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

被引：92

作者：

Geuijen, Cecile A. W. ^{[1
]}

De Nardis, Camilla ^{[2
]}

Maussang, David ^{[1
]}

Rovers, Eric ^{[1
]}

Gallenne, Tristan ^{[1
]}

Hendriks, Linda J. A. ^{[1
]}

Visser, Therese ^{[1
]}

Nijhuis, Roy ^{[1
]}

Logtenberg, Ton ^{[1
]}

de Kruif, John ^{[1
]}

Gros, Piet ^{[2
]}

Throsby, Mark ^{[1
]}

机构：

[1] Merus NV, NL-3584 Utrecht, Netherlands

[2] Univ Utrecht, Fac Sci, Dept Chem, Crystal & Struct Chem,Bijvoet Ctr Biomol Res, NL-3584 Utrecht, Netherlands

来源：

CANCER CELL | 2018年 / 33卷 / 05期

关键词：

GROWTH-FACTOR RECEPTOR; BREAST-CANCER; DOWN-REGULATION; ONCOGENIC UNIT; TRASTUZUMAB; ANTIBODY; ERBB3; THERAPY; CELLS; RESISTANCE;

D O I：

10.1016/j.ccell.2018.04.003

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

收藏

页码：922 / +

页数：25

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