2. Academic Validation
  3. Monovalent antibody design and mechanism of action of onartuzumab, a MET antagonist with anti-tumor activity as a therapeutic agent

Monovalent antibody design and mechanism of action of onartuzumab, a MET antagonist with anti-tumor activity as a therapeutic agent

  • Proc Natl Acad Sci U S A. 2013 Aug 6;110(32):E2987-96. doi: 10.1073/pnas.1302725110.
Mark Merchant 1,  Xiaolei Ma,  Henry R Maun,  Zhong Zheng,  Jing Peng,  Mally Romero,  Arthur Huang,  Nai-ying Yang,  Merry Nishimura,  Joan Greve,  Lydia Santell,  Yu-Wen Zhang,  Yanli Su,  Dafna W Kaufman,  Karen L Billeci,  Elaine Mai,  Barbara Moffat,  Amy Lim,  Eileen T Duenas,  Heidi S Phillips,  Hong Xiang,  Judy C Young,  George F Vande Woude,  Mark S Dennis,  Dorothea E Reilly,  Ralph H Schwall,  Melissa A Starovasnik,  Robert A Lazarus,  Daniel G Yansura
Affiliations

Affiliation

  • 1 Department of Translational Oncology, Genentech, Inc., South San Francisco, CA 94080, USA. merchant.mark@gene.com
PMID: 23882082 DOI: 10.1073/pnas.1302725110
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 coli-derived, 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 β-chain demonstrate that onartuzumab acts specifically by blocking HGF α-chain (but not β-chain) binding to MET. These data suggest a likely binding site of the HGF α-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.

Keywords

HGFR; MetMAb; OA5D5; scatter factor.

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