Compositions and methods of treating fibrotic disorders

• US 20060171943A1
• Filed: 01/31/2006
• Published: 08/03/2006
• Est. Priority Date: 02/01/2005
• Status: Abandoned Application

• Current Assignee: Amgen Inc.
• Original Assignee: Amgen Inc.
• Inventors: Fitzpatrick, David R., Comeau, Michael R.
• Application Number:
  US11/344,379
• Publication Number:
  US 20060171943A1
• Time in Patent Office: Days
• US Class Current: 424/133.100
• CPC Class Codes: A61K 31/7088 Compounds having three or more nucleosides or nucleotides
• CPC Class Codes: A61K 38/1793 for cytokines; for lymphokines; for interferons
• CPC Class Codes: A61K 38/2046 IL-7
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07K 16/24 against cytokines, lymphokines or interferons
• CPC Class Codes: C12N 15/1136 against growth factors, growth regulators, cytokines, lymphokines or hormones
• CPC Class Codes: C12N 2310/11 Antisense
• CPC Class Codes: C12N 2310/14 interfering N.A.

Abstract

The invention provides methods and compositions for reducing or preventing fibrosis in a subject suffering from a fibrotic disorder by administering a therapeutically effective amount of at least one antagonist to the cytokine thymic stromal lymphopoietin to the subject. In one embodiment, the methods and compositions further comprise administering at least one additional antagonist to an additional profibrotic cytokine, growth factor or chemokine.

Claims

1. A method of reducing or preventing fibrosis in a subject suffering from a fibrotic disorder comprising administering a therapeutically effective amount of a thymic stromal lymphopoietin antagonist to the subject.

2. The method of claim 1, wherein the antagonist is a thymic stromal lymphopoietin binding agent.

3. The method of claim 2, wherein the agent is selected from the group consisting of an antagonistic antibody, a peptide or polypeptide binding agent, a soluble thymic stromal lymphopoietin receptor, a soluble IL-7 receptor a/thymic stromal lymphopoietin heterodimer receptor, or a small molecule antagonist, wherein the agent binds to thymic stromal lymphopoietin.

4. The method of claim 3, wherein the antagonist antibody is selected from the group consisting of a human antibody, a humanized antibody, a single chain antibody, or an antibody fragment.

5. The method of claim 3, wherein the peptide or polypeptide binding agent, soluble receptor or soluble heterodimer receptor further comprises an Fc domain.

6. The method of claim 1, wherein the antagonist is a thymic stromal lymphopoietin receptor antagonist.

7. The method of claim 6, wherein the antagonist is selected from the group consisting of an antagonistic antibody, a soluble ligand, and a small molecule, wherein the antagonist binds to the thymic stromal lymphopoietin receptor.

8. The method of claim 7, wherein the antibody is selected from the group consisting of a human antibody, a humanized antibody, single chain antibody, or antibody fragment.

9. The method of claim 7, wherein the soluble ligand further comprises an Fc domain.

10. The method of claim 6, wherein the antagonist is selected from the group consisting of an antagonistic antibody, a soluble ligand, and a small molecule, wherein the antagonist binds to the IL-7 receptor a/thymic stromal lymphoietin receptor heterodimer.

11. The method of claim 10, wherein the antibody selected from the group consisting of a human antibody, a humanized antibody, single chain antibody, or antibody fragment.

12. The method of claim 10, wherein the soluble ligand further comprises an Fc domain.

13. The method of claim 1, wherein the fibrotic disorder is selected from the group consisting of scleroderma, interstitial lung disease, idiopathic pulmonary fibrosis, fibrosis arising from chronic hepatitis B or C, radiation-induced fibrosis, and fibrosis arising from wound healing.

