METHODS AND COMPOSITIONS FOR TREATMENT OF PULMONARY FIBROTIC DISORDERS

• US 20110044981A1
• Filed: 08/20/2010
• Published: 02/24/2011
• Est. Priority Date: 08/21/2009
• Status: Abandoned Application

• Current Assignee: Gilead Biologics, Inc. (Gilead Sciences Inc.)
• Original Assignee: Gilead Biologics, Inc. (Gilead Sciences Inc.)
• Inventors: SPANGLER, Rhyannon, SMITH, Victoria
• Application Number:
  US12/860,834
• Publication Number:
  US 20110044981A1
• Time in Patent Office: Days
• US Class Current: 424/133.1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 49/0008 Screening agents using (non-human) animal models or transgenic animal models or chimeric hosts, e.g. Alzheimer disease animal model, transgenic model for heart failure
• CPC Class Codes: A61K 49/0047 Green fluorescent protein [GFP]
• 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 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07K 16/40 against enzymes
• CPC Class Codes: C07K 2317/24 containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered

Abstract

Disclosed herein are methods and compositions for preventing and treating pulmonary fibrotic disorders, and for reducing or reversing the symptoms of pulmonary fibrotic disorders, such as idiopathic pulmonary fibrosis. The compositions include inhibitors of the LOXL2 protein, and the methods include methods for making and using the inhibitors.

Claims

1. A method for the prevention of a pulmonary fibrotic disorder in a subject, the method comprising administering to the subject an inhibitor of the activity of the lysyl oxidase-related-2 protein (LOXL2).

2. The method of claim 1, wherein the pulmonary fibrotic disorder is selected from the group consisting of interstitial pneumonia, acute respiratory distress syndrome (ARDS) and idiopathic pulmonary fibrosis (IPF).

3. The method of claim 1, wherein the inhibitor is an antibody to LOXL2.

4. The method of claim 3, wherein the antibody comprises heavy chain sequences as set forth in SEQ ID NO:

1 and light chain sequences as set forth in SEQ ID NO;

2.

5. The method of claim 3, wherein the antibody is a humanized antibody.

6. The method of claim 5, wherein the antibody comprises heavy chain sequences as set forth in SEQ ID NO:

3 and light chain sequences as set forth in SEQ ID NO;

4.

7. A method for the treatment of a pulmonary fibrotic disorder in a subject, the method comprising administering to the subject an inhibitor of the activity of the lysyl oxidase-related-2 protein (LOXL2).

8. The method of claim 7, wherein the pulmonary fibrotic disorder is selected from the group consisting of interstitial pneumonia, acute respiratory distress syndrome (ARDS) and idiopathic pulmonary fibrosis (IPF).

9. The method of claim 7, wherein the inhibitor is an antibody to LOXL2.

10. The method of claim 9, wherein the antibody comprises heavy chain sequences as set forth in SEQ ID NO:

1 and light chain sequences as set forth in SEQ ID NO;

2.

11. The method of claim 9, wherein the antibody is a humanized antibody.

12. The method of claim 11, wherein the antibody comprises heavy chain sequences as set forth in SEQ ID NO:

3 and light chain sequences as set forth in SEQ ID NO;

4.

13. A method for reversing the symptoms of a pulmonary fibrotic disorder in a subject, the method comprising administering to the subject an inhibitor of the activity of the lysyl oxidase-related-2 protein (LOXL2).

14. The method of claim 13, wherein the pulmonary fibrotic disorder is selected from the group consisting of interstitial pneumonia, acute respiratory distress syndrome (ARDS) and idiopathic pulmonary fibrosis (IPF).

15. The method of claim 13, wherein the inhibitor is an antibody to LOXL2.

16. The method of claim 15, wherein the antibody comprises heavy chain sequences as set forth in SEQ ID NO:

1 and light chain sequences as set forth in SEQ ID NO;

2.

17. The method of claim 15, wherein the antibody is a humanized antibody.

18. The method of claim 17, wherein the antibody comprises heavy chain sequences as set forth in SEQ ID NO:

3 and light chain sequences as set forth in SEQ ID NO;

4.

19. The method of claim 13, wherein the symptom is selected from the group consisting of decreased body weight, increased lung weight, fibrosis, lung architecture, increased Ashcroft score, increased pulmonary collagen levels, and increased number of CD45⁺/collagen⁺ cells.

20. The method of claim 13, wherein the symptom is an increased level of one or more molecules selected from the group consisting of LOXL2, α

-smooth muscle actin (α

-SMA), transforming growth factor β

-1 (TGFβ

-1), stromal derived factor-1α

(SDF-1α

), endothelin-1 (ET-1) and phosphorylated SMAD2.

