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Inhibition of ErbB3 by a monoclonal antibody that locks the extracellular domain in an inactive configuration

Sangwon Lee1, Etienne B Greenlee1, Joseph R Amick1

  • 1Department of Pharmacology, Yale School of Medicine, New Haven, CT 06520;

Proceedings of the National Academy of Sciences of the United States of America
|October 14, 2015
PubMed

Insights

An antibody targeting ErbB3 (HER3) cancer protein locks it in an inactive state, offering a new therapeutic strategy. This structural insight into ErbB3 inhibition could guide the development of similar antibodies for related cancer-driving receptors.

Area of Science:

  • Molecular Biology
  • Structural Biology
  • Oncology

Background:

  • ErbB3 (HER3) is a receptor tyrosine kinase implicated in various cancers.
  • Unlike other ErbB receptors, ErbB3 possesses a pseudo kinase domain.
  • ErbB3 activation in cancer involves ligand-dependent or ligand-independent mechanisms, often through heterodimerization.

Purpose of the Study:

  • To elucidate the structural basis of ErbB3 inhibition by an antagonistic antibody.
  • To understand the allosteric mechanism by which the antibody neutralizes ErbB3 activity.
  • To explore potential therapeutic applications of this inhibition mechanism in cancer treatment.

Main Methods:

  • X-ray crystallography was used to determine the structure of the antibody fragment (Fab) in complex with the ErbB3 extracellular domain.
  • Structural analysis focused on the antibody's binding epitope and its effect on ErbB3 conformation.

Main Results:

  • The crystal structure revealed that the antibody KTN3379 binds to a unique epitope on ErbB3.
  • This binding induces an allosteric conformational change, locking ErbB3 in an inactive state.
  • The antibody effectively inhibits both ligand-dependent and ligand-independent ErbB3 activation pathways.

Conclusions:

  • The antibody KTN3379 employs a novel allosteric mechanism to inhibit ErbB3.
  • This structural understanding can inform the design of new antibodies targeting ErbB3 and potentially other ErbB family members.
  • The findings support the clinical development of KTN3379 for ErbB3-driven cancers.
Keywords:
cancercell signalingcrystal structuresurface receptortherapeutic antibodies

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