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

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10.1016/j.ccell.2018.04.003

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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 - https://www.scopus.com/pages/publications/85046170217

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

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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))

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