21. The method of claim 13, wherein the symptom is increased leukocyte number in bronchioalveolar lavage (BAL) fluid.

22. A pharmaceutical composition for the prevention or treatment of a pulmonary fibrotic disorder, or for reversing the symptoms of a pulmonary fibrotic disorder in a subject, wherein the composition comprises an inhibitor of the activity of the lysyl oxidase-related-2 protein (LOXL2) and a pharmaceutically acceptable excipient.

23. The composition of claim 22, wherein the pulmonary fibrotic disorder is selected from the group consisting of interstitial pneumonia, acute respiratory distress syndrome (ARDS) and idiopathic pulmonary fibrosis (IPF).

24. The composition of claim 22, wherein the inhibitor is an antibody to LOXL2.

25. The composition of claim 24, wherein the antibody comprises heavy chain sequences as set forth in SEQ ID NO:

1 and light chain sequences as set forth in SEQ ID NO;

2.

26. The composition of claim 24, wherein the antibody is a humanized antibody.

27. The composition of claim 26, wherein the antibody comprises heavy chain sequences as set forth in SEQ ID NO:

3 and light chain sequences as set forth in SEQ ID NO;

4.

28. The composition of claim 22, wherein the symptom is selected from the group consisting of decreased body weight, increased lung weight, fibrosis, lung architecture, increased Ashcroft score, increased pulmonary collagen levels, and increased number of CD45⁺/collagen⁺ cells.

29. The composition of claim 22, wherein the symptom is an increased level of one or more molecules selected from the group consisting of LOXL2, α

-smooth muscle actin (α

-SMA), transforming growth factor β

-1 (TGFβ

-1), stromal derived factor-1α

(SDF-1α

), endothelin-1 (ET-1) and phosphorylated SMAD2.

30. The composition of claim 22, wherein the symptom is increased leukocyte number in bronchioalveolar lavage (BAL) fluid.

31. A method for diagnosing a pulmonary fibrotic disorder in a subject, the method comprising:

(a) obtaining a sample of pulmonary tissue from the subject; and

(b) determining the levels of LOXL2 in the sample;

wherein an increased level of LOXL2 in the sample, compared to a control sample, indicates the existence of a pulmonary fibrotic disorder.

32. The method of claim 31, wherein the pulmonary fibrotic disorder is selected from the group consisting of interstitial pneumonia, acute respiratory distress syndrome (ARDS) and idiopathic pulmonary fibrosis (IPF).

33. The method of claim 31, wherein the levels of LOXL2 in the sample are determined by contacting the sample with an antibody to LOXL2, so as to allow the formation of a complex between the antibody and the LOXL2 in the sample, and measuring the amount of complex that is formed.

34. The method of claim 33, wherein the antibody comprises heavy chain sequences as set forth in SEQ ID NO:

1 and light chain sequences as set forth in SEQ ID NO;

2.

35. The method of claim 33, wherein the antibody is a humanized antibody.

36. The method of claim 35, wherein the antibody comprises heavy chain sequences as set forth in SEQ ID NO:

3 and light chain sequences as set forth in SEQ ID NO;

4.

37. A method for monitoring a subject'"'"'s response to a therapy for treating a pulmonary fibrotic disorder, the method comprising:

(a) obtaining a sample of pulmonary tissue from the subject; and

(b) determining the levels of LOXL2 in the sample;

wherein a decreased level of LOXL2 in the sample, compared to a control sample, indicates an amelioration of the pulmonary fibrotic disorder.

38. The method of claim 37, wherein the pulmonary fibrotic disorder is selected from the group consisting of interstitial pneumonia, acute respiratory distress syndrome (ARDS) and idiopathic pulmonary fibrosis (IPF).

39. The method of claim 37, wherein the levels of LOXL2 in the sample are determined by contacting the sample with an antibody to LOXL2, so as to allow the formation of a complex between the antibody and the LOXL2 in the sample, and measuring the amount of complex that is formed.

40. The method of claim 39, wherein the antibody comprises heavy chain sequences as set forth in SEQ ID NO:

1 and light chain sequences as set forth in SEQ ID NO;

2.

41. The method of claim 39, wherein the antibody is a humanized antibody.

42. The method of claim 41, wherein the antibody comprises heavy chain sequences as set forth in SEQ ID NO:

3 and light chain sequences as set forth in SEQ ID NO;

4.

43. The method of claim 37, wherein the treatment comprises administering, to the subject, an inhibitor of LOXL2.

44. The method of claim 43, wherein the inhibitor is an antibody.

45. The method of claim 44, wherein the inhibitor comprises heavy chain sequences as set forth in SEQ ID NO:

1 and light chain sequences as set forth in SEQ ID NO;

2.

46. The method of claim 44, wherein the inhibitor is a humanized antibody.

47. The method of claim 46, wherein the inhibitor comprises heavy chain sequences as set forth in SEQ ID NO:

3 and light chain sequences as set forth in SEQ ID NO;

4.