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Validated Immunochemical Assay for Comprehensive Determination of the Human Epidermal Growth Factor Receptor 2 Released from and Bound to Cells
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A combination of two antibodies recognizing non-overlapping epitopes of HER2 induces kinase activity-dependent

Monika Szymanska1,2, Anne M Fosdahl1,2, Filip Nikolaysen1,2

  • 1Department of Pathology, Oslo University Hospital, Oslo, Norway.

Journal of Cellular and Molecular Medicine
|July 30, 2016
PubMed

Insights

A combination of two antibodies targeting human epidermal growth factor receptor 2 (HER2) effectively triggers its internalization and degradation, offering a promising cancer treatment strategy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Immunology

Background:

  • Human epidermal growth factor receptor 2 (HER2/ErbB2) overexpression is common in human cancers.
  • HER2's resistance to endocytic down-regulation and role as a heterodimerization partner contribute to its oncogenic potential.

Purpose of the Study:

  • To investigate the effect of a mixture of two monoclonal antibodies against non-overlapping HER2 epitopes on HER2 localization and stability.
  • To understand the mechanisms of antibody-mediated HER2 internalization and degradation.

Main Methods:

  • Treatment of cells with individual and combined monoclonal antibodies against HER2.
  • Analysis of HER2 localization, stability, phosphorylation, and ubiquitination.
  • Assessment of HER2 kinase activity's role in down-regulation.

Main Results:

  • Individual antibodies showed limited effects on HER2.
  • The antibody combination induced significant internalization and degradation of HER2 via multiple endocytic pathways.
  • HER2 phosphorylation and ubiquitination were observed upon treatment with the antibody combination.
  • HER2 kinase activity was crucial for antibody-induced HER2 down-regulation.

Conclusions:

  • A combination of antibodies targeting distinct HER2 epitopes can overcome resistance to endocytic down-regulation.
  • Antibody-induced HER2 internalization and degradation are dependent on its kinase activity.
  • This combination therapy presents a potential strategy for targeting HER2-overexpressing cancers.
Keywords:
HER2/ErbB2antibody combinationsdegradationendocytosiskinase activitymonoclonal antibodies

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