COMPOSITIONS AND METHODS FOR THE TREATMENT OF IMMUNOLOGIC DISORDERS

• US 20080187542A1
• Filed: 12/26/2007
• Published: 08/07/2008
• Est. Priority Date: 12/26/2006
• Status: Active Grant

• Current Assignee: Johns Hopkins University
• Original Assignee: Johns Hopkins University
• Inventors: Chen, Lieping, Tamada, Koji
• Granted Patent: US 8,440,185 B2
• Time in Patent Office: Days
• US Class Current: 424/152.1
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: C07K 16/00 Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies antibodies with enzymatic activity, e.g. abzymes C12N9/0002
• CPC Class Codes: C07K 16/2875 against the NGF/TNF superfamily, e.g. CD70, CD95L, CD153, CD154 against NGF C07K16/22, against TNF C07K16/241
• CPC Class Codes: C07K 2317/73 Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
• CPC Class Codes: C07K 2319/30 Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto

Abstract

Compositions and methods for preventing, reducing or inhibiting immunologic disorders are provided. Suitable compositions include one or more LIGHT-HVEM antagonists. LIGHT-HVEM antagonists include compounds that inhibit, reduce, or block the biological activity or expression of LIGHT and/or HVEM. LIGHT-HVEM antagonists can reduce or inhibit the binding of LIGHT to HVEM, but do not significantly modulate the binding of LTβ to LTβR. Suitable compositions include antibodies and antibody fragments, decoy polypeptides, small molecule inhibitors and inhibitory nucleic acids. Methods for using LIGHT-HVEM antagonists to reduce or inhibit T cell activation and survival are also provided. Therapeutic uses for LIGHT-HVEM antagonists to prevent or treat immunologic diseases and disorders including graft rejection, graft-versus-host disease, inflammatory immune responses, and autoimmune disorders are provided.

Claims

1. A pharmaceutical composition comprising a LIGHT-HVEM antagonist in an amount effective to reduce or inhibit one or more symptoms associated with an immunologic disorder in a host,

wherein the LIGHT-HVEM antagonist does not significantly modulate the binding of LTβ

to LTβ

R.

2. The pharmaceutical composition of claim 1 further comprising an excipient.

3. The pharmaceutical composition of claim 1, wherein the LIGHT-HVEM antagonist reduces or inhibits the binding of LIGHT to HVEM.

4. The pharmaceutical composition of claim 3, wherein the LIGHT-HVEM antagonist is selected from the group consisting of antibodies, polypeptides, small molecules.

5. The pharmaceutical composition of claim 4, wherein the LIGHT-HVEM antagonist is an antibody that specifically binds to the extracellular portion of LIGHT or HVEM.

6. The pharmaceutical composition of claim 5, wherein the antibody is a monoclonal antibody.

7. The pharmaceutical composition of claim 6, wherein the antibody is mAb LBH1.

8. The pharmaceutical composition of claim 4, wherein the LIGHT-HVEM antagonist is a polypeptide that binds to LIGHT or HVEM.

9. The pharmaceutical composition of claim 8, wherein the polypeptide is a soluble fragment of LIGHT or HVEM.

10. The pharmaceutical composition of claim 1, wherein the LIGHT-HVEM antagonist reduces or inhibits the expression of LIGHT or HVEM.

11. The pharmaceutical composition of claim 10, wherein the LIGHT-HVEM antagonist is selected from the group consisting of ribozymes, triplex-forming oligonucleotides (TFOs), antisense DNA, siRNA, and microRNA specific for nucleic acids encoding LIGHT or HVEM.

12. The pharmaceutical composition of claim 1, wherein the immunologic disorder is rejection of a graft or graft-versus-host disease.

13. The pharmaceutical composition of claim 12, wherein the graft is an allograft selected from the group consisting of heart, kidney, liver, lung, pancreas, heart valve, cornea, eye lens, bone marrow tissue or endothelial tissue.

14. The pharmaceutical composition of claim 1, wherein the immunologic disorder is an inflammatory disease or disorder.

15. The pharmaceutical composition of claim 1, wherein the immunologic disorder is an autoimmune disease or disorder.

16. A method for treating an immunologic disorder in a host comprising

administering a LIGHT-HVEM antagonist in an amount effective to reduce or inhibit one or more symptoms associated with an immunologic disorder in a host,

wherein the LIGHT-HVEM antagonist does not significantly modulate the binding of LTβ

to LTβ

R.

17. The method of claim 16, wherein the LIGHT-HVEM antagonist reduces or inhibits the binding of LIGHT to HVEM.

18. The method of claim 17, wherein the LIGHT-HVEM antagonist is selected from the group consisting of antibodies, polypeptides, small molecules.

19. The method of claim 18, wherein the LIGHT-HVEM antagonist is an antibody that specifically binds to the extracellular portion of LIGHT or HVEM.

20. The method of claim 19, wherein the antibody is a monoclonal antibody.

21. The method of claim 20, wherein the antibody is mAb LBH1.

22. The method of claim 17, wherein the LIGHT-HVEM antagonist is a polypeptide that binds to LIGHT or HVEM.

23. The method of claim 22, wherein the polypeptide is a soluble fragment of LIGHT or HVEM.

24. The method of claim 16, wherein the LIGHT-HVEM antagonist reduces or inhibits the expression of LIGHT or HVEM.

25. The method of claim 24, wherein the LIGHT-HVEM antagonist is selected from the group consisting of ribozymes, triplex-forming oligonucleotides (TFOs), antisense DNA, siRNA, and microRNA specific for nucleic acids encoding LIGHT or HVEM.

26. The method of claim 16, wherein the immunologic disorder is rejection of a graft or graft-versus-host disease.

27. The method of claim 26, wherein the graft is an allograft selected from the group consisting of heart, kidney, liver, lung, pancreas, heart valve, cornea, eye lens, bone marrow tissue or endothelial tissue.

28. The method of claim 16, wherein the immunologic disorder is an inflammatory disease or disorder.

29. The method of claim 16, wherein the immunologic disorder is an autoimmune disease or disorder.