We have identified a new role for the matrix enzyme lysyl oxidase–like-2 (LOXL2) in the creation and maintenance of the pathologic microenvironment of cancer and fibrotic disease. Our analysis of biopsies from human tumors and fibrotic lung and liver tissues revealed an increase in LOXL2 in disease-associated stroma and limited expression in healthy tissues. Targeting LOXL2 with an inhibitory monoclonal antibody (AB0023) was efficacious in both primary and metastatic xenograft models of cancer, as well as in liver and lung fibrosis models. Inhibition of LOXL2 resulted in a marked reduction in activated fibroblasts, desmoplasia and endothelial cells, decreased production of growth factors and cytokines and decreased transforming growth factor-β (TGF-β) pathway signaling. AB0023 outperformed the small-molecule lysyl oxidase inhibitor β-aminoproprionitrile. The efficacy and safety of LOXL2-specific AB0023 represents a new therapeutic approach with broad applicability in oncologic and fibrotic diseases.
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We thank S. Lyle for guidance and interpretation of tissue pathology and J. Adamkewicz, S. Lyle, M. Longaker and F. McCormick for their review of this manuscript. We thank G. Rosen and J. Belperio for guidance with bleomycin-induced lung fibrosis studies and G. Gurtner for help with wound-healing study design. We thank J. Tambaoan for program support.
As current or former employees of Arresto BioSciences, V.B.-H., R.S., D.M., S.M., H.M.R., M.O., A.M., M.V., H.G., C.W., C.A.G., A.C.V., B.J., D.B., D.T., A.H., S.O., D.T., P.V.V. & V.S. have an equity stake in the company.
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Barry-Hamilton, V., Spangler, R., Marshall, D. et al. Allosteric inhibition of lysyl oxidase–like-2 impedes the development of a pathologic microenvironment. Nat Med 16, 1009–1017 (2010). https://doi.org/10.1038/nm.2208
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