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Methods and Compositions Inhibiting a Lysyl Oxidase (-Like) Protein for Treatment and Diagnosis of Fibrosis, Tumor Invasion, Angiogenesis, and Metastasis

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Methods and Compositions Inhibiting a Lysyl Oxidase (-Like) Protein for Treatment and Diagnosis of Fibrosis, Tumor Invasion, Angiogenesis, and Metastasis (19) TZZ 54¥¥9A T (11) EP 2 543 389 A2 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: 09.01.2013 Bulletin 2013/02 A61K 39/395 (2006.01) A61P 35/00 (2006.01) C07K 16/40 (2006.01) (21) Application number: 12172214.4 (22) Date of filing: 01.08.2008 (84) Designated Contracting States: • Van Vlasselaer, Peter AT BE BG CH CY CZ DE DK EE ES FI FR GB GR Foster City, CA 94404 (US) HR HU IE IS IT LI LT LU LV MC MT NL NO PL PT • Barry, Vivian E. RO SE SI SK TR Foster City, CA 94404 (US) • Marshall, Derek (30) Priority: 02.08.2007 US 963214 P Foster City, CA 94404 (US) 02.08.2007 US 963246 P • Holzer, Alison Kay 02.08.2007 US 963282 P Foster City, CA 94404 (US) 02.08.2007 US 963249 P • Rodriguez, Hector 02.08.2007 US 963248 P Foster City, CA 94404 (US) • Oyasu, Miho (62) Document number(s) of the earlier application(s) in Foster City, CA 94404 (US) accordance with Art. 76 EPC: • McCauley, Scott Alan 08795003.6 / 2 182 981 Foster City, CA 94404 (US) (71) Applicant: Gilead Biologics, Inc. (74) Representative: Brasnett, Adrian Hugh Foster City, CA 94404 (US) Mewburn Ellis LLP 33 Gutter Lane (72) Inventors: London EC2V 8AS (GB) • Smith, Victoria Foster City, CA 94404 (US) Remarks: • Garcia, Carlos Aurelio •This application was filed on 15-06-2012 as a Foster City, CA 94404 (US) divisional application to the application mentioned • Biermann, Donna Hiroko Tokuoka under INID code 62. Foster City, CA 94404 (US) •Claims filed after the date of filing of the application • Ogg, Scott / after the date of receipt of the divisional application Foster City, CA 94404 (US) (Rule 68(4) EPC). (54) Methods and compositions inhibiting a lysyl oxidase (-like) protein for treatment and diagnosis of fibrosis, tumor invasion, angiogenesis, and metastasis (57) The present disclosure provides innovative with abnormal cell proliferation, angiogenesis and fibro- methodology and related compositions and kits for pre- sis, by using molecules or agents that specifically recog- venting and treating various diseases associated with nize processed forms of LOX or LOXL are also provided. abnormal cell proliferation, angiogenesis and fibrosis, by Also provided herein are methods and related composi- using an inhibitor of processed forms of lysyl oxidase or tions, medical devices, systems and kits for preventing lysyl oxidase-like proteins, an inhibitor of LOX and an or treating various diseases and conditions associated inhibitor of a LOXL, or a synergistic combination of an with fibrosis with compositions comprising inhibitors of inhibitor of LOX or LOXL combined with other therapeutic LOX or LOXL. Such diseases or conditions include path- agents. Also provided are innovative methods for select- ological cardiovascular conditions and diseases such as ing agents that prevent or inhibit tumor invasion, angio- hypertension, hypertensive heart disease, myocardial in- genesis and metastasis, by contacting cells that are in farction, atherosclerosis, and restenosis, liver fibrosis, an epithelial-mesenchymal transition (EMT) state with a kidney fibrosis, lung fibrosis, dermal scaring, keloid for- candidate agent and detecting a change in the EMT state mation, and Alzheimer’s disease. of the cells. Methods and related compositions and kits for diagnosing or monitoring various diseases associated EP 2 543 389 A2 Printed by Jouve, 75001 PARIS (FR) (Cont. next page) EP 2 543 389 A2 2 EP 2 543 389 A2 Description CROSS-REFERENCE 5 [0001] Thisapplication claimsthe benefit ofU.S. ProvisionalApplication No. 60/963,282,entitled "Methods for Selecting Inhibitors of Tumor Invasion, Angiogenesis, and Metastasis," filed August 2, 2007 (Attorney Docket No. 35120-704.101); U.S. Provisional Application No. 60/963,249, entitled "Treatment of Diseases With Inhibitors of Active Lysyl Oxidase," filed August 2, 2007 (Attorney Docket No. 35120-706.101); U.S. Provisional Application No. 60/963,214, entitled "Treat- ment of Diseases Through Inhibition of Both Lysyl Oxidase and Lysyl Oxidase-Like Proteins," filed August 2, 2007 10 (Attorney Docket No. 35120-706.102); U.S. Provisional Application No. 60/963,248, entitled "Diagnosis or Monitoring of Diseases by Assessing Active Lysyl Oxidase Levels or Activity," filed August 2, 2007 (Attorney Docket No. 35120-706.103); and U.S. Provisional Application No. 60/963,246, entitled "Combination Therapy Including Lysyl Oxi- dase Modulators," filed August 2, 2007 (Attorney Docket No. 35120-707.101), and is related to co- pending U.S. Patent Application entitled "LOX and LOXL2 Inhibitors and Uses Thereof" (Attorney Docket No. 35120-715.201), filed August 15 