Methods for inhibiting lymphotoxin β receptor signalling
View Patent ↗This invention relates to compositions and methods comprising “lymphotoxin-β receptor blocking agents”, which block lymphotoxin-β receptor signalling. Lymphotoxin-β receptor blocking agents are useful for treating lymphocyte-mediated immunological diseases, and more particularly, for inhibiting Th1 cell-mediated immune responses. This invention relates to soluble forms of the lymphotoxin-β receptor extracellular domain that act as lymphotoxin-β receptor blocking agents. This invention also relates to the use of antibodies directed against either the lymphotoxin-β receptor or its ligand, surface lymphotoxin, that act as lymphotoxin-β receptor blocking agents. A novel screening method for selecting soluble receptors, antibodies and other agents that block LT-β receptor signalling is provided.
1. A method for inhibiting lymphotoxin-β-receptor (LT-β-R) signaling in a subject having a Th1 cell-mediated autoimmune disorder comprising administering to the subject a pharmaceutical composition comprising an effective amount of an LT-β-R blocking agent, and a pharmaceutically acceptable carrier, wherein the LT-β-R blocking agent comprises a soluble LT-β-R.
2. The method according to claim 1 , wherein the subject is a human.
3. The method according to claim 1 , wherein the LT-β-R blocking agent comprises a soluble LT-β-R having a ligand binding domain that can selectively bind to a surface LT ligand.
4. The method according to claim 3 , wherein the soluble LT-β-R is administered in an amount sufficient to coat LT-β ligand-positive cells for 1 to 14 days.
5. The method according to claim 1 , wherein the LT-β-R blocking agent comprises a soluble LT-β-R fused to one or more heterologous protein domains.
6. The method according to claim 5 , wherein the pharmaceutical composition is administered to the subject at a dose of about 1 mg/kg.
7. The method according to claim 5 , wherein the pharmaceutical composition is administered to the subject via oral administration.
8. The method according to claim 5 , wherein the pharmaceutical composition is administered to the subject via parenteral administration.
9. The method according to claim 8 , wherein the parenteral administration is subcutaneous.
10. The method according to claim 8 , wherein the parenteral administration is intravenous.
11. The method according to claim 8 , wherein the parenteral administration is intralesional.
12. The method according to claim 5 , wherein the heterologous protein domain further comprises a human immunoglobulin Fc domain.
13. The method according to claim 1 , wherein the autoimmune disorder is selected from the group consisting of psoriasis, diabetes mellitus, multiple sclerosis, sympathetic ophthalmia, and uveitis.
14. The method according to claim 1 , wherein the autoimmune disorder is rheumatoid arthritis.
15. A method for inhibiting lymphotoxin-β receptor (LT-β-R) signaling in a subject having a Th1 cell-mediated autoimmune disorder comprising administering to the subject a pharmaceutical composition comprising an effective amount of an LT-β-R blocking agent comprising a soluble LT-β-R fused to one or more heterologous protein domains, and a pharmaceutically acceptable carrier, wherein the soluble LT-β-R has a ligand binding domain that can selectively bind to a surface LT ligand.
16. The method according to claim 15 , wherein the heterologous protein domain comprises a human immunoglobulin Fc domain.
17. The method according to claim 15 , wherein the soluble LT-β-R comprises a functional sequence of amino acids selected from the amino acids of SEQ ID NO: 1, wherein the functional sequence comprises the LT-β-R ligand binding domain.
18. The method according to claim 17 , wherein the heterologous domain further comprises a human immunoglobulin Fc domain.
19. The method according to claim 18 , wherein the composition is administered to the subject at a dose of about 1 mg/kg.
20. The method according to claim 18 , wherein the composition is administered to the subject via oral administration.
21. The method according to claim 18 , wherein the composition is administered to the subject via parenteral administration.
22. The method according to claim 21 , wherein the parenteral administration is subcutaneous.
23. The method according to claim 21 , wherein the parenteral administration is intravenous.
24. The method according to claim 21 , wherein the parenteral administration is intralesional.
25. The method according to claim 15 , wherein the autoimmune disorder is selected from the group consisting of psoriasis, diabetes mellitus, multiple sclerosis, sympathetic ophthalmia, and uveitis.
