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 platebased 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. Mol Cancer Ther; 13(2); 540-52. Ó2013 AACR.

Phase I Dose-Escalation Study of Onartuzumab as a Single Agent and in Combination with Bevacizumab in Patients with Advanced Solid Malignancies

“…On-treatment biopsies were unavailable to assess pharmacodynamic effects in the tumor directly. However, because the extracellular domain of the MET receptor is shed into circulation and serum was available at multiple time points, we evaluated soluble shed MET levels as a measure of target engagement and peripheral receptor occupancy (24). It is noteworthy that shed MET levels can increase in circulation as a result of complex formation with the drug, which has slower clearance than shed MET alone and could thereby result in an increase in serum-shed MET concentrations.…”

A “Prozone-Like” Effect Influences the Efficacy of the Monoclonal Antibody ABT-700 against the Hepatocyte Growth Factor Receptor

“…Small molecules include selective (Tivatinib, ArQule, MA, USA) [7] and broad spectrum (Cabozatinib, Exelixis, CA, USA [8,9]; Crizotinib, Pfizer, NY, USA [10,11]) kinase inhibitors that also target MET. Biologics targeting multiple aspects of signaling through the HGF-MET axis include the HGF-binding antibody Rilotumumab (Amgen, CA, USA) [12,13] and the one-armed antibody Onartuzumab (Genentech, CA, USA) [14,15] that binds MET. Development of a therapeutic antibody [16] requires that the antigen target should be expressed on the tumor cell surface and differential expression of this target should ideally be at a higher ratio on tumor versus normal tissue.…”

A phase I dose-escalation study of LY2875358, a bivalent MET antibody, given as monotherapy or in combination with erlotinib or gefitinib in Japanese patients with advanced malignancies

“…Circulating MET ECD has been proposed as a surrogate measure of target engagement in studies of MET antibodies [23, 26]. At the doses tested in the current study, MET ECD levels increased from baseline, but there was not a strong dose-dependent relationship between circulating MET ECD and doses of LY2875358.…”