Reference Detail

Ref Type

Journal Article

PMID

(23882082)

Authors

Merchant M, Ma X, Maun HR, Zheng Z, Peng J, Romero M, Huang A, Yang NY, Nishimura M, Greve J, Santell L, Zhang YW, 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, Yansura DG

Title

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

Journal	Vol	Issue	Date	Pages	Journal Short Title
Proceedings of the National Academy of Sciences of the United States of America	110	32	2013 Aug 06	E2987-96	Proc Natl Acad Sci U S A

URL

Abstract Text

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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
Onartuzumab	Onartuzumab	0	2

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
Onartuzumab		MetMAb\|RO5490258\|OA-5D5	MET Antibody 28	Onartuzumab is a monovalent antibody that binds MET and inhibits MET/HGF signaling, potentially resulting in decreased tumor growth (PMID: 23882082, PMID: 30472556).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References