26. The method according to claim 15 , wherein the autoimmune disorder is rheumatoid arthritis.
27. The method according to claim 15 , wherein the subject is a human.
28. A method for inhibiting lymphotoxin-β receptor (LT-β-R) signaling in a subject having a Th1 cell-mediated autoimmune disorder comprising administering to the subject a pharmaceutical composition comprising an effective amount of an LT-β-R blocking agent comprising a soluble LT-β-R fused to a heterologous domain comprising a human immunoglobulin Fc domain, and a pharmaceutically acceptable caffier, wherein the soluble LT-β-R comprises a functional sequence of amino acids selected from the amino acids of SEQ ID NO: 1, wherein the functional sequence comprises the LT-β-R ligand binding domain.
29. The method according to claim 28 , wherein the composition is administered to the subject at a dose of about 1 mg/kg.
30. The method according to claim 28 , wherein the composition is administered to the subject via oral administration.
31. The method according to claim 28 , wherein the composition is administered via parenteral administration.
32. The method according to claim 31 , wherein the parenteral administration is subcutaneous.
33. The method according to claim 31 , wherein the parenteral administration is intravenous.
34. The method according to claim 31 , wherein the parenteral administration is intralesional.
35. The method according to claim 28 , wherein the autoimmune disorder is selected from the group consisting of psoriasis, diabetes mellitus, multiple sclerosis, sympathetic ophthalmia, and uveitis.
36. The method according to claim 28 , wherein the autoimmune disorder is rheumatoid arthritis.
37. The method according to claim 28 , wherein the subject is a human.
38. A method for inhibiting lymphotoxin-β-receptor (LT-β-R) signaling in a subject having a Th1 cell-mediated chronic inflammatory disease comprising administering to the subject a pharmaceutical composition comprising an effective amount of an LT-β-R blocking agent, and a pharmaceutically acceptable carrier, wherein the LT-β-R blocking agent comprises a soluble LT-β-R.
39. The method according to claim 38 , wherein the chronic inflammatory disorder is inflammatory bowel disease.
40. The method according to claim 39 , wherein the chronic inflammatory bowel disease is Crohn's disease or ulcerative colitis.
41. The method according to claim 38 , wherein the LT-β-R blocking agent comprises a soluble LT-β-R having a ligand binding domain that can selectively bind to a surface LT ligand.
42. The method according to claim 38 , wherein the soluble LT-β-R comprises a functional sequence of amino acids selected from the amino acids of SEQ ID NO: 1, wherein the functional sequence comprises the LT-β-R ligand binding domain.
43. The method according to claim 38 , wherein the LT-β-R blocking agent comprises a soluble LT-β-R fused to one or more heterologous protein domains.
44. The method according to claim 43 , wherein the heterologous protein domain comprises a human immunoglobulin Fc domain.
45. The method according to claim 38 , wherein the pharmaceutical composition is administered to the subject at a dose of about 1 mg/kg.
46. The method according to claim 38 , wherein the pharmaceutical composition is administered to the subject via oral administration.
47. The method according to claim 38 , wherein the pharmaceutical composition is administered to the subject via parenteral administration.
48. The method according to claim 47 , wherein the parenteral administration is subcutaneous.
49. The method according to claim 47 , wherein the parenteral administration is intravenous.
50. The method according to claim 47 , wherein the parenteral administration is intralesional.
51. The method according to claim 38 , wherein the subject is a human.
52. A method for inhibiting lymphotoxin-β-receptor (LT-β-R) signaling in a subject having a Th1 cell-mediated autoimmune disorder or a Th1 cell-mediated chronic inflammatory disease comprising administering to the subject a pharmaceutical composition comprising an effective amount of an LT-β-R blocking agent, and a pharmaceutically acceptable carrier, wherein the LT-β-R blocking agent comprises an antibody directed against LT-β-R.
53. The method according to claim 52 , wherein the LT-β-R blocking agent comprises a monoclonal antibody directed against LT-β-R.
