LOX and LOXL2 inhibitors and uses thereof

• US 9,176,139 B2
• Filed: 05/06/2013
• Issued: 11/03/2015
• Est. Priority Date: 08/02/2007
• Status: Expired due to Fees

• Current Assignee: Gilead Biologics, Inc. (Gilead Sciences Inc.)
• Original Assignee: Gilead Biologics, Inc. (Gilead Sciences Inc.)
• Inventors: Smith, Victoria, Ogg, Scott, Van Vlasselaer, Peter, Barry, Vivian E., Marshall, Derek, Holzer, Alison Kay, Rodriguez, Hector, Oyasu, Miho, McCauley, Scott Alan, Garcia, Carlos Aurelio, Biermann, Donna Hiroko Tokuoka
• Primary Examiner(s): Sang, Hong
• Application Number:
  US13/888,293
• Publication Number:
  US 20130324705A1
• Time in Patent Office: 911 Days
• Field of Search: None
• US Class Current: 1/1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• 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 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 13/10 of the bladder
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• 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 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/04 for non-specific disorders of the connective tissue
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/04 : specific for metastasis
• 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: A61P 9/12 : Antihypertensives
• 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
• CPC Class Codes: C07K 2317/30 : characterized by aspects of specificity or valency
• CPC Class Codes: C07K 2317/33 : Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
• CPC Class Codes: C07K 2317/34 : Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
• CPC Class Codes: C07K 2317/565 : Complementarity determining region [CDR]
• CPC Class Codes: C07K 2317/76 : Antagonist effect on antigen, e.g. neutralization or inhibition of binding
• CPC Class Codes: C07K 2317/77 : Internalization into the cell
• CPC Class Codes: C07K 2317/92 : Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
• CPC Class Codes: C12Q 1/6886 : for cancer immunoassay for cancer G01N33/574
• CPC Class Codes: G01N 2333/90633 : with oxygen as acceptor (1.4.3) in general
• CPC Class Codes: G01N 33/57423 : of lung
• CPC Class Codes: G01N 33/57438 : of liver, pancreas or kidney
• CPC Class Codes: G01N 33/57484 : involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites

Abstract

The present application relates to anti-LOX and anti-LOXL2 antibodies and their use in purification, diagnostic and therapeutic methods. Antibodies include monoclonal antibodies, humanized antibodies and functional fragments thereof. Anti-LOX and anti-LOXL2 antibodies can be used to identify and treat conditions such as a fibrotic condition, angiogenesis, or to prevent a transition from an epithelial cell state to a mesenchymal cell state.

Claims

1. A method of treating or inhibiting a fibrosis disease in a human in need thereof comprising, administering to the human an isolated antibody or antigen binding fragment thereof, wherein the antibody or antigen binding fragment thereof specifically binds to human lysyl oxidase-like 2 (LOXL2) protein and comprises a heavy chain variable region complementarity determining regions (CDRs) comprising the amino acid sequences set forth as SEQ ID NOs:

41, 42, and 70, and light chain variable region CDRs comprising the amino acid sequences set forth as SEQ ID NOs;

, 57, 58, and 59.

2. The method of claim 1, wherein the fibrosis disease is selected from the group consisting of a liver fibrosis, a lung fibrosis, a kidney fibrosis, a cardiac fibrosis, and scleroderma.

8. The method of claim 1, wherein the isolated antibody or antigen binding fragment thereof is a Fv, a scFv, a Fab, a F(ab′

)₂, or monoclonal.

9. The method of claim 1, wherein the isolated antibody or antigen binding fragment thereof is humanized.

10. The method of claim 1, wherein the isolated antibody or antigen binding fragment thereof is labeled with a detectable label, a therapeutic agent or both.

11. The method of claim 1, further comprising co-administering a second therapeutic agent.

12. The method of claim 11, wherein the second therapeutic agent is an antibody or an anti-fibrotic agent.

13. The method of claim 12, wherein the anti-fibrotic agent is selected from the group consisting of ethylenediamine, hydrazine, phenylhydrazine, semicarbazide, urea, aminonitriles, beta-aminopropionitrile (BAPN), 2-nitroethylamine, unsaturated or saturated haloamines, 2-bromo-ethylamine, 2-chloroethylamine, 2-trifluoroethylamine, 3-bromopropylamine, p-halobenzylamines, selenohomocysteine lactone, copper chelating agents, thiolamines, D-penicillamine, 2-amino-5-mercapto-5-methylhexanoic acid, D-2-amino-3-methyl-3-((2-acetamidoethyl)dithio)butanoic acid, p-2-amino-3-methyl-3-((2-aminoethyl)dithio)butanoic acid, sodium-4-((p-1-dimethyl-2-amino-2-carboxyethyl)dithio) butane sulphinate, 2-acetamidoethyl-2-acetamidoethanethiol suiphanate, and sodium-4-mercaptobutanesuiphinate trihydrate.

