Merchant, M, Ma, X, Maun, HR, Zheng, Z, Peng, J, Romero, M, Huang, A, Yang, N, Nishimura, M, Greve, J, Santell, L, Zhang, Y, Su, Y, Kaufman, DW, Billeci, KL, Mai, E, Moffat, B, Lim, A, Duenas, ET, Phillips, HS, Xiang, H, Young, JC, Vande Woude, GF, Dennis, MS, Reilly, DE, Schwall, RH, Starovasnik, MA, Lazarus, RA and Yansura, DG (2013) Monovalent antibody design and mechanism of action of onartuzumab, a MET antagonist with anti-tumor activity as a therapeutic agent. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA. E2987-E2996.

Abstract

Binding of hepatocyte growth factor (HGF) to the receptor tyrosine kinase MET is implicated in the malignant process of multiple cancers, making disruption of this interaction a promising therapeutic strategy. However, targeting MET with bivalent antibodies can mimic HGF agonism via receptor dimerization. To address this limitation, we have developed onartuzumab, an Escherichia coliderived, humanized, and affinity-matured monovalent monoclonal antibody against MET, generated using the knob-into-hole technology that enables the antibody to engage the receptor in a one-to-one fashion. Onartuzumab potently inhibits HGF binding and receptor phosphorylation and signaling and has antibody-like pharmacokinetics and antitumor activity. Biochemical data and a crystal structure of a ternary complex of onartuzumab antigen- binding fragment bound to a MET extracellular domain fragment, consisting of the MET Sema domain fused to the adjacent Plexins, Semaphorins, Integrins domain (MET Sema-PSI), and the HGF beta-chain demonstrate that onartuzumab acts specifically by blocking HGF alpha-chain (but not beta-chain) binding to MET. These data suggest a likely binding site of the HGF alpha-chain on MET, which when dimerized leads to MET signaling. Onartuzumab, therefore, represents the founding member of a class of therapeutic monovalent antibodies that overcomes limitations of antibody bivalency for targets impacted by antibody crosslinking

Item Type:	Article
Additional Information:	pubid: 151 nvp_institute: NIBR contributor_address: (Merchant, Zheng, Peng, Romero, Yang, Nishimura, Phillips, Schwall) Departments of Translational Oncology, Genentech, Inc., South San Francisco, CA 94080, United States (Ma, Starovasnik) Departments of Structural Biology, Genentech, Inc., South San Francisco, CA 94080, United States (Maun, Santell, Lazarus) Departments of Early Discovery Biochemistry, Genentech, Inc., South San Francisco, CA 94080, United States (Huang, Dennis, Yansura) Departments of Antibody Engineering, Genentech, Inc., South San Francisco, CA 94080, United States (Greve) Departments of Biomedical Imaging, Genentech, Inc., South San Francisco, CA 94080, United States (Zhang, Su, Kaufman, Vande Woude) Departments of Protein Chemistry, Genentech, Inc., South San Francisco, CA 94080, United States (Billeci, Moffat) Departments of Biochemical and Cellular Pharmacology, Genentech, Inc., South San Francisco, CA 94080, United States (Mai, Young) Departments of Purification Development, Genentech, Inc., South San Francisco, CA 94080, United States (Lim, Duenas) Departments of Pharmacokinetic and Pharmacodynamic Sciences, Genentech, Inc., South San Francisco, CA 94080, United States (Xiang) Departments of Early Stage Cell Culture, Genentech, Inc., South San Francisco, CA 94080, United States (Reilly) Laboratory of Molecular Oncology, Van Andel Research Institute, Grand Rapids, MI 49503, United States (Ma) Department of Structural Chemistry, Novartis Institutes for Biomedical Research, Emeryville, CA 94608, United States (Romero) Department of Pharmacology, Celgene, Inc., San Diego, CA 92121., United States (Huang) Laboratory of Circuit and Behavioral Physiology, RIKEN Brain Science Institute, Wako-shi, Saitama 351-0198, Japan
Date Deposited:	13 Oct 2015 13:12
Last Modified:	13 Oct 2015 13:12
URI:	https://oak.novartis.com/id/eprint/21983