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.