1, 2008, Serial No. _____, and PCT Patent Application entitled "LOX and LOXL2 Inhibitors and Uses Thereof" (Attorney Docket No. 35120-715.601), filed August 1, 2008, Serial No. _____, each of which applications is incorporated herein in its entirety by reference. BACKGROUND 20 1. Cancer [0002] Cancer is a serious public health problem in the United States and other developed countries. Currently, one in four deaths in the United States is due to cancer. Cancer therapy involves treating patients with chemotherapeutic 25 drugs to kill tumor cells. However, subsets of tumor cells are frequently resistant to drug therapy and survive to re- populate at sites of origin and at distant metastatic sites, leading to detectable disease recurrence and morbidity. Many carcinoma tumor cells that have the properties of increased invasive and metastatic capacity, and altered drug resistance, are thought to have undergone a morphological transformation encompassing or similar to EMT (epithelial- mesenchymal transition). Cells undergoing EMT lose the normal adhesive properties of epithelial cells and undergo a spectrum of 30 changes including loss of E- cadherin expression and expression of mesenchymal markers, increased motility, increased invasiveness, and increased resistance to cell death. [0003] The leading therapies for cancer are currently surgery, radiation and chemotherapy. Chemotherapeutic ap- proaches such as antitumor antibiotics, alkylating agents, nitrosourea compounds, vinca alkaloids, steroid hormones, and anti-metabolites form the bulk of therapies available to oncologists. Despite advances in the field of cancer treatment, 35 cancer remains a major health problem. 2. Angiogenesis [0004] Angiogenesis, the formation of new blood vessels out of pre-existing capillaries, is a sequence of events that 40 is of key importance in a broad array of physiologic and pathologic processes. Normal tissue growth, such as in embryonic development, wound healing, and the menstrual cycle, is characterized by dependence on new vessel formation for the supply of oxygen and nutrients as well as removal of waste products. A large number of different and unrelated diseases are also associated with formation of new vasculature. Among certain pathologies are conditions in which angiogenesis is low, and should be enhanced to improve disease conditions. More frequently, however, excessive angiogenesis is 45 an important characteristic of various pathologies, including pathologies characterized or associated with an abnormal or uncontrolled proliferation of cells. Pathologies which involve excessive angiogenesis include, for example, cancer (both solid and hematologic tumors), cardiovascular diseases (such as atherosclerosis and restenosis), chronic inflam- mation (rheumatoid arthritis, Crohn’s disease), diabetes (diabetic retinopathy), psoriasis, endometriosis, neovascular glaucoma and adiposity. These conditions may benefit from chemotherapeutic inhibition of angiogenesis. 50 [0005] Generally speaking, the angiogenic process entails the proliferation and migration of a normally quiescent endothelium, the controlled proteolysis of the pericellular matrix, and the synthesis of new extracellular matrix components by developing capillaries. The establishment of new intra- and intercellular contacts and the morphological differentiation of endothelial cells to capillary- like tubular networks provide support for their subsequent maturation, branching, remod- eling and selective regression to form a highly organized, functional microvascular network. The autocrine, paracrine 55 and amphicrine interactions of the vascular endothelium with its surrounding stromal components, as well as with the pro-angiogenic and angiostatic cytokines and growth factors orchestrating physiologic angiogenesis, are normally tightly regulated both spatially and temporally. [0006] Angiogenesis is crucial to the growth of neoplastic tissues. For more than 100 years, tumors have been observed 3 EP 2 543 389 A2 to be more vascular than normal tissues. Several experimental studies have suggested that both primary tumor growth and metastasis require neovascularization. In contrast to the well orchestrated process described above for normal tissue growth, the pathologic angiogenesis necessary for active tumor growth is generally sustained and persistent, with the initial acquisition of the angiogenic phenotype being a common mechanism for the development of a variety of solid 5 and hematopoietic tumor types. Tumors that are unable to recruit and sustain a vascular network typically remain dormant as asymptomatic lesions in situ. Metastasis is also angiogenesis- dependent: for a tumor cell to metastasize successfully, it generally gains access to the vasculature in the primary tumor, survive the circulation, arrest in the microvasculature of the target organ, exit from this vasculature, grow in the target organ, and induce angiogenesis at the
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