title: Nonclinical evaluation of the serum pharmacodynamic biomarkers HGF and shed MET following dosing with the anti-MET monovalent monoclonal antibody onartuzumab.
abstract: Onartuzumab, a humanized, monovalent monoclonal anti-MET antibody, antagonizes MET signaling by inhibiting binding of its ligand, hepatocyte growth factor (HGF). We investigated the effects of onartuzumab on cell-associated and circulating (shed) MET (sMET) and circulating HGF in vitro and nonclinically to determine their utility as pharmacodynamic biomarkers for onartuzumab. Effects of onartuzumab on cell-associated MET were assessed by flow cytometry and immunofluorescence. sMET and HGF were measured in cell supernatants and in serum or plasma from multiple species (mouse, cynomolgus monkey, and human) using plate-based immunoassays. Unlike bivalent anti-MET antibodies, onartuzumab stably associates with MET on the surface of cells without inducing MET internalization or shedding. Onartuzumab delayed the clearance of human xenograft tumor-produced sMET from the circulation of mice, and endogenous sMET in cynomolgus monkeys. In mice harboring MET-expressing xenograft tumors, in the absence of onartuzumab, levels of human sMET correlated with tumor size, and may be predictive of MET-expressing tumor burden. Because binding of sMET to onartuzumab in circulation resulted in increasing sMET serum concentrations due to reduced clearance, this likely renders sMET unsuitable as a pharmacodynamic biomarker for onartuzumab. There was no observed effect of onartuzumab on circulating HGF levels in xenograft tumor-bearing mice or endogenous HGF in cynomolgus monkeys. Although sMET and HGF may serve as predictive biomarkers for MET therapeutics, these data do not support their use as pharmacodynamic biomarkers for onartuzumab.
authors.affiliation: Corresponding Author: Judy C. Young, Department of Biochemical and Cellular Pharmacology, Genentech Inc., 1 DNA Way, MS98, South San Francisco, CA 94080. jyoung@gene.com.
authors.forename: Elaine
authors.initials: E
authors.lastname: Mai
authors.forename: Zhong
authors.initials: Z
authors.lastname: Zheng
authors.forename: Youjun
authors.initials: Y
authors.lastname: Chen
authors.forename: Jing
authors.initials: J
authors.lastname: Peng
authors.forename: Christophe
authors.initials: C
authors.lastname: Severin
authors.forename: Ellen
authors.initials: E
authors.lastname: Filvaroff
authors.forename: Mally
authors.initials: M
authors.lastname: Romero
authors.forename: William
authors.initials: W
authors.lastname: Mallet
authors.forename: Surinder
authors.initials: S
authors.lastname: Kaur
authors.forename: Thomas
authors.initials: T
authors.lastname: Gelzleichter
authors.forename: Ihsan
authors.initials: I
authors.lastname: Nijem
authors.forename: Mark
authors.initials: M
authors.lastname: Merchant
authors.forename: Judy C
authors.initials: JC
authors.lastname: Young
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D015415:Biomarkers / Q000097:blood*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004705:Endocytosis; D005434:Flow Cytometry; D006367:HeLa Cells; D017228:Hepatocyte Growth Factor / Q000097:blood*; D006801:Humans; D007118:Immunoassay / Q000379:methods; D008252:Macaca fascicularis; D008809:Mice, Inbred C3H; D008819:Mice, Nude; D016513:Mice, SCID; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy / Q000473:pathology; D019859:Proto-Oncogene Proteins c-met / Q000097:blood* / Q000235:genetics / Q000276:immunology; D034622:RNA Interference; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D015415:Biomarkers; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met; C584058:onartuzumab