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Updated: Feb 10, 2026

A GPC3-targeting Bispecific Antibody, GPC3-S-Fab, with Potent Cytotoxicity
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Unbiased Combinatorial Screening Identifies a Bispecific IgG1 that Potently Inhibits HER3 Signaling via HER2-Guided

Cecile A W Geuijen1, Camilla De Nardis2, David Maussang1

  • 1Merus NV, 3584 Utrecht, the Netherlands.

Cancer Cell
|May 16, 2018
PubMed

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:
HER2HER3MCLA-128NRG1PB4188PI3K/Aktbispecific antibodycancerheregulinzenocutuzumab

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