Unbiased Combinatorial Screening Identifies a Bispecific IgG1 that Potently Inhibits HER3 Signaling via HER2-Guided Ligand Blockade

Cancer Cell. 2018 May 14;33(5):922-936.e10. doi: 10.1016/j.ccell.2018.04.003.

Abstract

HER2-driven cancers require phosphatidylinositide-3 kinase (PI3K)/Akt signaling through HER3 to promote tumor growth and survival. The therapeutic benefit of HER2-targeting agents, which depend on PI3K/Akt inhibition, can be overcome by hyperactivation of the heregulin (HRG)/HER3 pathway. Here we describe an unbiased phenotypic combinatorial screening approach to identify a bispecific immunoglobulin G1 (IgG1) antibody against HER2 and HER3. In tumor models resistant to HER2-targeting agents, the bispecific IgG1 potently inhibits the HRG/HER3 pathway and downstream PI3K/Akt signaling via a "dock & block" mechanism. This bispecific IgG1 is a potentially effective therapy for breast cancer and other tumors with hyperactivated HRG/HER3 signaling.

Keywords: HER2; HER3; MCLA-128; NRG1; PB4188; PI3K/Akt; bispecific antibody; cancer; heregulin; zenocutuzumab.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Bispecific / administration & dosage*
  • Antibodies, Bispecific / pharmacology
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm / drug effects
  • Drug Screening Assays, Antitumor
  • Humans
  • Immunoglobulin G / administration & dosage*
  • Immunoglobulin G / pharmacology
  • MCF-7 Cells
  • Mice
  • Models, Molecular
  • Neoplasms / drug therapy*
  • Neoplasms / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism
  • Protein Binding / drug effects
  • Proto-Oncogene Proteins c-akt / metabolism
  • Receptor, ErbB-2 / antagonists & inhibitors*
  • Receptor, ErbB-2 / chemistry
  • Receptor, ErbB-3 / chemistry
  • Receptor, ErbB-3 / metabolism*
  • Signal Transduction / drug effects*
  • Xenograft Model Antitumor Assays

Substances

  • Antibodies, Bispecific
  • Immunoglobulin G
  • Phosphatidylinositol 3-Kinases
  • ERBB2 protein, human
  • ERBB3 protein, human
  • Receptor, ErbB-2
  • Receptor, ErbB-3
  • Proto-Oncogene Proteins c-akt