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Molecular Cancer Therapeutics
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Large Molecule Therapeutics

Inhibition of Tumor Cell Growth and Cancer Stem Cell Expansion by a Bispecific Antibody Targeting EGFR and HER3

Alexander Rau, Wolfgang S. Lieb, Oliver Seifert, Jonas Honer, Dennis Birnstock, Fabian Richter, Nadine Aschmoneit, Monilola A. Olayioye and Roland E. Kontermann
Alexander Rau
1Institute of Cell Biology and Immunology, University of Stuttgart, Stuttgart, Germany.
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Wolfgang S. Lieb
1Institute of Cell Biology and Immunology, University of Stuttgart, Stuttgart, Germany.
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Oliver Seifert
1Institute of Cell Biology and Immunology, University of Stuttgart, Stuttgart, Germany.
2Stuttgart Research Center Systems Biology (SRCSB), University of Stuttgart, Stuttgart, Germany.
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Jonas Honer
1Institute of Cell Biology and Immunology, University of Stuttgart, Stuttgart, Germany.
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Dennis Birnstock
1Institute of Cell Biology and Immunology, University of Stuttgart, Stuttgart, Germany.
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Fabian Richter
1Institute of Cell Biology and Immunology, University of Stuttgart, Stuttgart, Germany.
2Stuttgart Research Center Systems Biology (SRCSB), University of Stuttgart, Stuttgart, Germany.
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Nadine Aschmoneit
1Institute of Cell Biology and Immunology, University of Stuttgart, Stuttgart, Germany.
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Monilola A. Olayioye
1Institute of Cell Biology and Immunology, University of Stuttgart, Stuttgart, Germany.
2Stuttgart Research Center Systems Biology (SRCSB), University of Stuttgart, Stuttgart, Germany.
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  • For correspondence: monilola.olayioye@izi.uni-stuttgart.de roland.kontermann@izi.uni-stuttgart.de
Roland E. Kontermann
1Institute of Cell Biology and Immunology, University of Stuttgart, Stuttgart, Germany.
2Stuttgart Research Center Systems Biology (SRCSB), University of Stuttgart, Stuttgart, Germany.
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  • For correspondence: monilola.olayioye@izi.uni-stuttgart.de roland.kontermann@izi.uni-stuttgart.de
DOI: 10.1158/1535-7163.MCT-19-1095 Published July 2020
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Abstract

The frequent activation of HER3 signaling as a resistance mechanism to EGFR-targeted therapy has motivated the development of combination therapies that block more than one receptor tyrosine kinase. Here, we have developed a novel tetravalent, bispecific single-chain diabody-Fc fusion protein targeting EGFR and HER3 (also known as ErbB3) that integrates the antigen-binding sites of a humanized version of cetuximab as well as a recently developed anti-HER3 antibody, IgG 3-43. This bispecific antibody combines the binding and neutralizing properties of the parental antibodies, as observed in biochemical and in vitro two-dimensional and three-dimensional cell culture assays, and gave rise to long-lasting growth suppression in a subcutaneous xenograft head and neck tumor model. In triple-negative breast cancer (TNBC) cell lines, treatment with the bispecific antibody inhibited the proliferation and oncosphere formation efficiency driven by HER3 signaling. In an orthotopic MDA-MB-468 tumor model, this translated into antitumor effects superior to those obtained by the parental antibodies alone or in combination and was associated with a reduced number of cells with stem-like properties. These findings demonstrate that the bispecific antibody efficiently blocks not only TNBC proliferation, but also the survival and expansion of the cancer stem cell population, holding promise for further preclinical development.

Footnotes

  • Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

  • Mol Cancer Ther 2020;19:1474–85

  • Received November 22, 2019.
  • Revision received March 12, 2020.
  • Accepted May 8, 2020.
  • Published first May 19, 2020.
  • ©2020 American Association for Cancer Research.
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Molecular Cancer Therapeutics: 19 (7)
July 2020
Volume 19, Issue 7
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Inhibition of Tumor Cell Growth and Cancer Stem Cell Expansion by a Bispecific Antibody Targeting EGFR and HER3
Alexander Rau, Wolfgang S. Lieb, Oliver Seifert, Jonas Honer, Dennis Birnstock, Fabian Richter, Nadine Aschmoneit, Monilola A. Olayioye and Roland E. Kontermann
Mol Cancer Ther July 1 2020 (19) (7) 1474-1485; DOI: 10.1158/1535-7163.MCT-19-1095

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Inhibition of Tumor Cell Growth and Cancer Stem Cell Expansion by a Bispecific Antibody Targeting EGFR and HER3
Alexander Rau, Wolfgang S. Lieb, Oliver Seifert, Jonas Honer, Dennis Birnstock, Fabian Richter, Nadine Aschmoneit, Monilola A. Olayioye and Roland E. Kontermann
Mol Cancer Ther July 1 2020 (19) (7) 1474-1485; DOI: 10.1158/1535-7163.MCT-19-1095
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Molecular Cancer Therapeutics
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