Methods and compositions for treatment and diagnosis of fibrosis, tumor invasion, angiogenesis, and metastasis

• US 8,658,167 B2
• Filed: 12/06/2012
• Issued: 02/25/2014
• Est. Priority Date: 08/02/2007
• Status: Active Grant

• 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:
  US13/707,495
• Publication Number:
  US 20130095101A1
• Time in Patent Office: 446 Days
• Field of Search: None
• US Class Current: 424/130.1
• 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

Provided are methodology, compositions and kits to prevent and treat diseases associated with abnormal cell proliferation, angiogenesis and fibrosis, using processed lysyl oxidase or lysyl oxidase-like protein inhibitors, LOX inhibitors and LOXL inhibitors, or synergistic combinations of such inhibitors with therapeutic agents. Provided are methods for selecting tumor invasion, angiogenesis and metastasis inhibiting agents, by contacting cells in EMT states with candidate agents and detecting changes in such states; and methods, compositions, and kits for diagnosing or monitoring diseases associated with abnormal cell proliferation, angiogenesis and fibrosis, using molecules or agents specifically recognizing processed LOX or LOXL. Provided are methods, compositions, medical devices, systems and kits for preventing or treating diseases and conditions associated with fibrosis, including pathological cardiovascular conditions and diseases, e.g., hypertension, hypertensive heart disease, myocardial infarction, atherosclerosis, restenosis, liver fibrosis, kidney fibrosis, lung fibrosis, dermal scaring, keloid formation, and Alzheimer'"'"'s disease, with LOX or LOXL inhibitors.

Claims

1. A method of treating fibrosis, comprising:

administering to a human in need thereof a monoclonal anti-lysyl oxidase-like 2 (LOXL2) antibody or antigen-binding fragment thereof, wherein the monoclonal antibody or fragment thereof specifically binds to SEQ ID NO.;

3 or 7.

2. The method of claim 1, wherein the fibrosis is or is associated with cardiac fibrosis, dermal scar formation, keloids, liver fibrosis, lung fibrosis, silicosis, asbestosis, kidney fibrosis, diabetic nephropathy, scleroderma, or glomerulosclerosis.

3. The method of claim 2, wherein the fibrosis is cardiac fibrosis associated with hypertension, hypertensive heart disease, myocardial infarction, atherosclerosis, or restenosis.

4. The method of claim 1, wherein the fibrosis occurs as a complication of haemochromatosis, Wilson'"'"'s disease, alcoholism, schistosomiasis, viral hepatitis, bile duct obstruction, exposure to toxins or a metabolic disorder.

5. The method of claim 2, wherein the fibrosis is lung fibrosis.

6. The method of claim 5, wherein the lung fibrosis is or is associated with idiopathic pulmonary fibrosis (IPF), idiopathic interstitial pneumonia, acute respiratory distress syndrome, cryptogenic fibrosing alveolitis, chronic fibrosing interstitial pneumonia, interstitial lung disease, or diffuse parenchymal lung disease.

7. The method of claim 6, wherein the lung fibrosis is IPF.

8. The method of claim 2, wherein the fibrosis is liver fibrosis.

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

10. The method of claim 1, further comprising administering to the human an anti-neoplastic agent, a chemotherapeutic agent, an anti-angiogenic agent, or an anti-fibrotic agent.

11. The method of claim 1, wherein the antibody or fragment is an inhibitor of LOXL2.

12. The method of claim 1, wherein the antibody or fragment thereof specifically binds to SEQ ID NO.:

3.

13. The method of claim 1, wherein the antibody or fragment thereof specifically binds to SEQ ID NO.:

7.

15. The method of claim 4, wherein the antibody or fragment is an inhibitor of LOXL2.

14. A method of treating fibrosis, comprising:

administering to a human in need thereof a monoclonal anti-LOXL2 antibody or antigen-binding fragment thereof, wherein the monoclonal antibody or fragment thereof specifically binds to SEQ ID NO.;

5.

16. The method of claim 14, wherein the antibody or fragment thereof is humanized or human.

17. The method of claim 14, further comprising administering to the human an anti-neoplastic agent, a chemotherapeutic agent, an anti-angiogenic agent, or an anti-fibrotic agent.

18. The method of claim 14, wherein the fibrosis is lung fibrosis.

19. The method of claim 18, wherein the lung fibrosis is or is associated with idiopathic pulmonary fibrosis (IPF), idiopathic interstitial pneumonia, acute respiratory distress syndrome, cryptogenic fibrosing alveolitis, chronic fibrosing interstitial pneumonia, interstitial lung disease, or diffuse parenchymal lung disease.

20. The method of claim 19, wherein the lung fibrosis is IPF.

21. A method of treating lung fibrosis, comprising:

administering to a human in need thereof a monoclonal anti-LOXL2 antibody or antigen-binding fragment thereof, wherein the antibody or fragment thereof specifically binds to SEQ ID NO.;

3 or 7.

22. The method of claim 21, wherein the antibody or fragment thereof is humanized or human.

23. The method of claim 21, further comprising administering to the human a chemotherapeutic agent, an anti-angiogenic agent, an anti-neoplastic agent, or an anti-fibrotic agent.

24. The method of claim 21, wherein the antibody or fragment is an inhibitor of LOXL2.

25. The method of claim 21, wherein the antibody or fragment thereof specifically binds to SEQ ID NO.:

3.

26. The method of claim 21, wherein the antibody or fragment thereof specifically binds to SEQ ID NO.:

7.

27. A method of treating fibrosis, comprising:

administering to a human in need thereof a monoclonal anti-lysyl oxidase-like 2 (LOXL2) antibody or antigen-binding fragment thereof, wherein the monoclonal antibody or fragment thereof specifically binds to a peptide consisting of SEQ ID NO.;

3 or 7.

28. The method of claim 27, wherein the fibrosis is or is associated with cardiac fibrosis, dermal scar formation, keloids, liver fibrosis, lung fibrosis, silicosis, asbestosis, kidney fibrosis, diabetic nephropathy, scleroderma, or glomerulosclerosis.

29. The method of claim 27, wherein the fibrosis is lung fibrosis.

30. The method of claim 29, wherein the lung fibrosis is idiopathic pulmonary fibrosis (IPF).