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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Amino Acid Sequence
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Animals
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Antibodies, Monoclonal / chemistry
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Antibodies, Monoclonal / genetics
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Antibodies, Monoclonal / metabolism
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Antibodies, Monoclonal / pharmacology*
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Antibodies, Monoclonal, Humanized / chemistry
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Antibodies, Monoclonal, Humanized / genetics
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Antibodies, Monoclonal, Humanized / pharmacology*
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Crystallography, X-Ray
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Drug Design
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Hepatocyte Growth Factor / chemistry
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Hepatocyte Growth Factor / metabolism
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Hepatocyte Growth Factor / pharmacology
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Humans
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Immunoglobulin Fab Fragments / chemistry
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Immunoglobulin Fab Fragments / genetics
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Immunoglobulin Fab Fragments / pharmacology*
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Mice
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Mice, Inbred BALB C
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Mice, Inbred C3H
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Mice, Nude
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Mice, SCID
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Mice, Transgenic
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Models, Molecular
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Molecular Sequence Data
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Neoplasms / drug therapy*
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Neoplasms / pathology
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Protein Binding / drug effects
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Protein Structure, Tertiary
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Proto-Oncogene Proteins c-met / antagonists & inhibitors*
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Proto-Oncogene Proteins c-met / chemistry
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Proto-Oncogene Proteins c-met / metabolism
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Sequence Homology, Amino Acid
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Xenograft Model Antitumor Assays*
Substances
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Antibodies, Monoclonal
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Antibodies, Monoclonal, Humanized
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Antineoplastic Agents
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Immunoglobulin Fab Fragments
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Hepatocyte Growth Factor
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Proto-Oncogene Proteins c-met
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onartuzumab