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

Abstract

The present disclosure provides innovative methodology and related compositions and kits for preventing and treating various diseases associated with abnormal cell proliferation, angiogenesis and fibrosis, by using an inhibitor of processed forms of lysyl oxidase or lysyl oxidase-like proteins, an inhibitor of LOX and an inhibitor of a LOXL, or a synergistic combination of an inhibitor of LOX or LOXL combined with other therapeutic agents. Also provided are innovative methods for selecting agents that prevent or inhibit tumor invasion, angiogenesis and metastasis, by contacting cells that are in an epithelial-mesenchymal transition (EMT) state with a candidate agent and detecting a change in the EMT state of the cells. Methods and related compositions and kits for diagnosing or monitoring various diseases associated with abnormal cell proliferation, angiogenesis and fibrosis, by using molecules or agents that specifically recognize processed forms of LOX or LOXL are also provided. Also provided herein are methods and related compositions, medical devices, systems and kits for preventing or treating various diseases and conditions associated with fibrosis with compositions comprising inhibitors of LOX or LOXL. Such diseases or conditions include pathological cardiovascular conditions and diseases such as hypertension, hypertensive heart disease, myocardial infarction, atherosclerosis, and restenosis, liver fibrosis, kidney fibrosis, lung fibrosis, dermal scaring, keloid formation, and Alzheimer's disease.

1 .- 94 . (canceled) 
     
     
         95 . A method for diagnosing cancer in a subject, comprising:
 contacting a sample obtained from an individual with an anti-LOXL2 antibody;   detecting the binding of the anti-LOXL2 antibody to an anti-LOXL2 antibody/LOXL2 complex;   wherein an increase in the level of an anti-LOXL2 antibody/LOXL2 complex compared to a reference sample indicates the presence of cancer.   
     
     
         96 . The method of  claim 95 , wherein the sample is sputum, blood, serum, plasma, or urine. 
     
     
         97 . The method of  claim 95 , wherein the cancer is selected from the group consisting of lung cancer, breast cancer, colorectal cancer, pancreatic cancer, prostate cancer, skin cancer, bone cancer, ovarian cancer, liver cancer, anal cancer, bile duct cancer, esophageal cancer, leukemia, lymphoma, bladder cancer, uterine cancer, brain cancer, kidney cancer, cancer of the head and neck, cancer of the stomach, myeloma, testicular cancer, germ cell tumor, neuroendocrine tumor, cervical cancer, and gastrointestinal cancer. 
     
     
         98 . The method of  claim 95 , wherein the cancer is selected from the group consisting of pancreatic, liver, and lung cancers. 
     
     
         99 . The method of  claim 95 , wherein the cancer is a pancreatic cancer. 
     
     
         100 . The method of  claim 95 , wherein the cancer is liver cancer. 
     
     
         101 . The method of  claim 95 , wherein the cancer is lung cancer. 
     
     
         102 . The method of  claim 95 , wherein the cancer is metastatic cancer. 
     
     
         103 . The method of  claim 95 , wherein the anti-LOXL2 antibody binds to any one of SEQ ID NO: 3, 5, 7, 11, or 16. 
     
     
         104 . The method of  claim 95 , wherein anti-LOXL2 antibody binds to both active LOXL2. 
     
     
         105 . The method of  claim 104 , wherein the active LOXL2 is a mature form of LOXL2 after proteolytic processing of the preproprotein. 
     
     
         106 . The method of  claim 95 , wherein the anti-LOXL2 antibody is humanized or human. 
     
     
         107 . The method of  claim 95 , wherein the binding of the anti-LOXL2 antibody to the anti-LOXL2 antibody/LOXL2 complex is detected by enzyme-linked immunosorbent assays (ELISA). 
     
     
         108 . A method for diagnosing cancer metastasis in a subject, comprising:
 contacting a sample obtained from an individual with an anti-LOXL2 antibody;   detecting the binding of the anti-LOXL2 antibody to an anti-LOXL2 antibody/LOXL2 complex;   wherein an increase in the level of an anti-LOXL2 antibody/LOXL2 complex compared to a reference sample indicates the presence of metastatic tumor growth.   
     
     
         109 . The method of  claim 108 , wherein the liquid sample is sputum, blood, serum, plasma, or urine. 
     
     
         110 . The method of  claim 108 , wherein the anti-LOXL2 antibody binds to any one of SEQ ID NO: 3, 5, 7, 11, or 16. 
     
     
         111 . The method of  claim 108 , wherein anti-LOXL2 antibody binds to both active LOXL2. 
     
     
         112 . The method of  claim 111 , wherein the active LOXL2 is a mature form of LOXL2 after proteolytic processing of the preproprotein. 
     
     
         113 . The method of  claim 108 , wherein the anti-LOXL2 antibody is humanized or human. 
     
     
         114 . The method of  claim 108 , wherein the binding of the anti-LOXL2 antibody to the anti-LOXL2 antibody/LOXL2 complex is detected by enzyme-linked immunosorbent assays (ELISA).