14. The method of claim 1, further comprising administering a second antagonist to a profibrotic cytokine, wherein the cytokine is selected from transforming growth factor β

(TGF-β

), interleukin-4 (IL-4), interleukin-5 (IL-5), interleukin-9 (IL-9), interleukin-13(IL-13), granulocyte/macrophage-colony stimulating factor (GM-CSF), tumor necrosis factor alpha (TNF-α

), interleukin-1 beta (IL-10), connective tissue growth factor (CTGF), interleukin-6 (IL-6), oncostatin M (OS M), platelet derived growth factor (PDGF), monocyte chemotactic protein 1 (CCL2/MCP-1), and pulmonary and activation-regulated chemokine (CCL18/PARC).

15. A pharmaceutical composition for reducing or preventing fibrosis in a subject suffering from a fibrotic disorder comprising a therapeutically effective amount of a thymic stromal lymphopoietin antagonist in admixture with a pharmaceutically acceptable carrier thereof.

16. The composition of claim 15, wherein the antagonist is a thymic stromal lymphopoietin binding agent.

17. The composition of claim 16, wherein the agent is selected from the group consisting of an antagonistic antibody, a peptide or polypeptide binding agent, a soluble thymic stromal lymphopoietin receptor, a soluble IL-7 receptor a/thymic stromal lymphopoietin heterodimer receptor, and a small molecule antagonist, wherein the agent binds to thymic stromal lymphopoietin.

18. The composition of claim 17, wherein the antagonist antibody is selected from the group consisting of a human antibody, a humanized antibody, single-chain antibody, or antibody fragment.

19. The composition of claim 17 wherein the soluble receptor further comprises an Fc domain.

20. The composition of claim 15, wherein the antagonist is a thymic stromal lymphopoietin receptor antagonist.

21. The composition of claim 20, wherein the antagonist is selected from the group consisting of an antagonistic antibody, a soluble ligand, and a small molecule, wherein the antagonist binds to the thymic stromal lymphopoietin receptor.

22. The composition of claim 21 wherein the antagonistic antibody is selected from the group consisting of a human antibody, a humanized antibody, a single chain antibody, or antibody fragment.

23. The composition of claim 21, wherein the soluble ligand further comprises an Fc domain.

24. The composition of claim 20, wherein the antagonist is selected from the group consisting of an antagonistic antibody, a soluble ligand, and a small molecule, wherein the antagonist binds to the IL-7 receptor a/thymic stromal lymphoietin receptor heterodimer.

25. The composition of claim 24, wherein the antagonistic antibody is selected from the group consisting of a human antibody, a humanized antibody, a single chain antibody, or antibody fragment.

26. The composition of claim 24, wherein the soluble ligand further comprises an Fc domain.

27. The composition of claim 15, wherein the fibrotic disorder is selected from the group consisting of scleroderma, interstitial lung disease, idopathic pulmonary fibrosis, liver fibrosis arising from chronic hepatitis B or C infection, radiation-induced fibrosis, and fibrosis arising from wound healing.

28. The composition of claim 15, further comprising a second antagonist to a profibrotic cytokine, wherein the cytokine is selected from transforming growth factor β

(TGF-β

), interleukin-4 (IL4), interleukin-5 (IL-5), interleukin-9 (IL-9), interleukin-13(IL-13), granulocyte/macrophage-colony stimulating factor (GM-CSF), tumor necrosis factor alpha (TNF-α

), interleukin-1 beta (IL-1β

), connective tissue growth factor (CTGF), interleukin-6 (IL-6), oncostatin M (OSM), platelet derived growth factor (PDGF), monocyte chemotactic protein I (CCL2/MCP-1), and pulmonary and activation-regulated chemokine (CCL18/PARC).

29. A method of modulating fibroblast accumulation and collagen deposition in a tissue comprising modulating the amount or activity of thymic stromal lymphopoietin in the tissue.

30. The method of claim 29, wherein the amount of thymic stromal lymphopoietin or thymic stromal lymphopoietin receptor is reduced.

31. The method of claim 30, wherein the amount of thymic stromal lymphopoietin or thymic stromal lymphopoietin receptor is reduced through the use of antisense oligonucleotides or interfering RNA.