Details

Autor(en) / Beteiligte

• Geuijen, Cecile A.W.
• De Nardis, Camilla
• Maussang, David
• Rovers, Eric
• Gallenne, Tristan
• Hendriks, Linda J.A.
• Visser, Therese
• Nijhuis, Roy
• Logtenberg, Ton
• de Kruif, John
• Gros, Piet
• Throsby, Mark

Titel

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

Ist Teil von

• Cancer cell, 2018-05, Vol.33 (5), p.922-936.e10

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2018

Link zum Volltext

Quelle

EZB Electronic Journals Library

Beschreibungen/Notizen

• 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. [Display omitted] •Unbiased phenotypic screening identifies bispecific antibody with unique properties•Therapeutic agent that potently and specifically blocks the HRG/HER3 pathway•Dock and block mechanism of action dependent on bispecific format 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.