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

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

doi:10.1016/j.ccell.2018.04.003

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

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

Research output: Contribution to journal › Article › Academic › peer-review

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.

Original language	English
Pages (from-to)	922-936.e10
Journal	Cancer Cell
Volume	33
Issue number	5
DOIs	https://doi.org/10.1016/j.ccell.2018.04.003
Publication status	Published - 2018

Keywords

PB4188
bispecific antibody
HER2
HER3
heregulin
NRG1
cancer
MCLA-128
zenocutuzumab
Pl3K/Akt

Access to Document

10.1016/j.ccell.2018.04.003

geuijenFinal published version, 5.37 MBLicence: Taverne

Cite this

Geuijen, C. A. W., De Nardis, C., Maussang, D., Rovers, E., Gallenne, T., Hendriks, L. J. A., Visser, T., Nijhuis, R., Logtenberg, T., de Kruif, J., Gros, P., & Throsby, M. (2018). Unbiased Combinatorial Screening Identifies a Bispecific IgG1 that Potently Inhibits HER3 Signaling via HER2-Guided Ligand Blockade. Cancer Cell, 33(5), 922-936.e10. https://doi.org/10.1016/j.ccell.2018.04.003

@article{cbd48cdd01c84b929d74aaf07f5bbf23,

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

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 = "PB4188, bispecific antibody, HER2, HER3, heregulin, NRG1, cancer, MCLA-128, zenocutuzumab, Pl3K/Akt",

author = "Geuijen, {Cecile A W} and {De Nardis}, Camilla and David Maussang and Eric Rovers and Tristan Gallenne and Hendriks, {Linda J A} and Therese Visser and Roy Nijhuis and Ton Logtenberg and {de Kruif}, John and Piet Gros and Mark Throsby",

year = "2018",

doi = "10.1016/j.ccell.2018.04.003",

language = "English",

volume = "33",

pages = "922--936.e10",

journal = "Cancer Cell",

issn = "1535-6108",

publisher = "Cell Press",

number = "5",

}

Geuijen, CAW, De Nardis, C, Maussang, D, Rovers, E, Gallenne, T, Hendriks, LJA, Visser, T, Nijhuis, R, Logtenberg, T, de Kruif, J, Gros, P & Throsby, M 2018, 'Unbiased Combinatorial Screening Identifies a Bispecific IgG1 that Potently Inhibits HER3 Signaling via HER2-Guided Ligand Blockade', Cancer Cell, vol. 33, no. 5, pp. 922-936.e10. https://doi.org/10.1016/j.ccell.2018.04.003

TY - JOUR

T1 - Unbiased Combinatorial Screening Identifies a Bispecific IgG1 that Potently Inhibits HER3 Signaling via HER2-Guided Ligand Blockade

AU - Geuijen, Cecile A W

AU - De Nardis, Camilla

AU - Maussang, David

AU - Rovers, Eric

AU - Gallenne, Tristan

AU - Hendriks, Linda J A

AU - Visser, Therese

AU - Nijhuis, Roy

AU - Logtenberg, Ton

AU - de Kruif, John

AU - Gros, Piet

AU - Throsby, Mark

PY - 2018

Y1 - 2018

N2 - 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.

AB - 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.

KW - PB4188

KW - bispecific antibody

KW - HER2

KW - HER3

KW - heregulin

KW - NRG1

KW - cancer

KW - MCLA-128

KW - zenocutuzumab

KW - Pl3K/Akt

U2 - 10.1016/j.ccell.2018.04.003

DO - 10.1016/j.ccell.2018.04.003

M3 - Article

C2 - 29763625

SN - 1535-6108

VL - 33

SP - 922-936.e10

JO - Cancer Cell

JF - Cancer Cell

IS - 5

ER -

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

Abstract

Keywords

Access to Document

Fingerprint

Cite this