title: Allosteric inhibition of lysyl oxidase-like-2 impedes the development of a pathologic microenvironment.
abstract: 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-beta (TGF-beta) pathway signaling. AB0023 outperformed the small-molecule lysyl oxidase inhibitor beta-aminoproprionitrile. The efficacy and safety of LOXL2-specific AB0023 represents a new therapeutic approach with broad applicability in oncologic and fibrotic diseases.
authors.affiliation: Arresto BioSciences, Palo Alto, California, USA.
authors.forename: Vivian
authors.initials: V
authors.lastname: Barry-Hamilton
authors.forename: Rhyannon
authors.initials: R
authors.lastname: Spangler
authors.forename: Derek
authors.initials: D
authors.lastname: Marshall
authors.forename: Scott
authors.initials: S
authors.lastname: McCauley
authors.forename: Hector M
authors.initials: HM
authors.lastname: Rodriguez
authors.forename: Miho
authors.initials: M
authors.lastname: Oyasu
authors.forename: Amanda
authors.initials: A
authors.lastname: Mikels
authors.forename: Maria
authors.initials: M
authors.lastname: Vaysberg
authors.forename: Haben
authors.initials: H
authors.lastname: Ghermazien
authors.forename: Carol
authors.initials: C
authors.lastname: Wai
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Garcia
authors.forename: Arleene C
authors.initials: AC
authors.lastname: Velayo
authors.forename: Brett
authors.initials: B
authors.lastname: Jorgensen
authors.forename: Donna
authors.initials: D
authors.lastname: Biermann
authors.forename: Daniel
authors.initials: D
authors.lastname: Tsai
authors.forename: Jennifer
authors.initials: J
authors.lastname: Green
authors.forename: Shelly
authors.initials: S
authors.lastname: Zaffryar-Eilot
authors.forename: Alison
authors.initials: A
authors.lastname: Holzer
authors.forename: Scott
authors.initials: S
authors.lastname: Ogg
authors.forename: Dung
authors.initials: D
authors.lastname: Thai
authors.forename: Gera
authors.initials: G
authors.lastname: Neufeld
authors.forename: Peter
authors.initials: P
authors.lastname: Van Vlasselaer
authors.forename: Victoria
authors.initials: V
authors.lastname: Smith
mesh_terms: D000594:Amino Acid Oxidoreductases / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D000629:Aminopropionitrile / Q000494:pharmacology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001943:Breast Neoplasms / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D007783:Lactones / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis / Q000473:pathology / Q000517:prevention & control; D011090:Polyenes / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D014158:Transcription, Genetic; D014162:Transfection; D014183:Transplantation, Heterologous
chemical_list: D000911:Antibodies, Monoclonal; D007783:Lactones; D011090:Polyenes; D034741:RNA, Small Interfering; D000629:Aminopropionitrile; D000594:Amino Acid Oxidoreductases; C119091:LOXL2 protein, human; C485601:Loxl2 protein, mouse
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