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Engineered Multivalency Enhances Affibody-Based HER3 Inhibition and Downregulation in Cancer Cells

John S Schardt1, Jinan M Oubaid1, Sonya C Williams1

  • 1Fischell Department of Bioengineering, University of Maryland , College Park, Maryland 20742, United States.

Molecular Pharmaceutics
|March 2, 2017
PubMed

Insights

Engineered multivalent affibodies show improved inhibition of HER3 signaling and cancer cell growth compared to monovalent versions. This protein engineering strategy enhances HER3-targeted therapies for various cancers.

Area of Science:

  • Oncology
  • Biotechnology
  • Molecular Biology

Background:

  • The receptor tyrosine kinase HER3 is a key therapeutic target in multiple cancers, including ovarian, prostate, breast, and lung cancer.
  • HER3 activation, particularly through HER2 dimerization, potently drives the PI3K/Akt pathway and confers drug resistance.
  • Enhancing the efficacy of HER3-targeted therapeutics is crucial for improving patient outcomes across various malignancies.

Purpose of the Study:

  • To evaluate the potential of engineered multivalency to enhance the effectiveness of HER3-targeted affibodies.
  • To compare the efficacy of multivalent affibodies against monovalent analogues in inhibiting HER3 signaling and cancer cell growth.
  • To investigate the mechanistic basis for enhanced affibody efficacy through engineered multivalency.

Main Methods:

  • Protein engineering was used to create multivalent HER3-targeted affibodies.
  • The activity of these affibodies was assessed on various cancer cell lines, measuring inhibition of Neuregulin (NRG)-induced HER3 and Akt phosphorylation.
  • Cancer cell growth inhibition was evaluated for affibodies as single agents and in combination therapies.
  • Mechanistic studies were performed to investigate HER3 downregulation mediated by engineered multivalency.

Main Results:

  • Multivalent affibodies demonstrated improved inhibition of NRG-induced HER3 and Akt phosphorylation compared to monovalent analogues across diverse cancer cell lines.
  • Engineered multivalency led to enhanced cancer cell growth inhibition, both as monotherapy and in combination treatments.
  • Mechanistic investigations confirmed that engineered multivalency promotes enhanced HER3 downregulation in multiple cancer types.
  • These findings suggest multivalent affibodies are effective alternatives to monoclonal antibodies for HER3-targeted therapy.

Conclusions:

  • Engineered multivalency is a promising strategy to enhance the efficacy of HER3-targeted affibodies.
  • Multivalent affibodies offer improved therapeutic potential for a broad spectrum of cancers driven by HER3 signaling.
  • This approach could lead to more effective HER3-targeted therapeutics, addressing drug resistance and improving patient outcomes.
Keywords:
HER3affibodyantibodycancermultivalent

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