A two-in-one antibody against HER3 and EGFR has superior inhibitory activity compared with monospecific antibodies

Cancer Cell. 2011 Oct 18;20(4):472-86. doi: 10.1016/j.ccr.2011.09.003.

Abstract

Extensive crosstalk among ErbB/HER receptors suggests that blocking signaling from more than one family member may be essential to effectively treat cancer and limit drug resistance. We generated a conventional IgG molecule MEHD7945A with dual HER3/EGFR specificity by phage display engineering and used structural and mutational studies to understand how a single antigen recognition surface binds two epitopes with high affinity. As a human IgG1, MEHD7945A exhibited dual action by inhibiting EGFR- and HER3-mediated signaling in vitro and in vivo and the ability to engage immune effector functions. Compared with monospecific anti-HER antibodies, MEHD7945A was more broadly efficacious in multiple tumor models, showing that combined inhibition of EGFR and HER3 with a single antibody is beneficial.

MeSH terms

  • Animals
  • Antibodies, Bispecific / chemistry
  • Antibodies, Bispecific / therapeutic use*
  • Antibodies, Bispecific / toxicity
  • Antibodies, Monoclonal / adverse effects
  • Antibodies, Monoclonal / therapeutic use
  • Antibodies, Monoclonal, Humanized
  • Antibody Specificity
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / therapeutic use*
  • Antineoplastic Agents / toxicity
  • Binding Sites, Antibody
  • Binding, Competitive
  • Cetuximab
  • Crystallography, X-Ray
  • Drug Evaluation, Preclinical
  • Drug Resistance, Neoplasm
  • ErbB Receptors / antagonists & inhibitors*
  • ErbB Receptors / chemistry
  • ErbB Receptors / immunology
  • Female
  • Humans
  • Immunoglobulin G / adverse effects
  • Immunoglobulin G / chemistry
  • Immunoglobulin G / therapeutic use*
  • MAP Kinase Signaling System
  • Macaca fascicularis
  • Mice
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt / metabolism
  • Receptor, ErbB-3 / antagonists & inhibitors*
  • Receptor, ErbB-3 / chemistry
  • Receptor, ErbB-3 / immunology
  • Signal Transduction

Substances

  • Antibodies, Bispecific
  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • Antineoplastic Agents
  • Immunoglobulin G
  • MEHD7945A
  • EGFR protein, human
  • ErbB Receptors
  • Receptor, ErbB-3
  • Proto-Oncogene Proteins c-akt
  • Cetuximab

Associated data

  • PDB/3P0V
  • PDB/3P0Y
  • PDB/3P11