14. The method of claim 1, wherein the human in need thereof is stabilized following administration of the antibody or antigen binding fragment thereof for a period of at least 1 month, 2 months, 3 months, 4 months, 6 months, 1 year, 2 years, or 3 years.

16. The method of claim 1, wherein the fibrosis disease is a kidney fibrosis associated with diabetic nephropathy, vesicoureteral reflux, tubulointerstitial renal fibrosis;

glomerulonephritis, glomerular nephritis including focal segmental glomerulosclerosis and membranous glomerulonephritis, or mesangiocapillary glomerular nephritis.

17. The method of claim 1, wherein the fibrosis disease is a cardiac fibrosis associated with congestive heart failure, cardiomyopathy, post-myocardial infarction defects in heart function, cardiovascular diseases, hypertensive heart disease (HHD), myocardial infarction (MI), atherosclerosis, restenosis, or heart disease associated with cardiac ischemic events.

18. The method of claim 1, wherein the fibrosis disease is a liver fibrosis associated with cirrhosis, chronic viral hepatitis, non-alcoholic fatty liver disease (NAFLD), alcoholic steatohepatitis (ASH), non-alcoholic steatohepatitis (NASH), primary biliary cirrhosis (PBC), biliary cirrhosis, or autoimmune hepatitis.

19. The method of claim 18, wherein the fibrosis disease is the liver fibrosis associated with cirrhosis.

20. The method of claim 18, wherein the fibrosis disease is non-alcoholic steatohepatitis (NASH).

21. The method of claim 18, wherein the fibrosis disease is primary biliary cirrhosis (PBC).

22. The method of claim 18, wherein the antibody or antigen binding fragment thereof comprising the heavy chain variable region comprising the amino acid sequence set forth as SEQ ID NOs:

25, 26, 27, or 28 and a light chain variable region comprising the amino acid sequence set forth as SEQ ID NOs;

30, 31, or 32.

23. The method of claim 18, wherein the antibody or antigen binding fragment thereof is labeled with a detectable label, a therapeutic agent or both.

24. The method of claim 18, wherein the antibody or antigen binding fragment thereof is a Fv, a scFv, a Fab, a F(ab′

)₂, or monoclonal.

25. The method of claim 18, further comprising co-administering a second therapeutic agent.

26. The method of claim 25, wherein said second therapeutic agent is an antibody or an anti-fibrotic agent.

27. The method of claim 1, wherein the fibrosis disease is associate with idiopathic pulmonary fibrosis (IPF), cryptogenic fibrosing alveolitis, chronic fibrosing interstitial pneumonia, interstitial lung disease (ILD), diffuse parenchymal lung disease (DPLD), emphysema and chronic obstructive pulmonary disease (COPD), chronic asthma, idiopathic interstitial pneumonia, or acute respiratory distress syndrome (ARDS).

28. The method of claim 27, wherein the fibrosis disease is idiopathic pulmonary fibrosis (IPF).

29. The method of claim 27, wherein the antibody or antigen binding fragment thereof comprising the heavy chain variable region comprising the amino acid sequence set forth as SEQ ID NOs:

25, 26, 27, or 28 and a light chain variable region comprising the amino acid sequence set forth as SEQ ID NOs;

30, 31, or 32.

30. The method of claim 28, wherein the antibody or antigen binding fragment thereof comprising the heavy chain variable region comprising the amino acid sequence of SEQ ID NO:

27 and the light chain variable region comprising the amino acid sequence of SEQ ID NO;

31.

31. The method of claim 27, wherein the antibody or antigen binding fragment thereof is labeled with a detectable label, a therapeutic agent or both.

32. The method of claim 27, wherein the antibody or antigen binding fragment thereof is a Fv, a soFv, a Fab, a F(ab′

)₂, or monoclonal.

33. The method of claim 27, further comprising co-administering a second therapeutic agent.

34. The method of claim 33, wherein said second therapeutic agent is an antibody or an anti-fibrotic agent.

35. The method of claim 1, wherein the antibody or antigen binding fragment thereof is administered intravenously, intraarterially, intramuscularly, subcutaneously, orally, or topically.

36. The method of claim 1, wherein the antibody or antigen binding fragment thereof is presented in a pharmaceutical composition.

37. The method of claim 30, wherein the antibody or antigen binding fragment thereof is presented in a pharmaceutical composition.

38. The method of claim 37, wherein the pharmaceutical composition is administered intravenously or subcutaneously.

39. The method of claim 20, wherein the antibody or antigen binding fragment thereof comprising the heavy chain variable region comprising the amino acid sequence of SEQ ID NO:

27 and the light chain variable region comprising the amino acid sequence of SEQ ID NO;

31.

