title: Monovalent antibody design and mechanism of action of onartuzumab, a MET antagonist with anti-tumor activity as a therapeutic agent.
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.
authors.affiliation: Department of Translational Oncology, Genentech, Inc., South San Francisco, CA 94080, USA. merchant.mark@gene.com
authors.forename: Mark
authors.initials: M
authors.lastname: Merchant
authors.forename: Xiaolei
authors.initials: X
authors.lastname: Ma
authors.forename: Henry R
authors.initials: HR
authors.lastname: Maun
authors.forename: Zhong
authors.initials: Z
authors.lastname: Zheng
authors.forename: Jing
authors.initials: J
authors.lastname: Peng
authors.forename: Mally
authors.initials: M
authors.lastname: Romero
authors.forename: Arthur
authors.initials: A
authors.lastname: Huang
authors.forename: Nai-ying
authors.initials: NY
authors.lastname: Yang
authors.forename: Merry
authors.initials: M
authors.lastname: Nishimura
authors.forename: Joan
authors.initials: J
authors.lastname: Greve
authors.forename: Lydia
authors.initials: L
authors.lastname: Santell
authors.forename: Yu-Wen
authors.initials: YW
authors.lastname: Zhang
authors.forename: Yanli
authors.initials: Y
authors.lastname: Su
authors.forename: Dafna W
authors.initials: DW
authors.lastname: Kaufman
authors.forename: Karen L
authors.initials: KL
authors.lastname: Billeci
authors.forename: Elaine
authors.initials: E
authors.lastname: Mai
authors.forename: Barbara
authors.initials: B
authors.lastname: Moffat
authors.forename: Amy
authors.initials: A
authors.lastname: Lim
authors.forename: Eileen T
authors.initials: ET
authors.lastname: Duenas
authors.forename: Heidi S
authors.initials: HS
authors.lastname: Phillips
authors.forename: Hong
authors.initials: H
authors.lastname: Xiang
authors.forename: Judy C
authors.initials: JC
authors.lastname: Young
authors.forename: George F
authors.initials: GF
authors.lastname: Vande Woude
authors.forename: Mark S
authors.initials: MS
authors.lastname: Dennis
authors.forename: Dorothea E
authors.initials: DE
authors.lastname: Reilly
authors.forename: Ralph H
authors.initials: RH
authors.lastname: Schwall
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Starovasnik
authors.forename: Robert A
authors.initials: RA
authors.lastname: Lazarus
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Yansura
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D015195:Drug Design; D017228:Hepatocyte Growth Factor / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008819:Mice, Nude; D016513:Mice, SCID; D008822:Mice, Transgenic; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011485:Protein Binding / Q000187:drug effects; D017434:Protein Structure, Tertiary; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D007140:Immunoglobulin Fab Fragments; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met; C584058:onartuzumab
keywords: HGFR; MetMAb; OA5D5; scatter factor