method according to claim 20 , wherein the heterologous protein domain is selected from the group consisting of immunoglobulins, serum albumin, lipoproteins, apolipoproteins, and transferrin.
23. The method according to claim 20 , wherein the heterologous protein domain comprises a human immunoglobulin Fc domain.
24. The method of claim 20 , wherein the hypersensitivity response is a type I response.
25. The method of claim 20 , wherein the hypersensitivity response is a type II or type III response.
26. A method of inhibiting a humoral response associated with graft rejection in a human subject comprising administering a pharmaceutical composition comprising an effective amount of a soluble human lymphotoxin-β receptor (LTβR) fused to one or more heterologous protein domains, wherein the soluble human LTβR comprises at least one ligand binding domain that can selectively bind to a human surface LT ligand, and a pharmaceutically acceptable carrier, such that the humoral immune response associated with graft rejection is inhibited.
27. The method according to claim 26 , wherein the ligand binding domain comprises SEQ ID NO: 1, or a functional fragment thereof encoding an LTβR ligand binding domain.
28. The method according to claim 26 , wherein the heterologous protein domain is selected from the group consisting of immunoglobulins, serum albumin, lipoproteins, apolipoproteins, and transferrin.
29. The method according to claim 26 , wherein the heterologous protein domain comprises a human immunoglobulin Fc domain.
30. The method according to claim 1 , wherein the soluble human lymphotoxin-β receptor (LTβR) comprises SEQ ID NO: 1.
31. A method for inhibiting a humoral immune response in a human comprising administering a pharmaceutical composition comprising a soluble human lymphotoxin-beta receptor (LTβR) comprising SEQ ID NO: 1 fused to a human IgG1 Fc domain and a pharmaceutically acceptable carrier, such that the humoral immune response is inhibited.
32. A method for inhibiting a humoral immune response by inhibiting LT-β receptor signaling without inhibiting TNF-R signaling in a human comprising administering a pharmaceutical composition comprising a soluble human lymphotoxin-beta receptor (LTβR) comprising SEQ ID NO: 1 fused to a human IgG1 Fc domain and a pharmaceutically acceptable carrier, such that the humoral immune response is inhibited by inhibiting human LT-β receptor signaling without inhibiting TNF-R signaling.
33. A method for disrupting the association of immune complexes and B cell follicles in a human comprising administering a pharmaceutical composition comprising a soluble human lymphotoxin-beta receptor (LTβR) comprising SEQ ID NO: 1 fused to a human IgG1 Fc domain and a pharmaceutically acceptable carrier, such that the association of immune complexes and B cell follicles is disrupted.
34. The method according to claim 5 wherein the soluble human lymphotoxin-β receptor (LTβR) comprises SEQ ID NO: 1.
35. The method according to claim 9 wherein the soluble human lymphotoxin-β receptor (LTβR) comprises SEQ ID NO: 1.