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:
HER2; HER3; MCLA-128; NRG1; PB4188; PI3K/Akt; bispecific antibody; cancer; heregulin; zenocutuzumab.
Copyright © 2018 Elsevier Inc. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antibodies, Bispecific / administration & dosage*
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Antibodies, Bispecific / pharmacology
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Cell Line, Tumor
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Drug Resistance, Neoplasm / drug effects
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Drug Screening Assays, Antitumor
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Humans
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Immunoglobulin G / administration & dosage*
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Immunoglobulin G / pharmacology
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MCF-7 Cells
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Mice
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Models, Molecular
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Neoplasms / drug therapy*
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Neoplasms / metabolism
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Phosphatidylinositol 3-Kinases / metabolism
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Protein Binding / drug effects
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Proto-Oncogene Proteins c-akt / metabolism
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Receptor, ErbB-2 / antagonists & inhibitors*
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Receptor, ErbB-2 / chemistry
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Receptor, ErbB-3 / chemistry
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Receptor, ErbB-3 / metabolism*
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Signal Transduction / drug effects*
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Xenograft Model Antitumor Assays
Substances
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Antibodies, Bispecific
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Immunoglobulin G
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Phosphatidylinositol 3-Kinases
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ERBB2 protein, human
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ERBB3 protein, human
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Receptor, ErbB-2
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Receptor, ErbB-3
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Proto-Oncogene Proteins c-akt