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

Publication date: 14 May 2018
Source:Cancer Cell, Volume 33, Issue 5
Author(s): Cecile A.W. Geuijen, Camilla De Nardis, David Maussang, Eric Rovers, Tristan Gallenne, Linda J.A. Hendriks, Therese Visser, Roy Nijhuis, Ton Logtenberg, John de Kruif, Piet Gros, Mark Throsby
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.

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Teaser

Geuijen et al. identify a bispecific IgG1 antibody against HER2 and HER3 using a phenotypic combinatorial screening approach. This antibody potently inhibits the heregulin/HER3 pathway and downstream PI3K/Akt signaling via a "dock & block" mechanism in tumor models resistant to agents targeting HER2.


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