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.