54. The method according to claim 52 , wherein the autoimmune disorder is selected from the group consisting of psoriasis, diabetes mellitus, multiple sclerosis, sympathetic ophthalmia, rheumatoid arthritis, and uveitis.
55. The method according to claim 52 , wherein the chronic inflammatory disease is inflammatory bowel disease.
56. The method according to claim 55 , wherein the chronic inflammatory disorder is selected from the group consisting of inflammatory bowel disease is Crohn's disease or ulcerative colitis.
57. A method for inhibiting lymphotoxin-β-receptor (LT-β-R) signaling in a human subject having rheumatoid arthritis comprising administering to the human subject a pharmaceutical composition comprising an effective amount of an LT-β-R blocking agent comprising a soluble LT-β-R fused to a heterologous domain comprising a human immunoglobulin Fc domain, and a pharmaceutically acceptable carrier, wherein the soluble LT-β-R comprises a functional sequence of amino acids selected from the amino acids of SEQ ID NO: 1, wherein the functional sequence comprises the LT-β-R ligand binding domain.
58. The method of claim 57 , wherein the pharmaceutical composition is administered to the subject at a dose of about 1 mg/kg.
59. The method of claim 57 , wherein the pharmaceutical composition is administered to the subject at a dose of 1 mg/kg to 5 mg/kg.
60. The method of claim 57 , wherein the pharmaceutical composition is administered to the subject via subcutaneous administration.
61. The method of claim 60 , wherein the pharmaceutical composition is administered to the subject at a dose of about 1 mg/kg.
62. The method of claim 60 , wherein the pharmaceutical composition is administered to the subject at a dose of 1 mg/kg to 5 mg/kg.
63. A method for inhibiting lymphotoxin-β-receptor (LT-β-R) signaling in a human subject having ulcerative colitis comprising administering to the human subject a pharmaceutical composition comprising an effective amount of an LT-β-R blocking agent comprising a soluble LT-β-R fused to a heterologous domain comprising a human immunoglobulin Fc domain, and a pharmaceutically acceptable carrier, wherein the soluble LT-β-R comprises a functional sequence of amino acids selected from the amino acids of SEQ ID NO: 1, wherein the functional sequence comprises the LT-β-R ligand binding domain.
64. The method of claim 63 , wherein the pharmaceutical composition is administered to the subject at a dose of about 1 mg/kg.
65. The method of claim 63 , wherein the pharmaceutical composition is administered to the subject at a dose of 1 mg/kg to 5 mg/kg.
66. The method of claim 63 , wherein the pharmaceutical composition is administered to the subject via subcutaneous administration.
67. The method of claim 66 , wherein the pharmaceutical composition is administered to the subject at a dose of about 1 mg/kg.
68. The method of claim 67 , wherein the pharmaceutical composition is administered to the subject at a dose of 1 mg/kg to 5 mg/kg.
69. A method for inhibiting lymphotoxin-β-receptor (LT-β-R) signaling in a human subject having Crohn's disease comprising administering to the human subject a pharmaceutical composition comprising an effective amount of an LT-β-R blocking agent comprising a soluble LT-β-R fused to a heterologous domain comprising a human immunoglobulin Fc domain, and a pharmaceutically acceptable carrier, wherein the soluble LT-β-R comprises a functional sequence of amino acids selected from the amino acids of SEQ ID NO: 1, wherein the functional sequence comprises the LT-β-R ligand binding domain.
70. The method of claim 69 , wherein the pharmaceutical composition is administered to the subject at a dose of about 1 mg/kg.
71. The method of claim 69 , wherein the pharmaceutical composition is administered to the subject at a dose of 1 mg/kg to 5 mg/kg.
72. The method of claim 69 , wherein the pharmaceutical composition is administered to the subject via subcutaneous administration.
73. The method of claim 72 , wherein the pharmaceutical composition is administered to the subject at a dose of about 1 mg/kg.
74. The method of claim 72 , wherein the pharmaceutical composition is administered to the subject at a dose of 1 mg/kg to 5 mg/kg.