40. The method of claim 39, wherein the antibody or antigen binding fragment thereof is presented in a pharmaceutical composition.

41. The method of claim 40, wherein the pharmaceutical composition is administered intravenously or subcutaneously.

42. The method of claim 21, wherein the antibody or antigen binding fragment thereof comprising the heavy chain variable region comprising the amino acid sequence of SEQ ID NO:

27 and the light chain variable region comprising the amino acid sequence of SEQ ID NO;

31.

43. The method of claim 42, wherein the antibody or antigen binding fragment thereof is presented in a pharmaceutical composition.

44. The method of claim 43, wherein the pharmaceutical composition is administered intravenously or subcutaneously.

3. A method of treating or inhibiting a fibrosis disease in a human in need thereof comprising, administering to the human an isolated antibody or antigen binding fragment thereof, wherein the antibody or antigen binding fragment thereof specifically binds to human LOXL2 protein and comprises the heavy chain variable region comprising the amino acid sequence set forth as SEQ ID NOs:

25, 26, 27, or 28.

4. The method of claim 3, wherein the heavy chain variable region comprises the amino acid sequence set forth as SEQ ID NO:

27.

5. The method of claim 3, wherein the antibody antigen binding fragment thereof further comprising a light chain variable region comprising the amino acid sequence set forth as SEQ ID NOs:

30, 31, or 32.

6. The method of claim 5, wherein the light chain variable region comprises the amino acid sequence set forth as SEQ ID NO:

31.

7. The method of claim 5, wherein the isolated antibody or antigen binding fragment thereof comprising the heavy chain variable region comprises the amino acid sequence set forth as SEQ ID NO:

27 and the light chain variable region comprises the amino acid sequence set forth as SEQ ID NO;

31.

15. The method of claim 4, wherein the fibrosis disease is selected from the group consisting of a liver fibrosis, a lung fibrosis, a kidney fibrosis, a cardiac fibrosis and scleroderma.

45. The method of claim 7, wherein the antibody or antigen binding fragment thereof is labeled with a detectable label, a therapeutic agent or both.

46. The method of claim 7, further comprising co-administering a second therapeutic agent.

47. The method of claim 46, wherein said second therapeutic agent is an antibody or an anti-fibrotic agent.

48. The method of claim 7, wherein the antibody or antigen binding fragment thereof is administered intravenously, intraarterially, intramuscularly, subcutaneously, orally, or topically.

49. The method of claim 7, wherein the antibody or antigen binding fragment thereof is presented in a pharmaceutical composition.

50. The method of claim 49, wherein the pharmaceutical composition is administered intravenously or subcutaneously.

51. The method of claim 15, wherein the antibody or antigen binding fragment thereof is presented in a pharmaceutical composition.

52. The method of claim 51, wherein the pharmaceutical composition is administered intravenously or subcutaneously.

53. The method of claim 52, wherein the fibrosis disease is a kidney fibrosis associated with diabetic nephropathy, vesicoureteral reflux, tubulointerstitial renal fibrosis;

glomerulonephritis, glomerular nephritis including focal segmental glomerulosclerosis and membranous glomerulonephritis, or mesangiocapillary glomerular nephritis.

54. The method of claim 52, wherein the fibrosis disease is a cardiac fibrosis associated with congestive heart failure, cardiomyopathy, post-myocardial infarction defects in heart function, cardiovascular diseases, hypertensive heart disease (HHD), myocardial infarction (MI), atherosclerosis, restenosis, or heart disease associated with cardiac ischemic events.

55. The method of claim 52, wherein the fibrosis disease is a liver fibrosis associated with cirrhosis, chronic viral hepatitis, non-alcoholic fatty liver disease (NAFLD), alcoholic steatohepatitis (ASH), non-alcoholic steatohepatitis (NASH), primary biliary cirrhosis (PBC), biliary cirrhosis, or autoimmune hepatitis.

56. The method of claim 55, wherein the fibrosis disease is the liver fibrosis associated with cirrhosis.

57. The method of claim 55, wherein the fibrosis disease is non-alcoholic steatohepatitis (NASH).

58. The method of claim 55, wherein the fibrosis disease is primary biliary cirrhosis (PBC).

59. The method of claim 52, wherein the fibrosis disease is associate with idiopathic pulmonary fibrosis (IPF), cryptogenic fibrosing alveolitis, chronic fibrosing interstitial pneumonia, interstitial lung disease (ILD), diffuse parenchymal lung disease (DPLD), emphysema and chronic obstructive pulmonary disease (COPD), chronic asthma, idiopathic interstitial pneumonia, or acute respiratory distress syndrome (ARDS).

60. The method of claim 59, wherein the fibrosis disease is idiopathic pulmonary fibrosis (IPF).