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^*

^*Corresponding author for this work

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

1 Citation (Scopus)

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. 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.

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 - 14 May 2018
Externally published	Yes

Keywords

bispecific antibody
cancer
HER2
HER3
heregulin
MCLA-128
NRG1
PB4188
PI3K/Akt
zenocutuzumab

Access to Document

10.1016/j.ccell.2018.04.003

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{75d0be0612a84a3db9910eb9beeb31fb,

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. 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.",

keywords = "bispecific antibody, cancer, HER2, HER3, heregulin, MCLA-128, NRG1, PB4188, PI3K/Akt, zenocutuzumab",

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",

note = "Funding Information: We would like to thank Leo Price and Maarten Klop at Ocello for their contributions to the 3D in vitro models; Stefan Braam at Pluriomics for his contribution to the cardiomyocyte in vitro experiments; Carsten H. Nielsen and Mette M. Jensen at Minerva Imaging for their contributions to the design and execution of the intracranial ST1360B PDX study; Matt Harris and Amos Hedt at Clarity Pharmaceuticals for their contributions to the in vivo imaging study; U-Protein Express BV for the provision of protein expression facilities; Ron Schackmann for database mining and critical reading of the manuscript; Andres Sirulnik, Ernesto Wasserman, Afrodite Lourbakos, Livio Trusolino, and Eduard Batlle for critical reading of the manuscript; Sally Hill for writing and editing assistance; the European Synchrotron Radiation Facility (ESRF) and the Swiss Light Source (SLS) for the provision of synchrotron radiation facilities; and beamline scientists of the ESRF, SLS, and the European Molecular Biology Laboratory for assistance. Financial support was provided by the ManiFold project (grant no. 317371 ) and the BioStruct-X project (grant no. 283570 ) embedded in the European Union's Seventh Framework Programme ( FP7/2007-2013 ), and by the Eurostars ReBAT project (grant no. E!6121 ). Funding Information: We would like to thank Leo Price and Maarten Klop at Ocello for their contributions to the 3D in vitro models; Stefan Braam at Pluriomics for his contribution to the cardiomyocyte in vitro experiments; Carsten H. Nielsen and Mette M. Jensen at Minerva Imaging for their contributions to the design and execution of the intracranial ST1360B PDX study; Matt Harris and Amos Hedt at Clarity Pharmaceuticals for their contributions to the in vivo imaging study; U-Protein Express BV for the provision of protein expression facilities; Ron Schackmann for database mining and critical reading of the manuscript; Andres Sirulnik, Ernesto Wasserman, Afrodite Lourbakos, Livio Trusolino, and Eduard Batlle for critical reading of the manuscript; Sally Hill for writing and editing assistance; the European Synchrotron Radiation Facility (ESRF) and the Swiss Light Source (SLS) for the provision of synchrotron radiation facilities; and beamline scientists of the ESRF, SLS, and the European Molecular Biology Laboratory for assistance. Financial support was provided by the ManiFold project (grant no. 317371) and the BioStruct-X project (grant no. 283570) embedded in the European Union's Seventh Framework Programme (FP7/2007-2013), and by the Eurostars ReBAT project (grant no. E!6121). Publisher Copyright: {\textcopyright} 2018 Elsevier Inc.",

year = "2018",

month = may,

day = "14",

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

N1 - Funding Information: We would like to thank Leo Price and Maarten Klop at Ocello for their contributions to the 3D in vitro models; Stefan Braam at Pluriomics for his contribution to the cardiomyocyte in vitro experiments; Carsten H. Nielsen and Mette M. Jensen at Minerva Imaging for their contributions to the design and execution of the intracranial ST1360B PDX study; Matt Harris and Amos Hedt at Clarity Pharmaceuticals for their contributions to the in vivo imaging study; U-Protein Express BV for the provision of protein expression facilities; Ron Schackmann for database mining and critical reading of the manuscript; Andres Sirulnik, Ernesto Wasserman, Afrodite Lourbakos, Livio Trusolino, and Eduard Batlle for critical reading of the manuscript; Sally Hill for writing and editing assistance; the European Synchrotron Radiation Facility (ESRF) and the Swiss Light Source (SLS) for the provision of synchrotron radiation facilities; and beamline scientists of the ESRF, SLS, and the European Molecular Biology Laboratory for assistance. Financial support was provided by the ManiFold project (grant no. 317371 ) and the BioStruct-X project (grant no. 283570 ) embedded in the European Union's Seventh Framework Programme ( FP7/2007-2013 ), and by the Eurostars ReBAT project (grant no. E!6121 ). Funding Information: We would like to thank Leo Price and Maarten Klop at Ocello for their contributions to the 3D in vitro models; Stefan Braam at Pluriomics for his contribution to the cardiomyocyte in vitro experiments; Carsten H. Nielsen and Mette M. Jensen at Minerva Imaging for their contributions to the design and execution of the intracranial ST1360B PDX study; Matt Harris and Amos Hedt at Clarity Pharmaceuticals for their contributions to the in vivo imaging study; U-Protein Express BV for the provision of protein expression facilities; Ron Schackmann for database mining and critical reading of the manuscript; Andres Sirulnik, Ernesto Wasserman, Afrodite Lourbakos, Livio Trusolino, and Eduard Batlle for critical reading of the manuscript; Sally Hill for writing and editing assistance; the European Synchrotron Radiation Facility (ESRF) and the Swiss Light Source (SLS) for the provision of synchrotron radiation facilities; and beamline scientists of the ESRF, SLS, and the European Molecular Biology Laboratory for assistance. Financial support was provided by the ManiFold project (grant no. 317371) and the BioStruct-X project (grant no. 283570) embedded in the European Union's Seventh Framework Programme (FP7/2007-2013), and by the Eurostars ReBAT project (grant no. E!6121). Publisher Copyright: © 2018 Elsevier Inc.

PY - 2018/5/14

Y1 - 2018/5/14

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. 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.

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. 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.

KW - bispecific antibody

KW - cancer

KW - HER2

KW - HER3

KW - heregulin

KW - MCLA-128

KW - NRG1

KW - PB4188

KW - PI3K/Akt

KW - zenocutuzumab

UR - http://www.scopus.com/inward/record.url?scp=85046170217&partnerID=8YFLogxK

U2 - 10.1016/j.ccell.2018.04.003

DO - 10.1016/j.ccell.2018.04.003

M3 - Article

AN - SCOPUS:85046170217

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

Other files and links

Fingerprint

Erratum: Unbiased Combinatorial Screening Identifies a Bispecific IgG1 that Potently Inhibits HER3 Signaling via HER2-Guided Ligand Blockade (Cancer Cell (2018) 33(5) (922–936.e10), (S1535610818301740), (10.1016/j.ccell.2018.04.003))

Cite this