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

  1. Author:
    Schardt, John S.
    Oubaid, Jinan M.
    Williams, Sonya C.
    Howard, James L.
    Aloimonos, Chloe M.
    Bookstaver, Michelle L.
    Lamichhane, Tek N.
    Sokic, Sonja
    Liyasova, Mariya
    O'Neill, Maura
    Andresson, Thorkell
    Hussain, Arif
    Lipkowitz, Stanley
    Jay, Steven M.

  2. Author Address

    Univ Maryland, Fischell Dept Bioengn, College Pk, MD 20742 USA.NCI, Womens Malignancies Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA.Frederick Natl Lab Canc Res, Prot Characterizat Lab, Frederick, MD 21702 USA.Baltimore VA Med Ctr, Baltimore, MD 21201 USA.Univ Maryland, Marlene & Stewart Greenebaum Comprehens Canc Ctr, Sch Med, Baltimore, MD 21201 USA.Univ Maryland, Program Mol & Cellular Biol, College Pk, MD 20742 USA.
    1. Year: 2017
    2. Date: Apr
  2. Journal: MOLECULAR PHARMACEUTICS
  3. AMER CHEMICAL SOC,
    1. 14
    2. 4
    3. Pages: 1047-1056
  5. Type of Article: Article
  6. ISSN: 1543-8384
  1. Abstract:

    The receptor tyrosine kinase HER3-has emerged as a therapeutic target in ovarian, prostate, breast, lung, and other cancers due to its ability to potently.activate the PI3K/Akt pathway, especially via dimerization with HER2, as well as for its role in mediating drug resistance. Enhanced efficacy of HER3-targeted therapeutics would therefore benefit a wide range of patients. This study evaluated the potential of multivalent presentation, through protein engineering, to enhance the effectiveness of HER3-targeted affibodies as alternatives to monoclonal antibody therapeutics. Assessment of multivalent affibodies on a variety of cancer cell, lines revealed their broad ability to improve inhibition of Neuregulin (NRG)-induced HER3 and Akt phosphorylation compared to monovalent analogues. Engineered multivalency also promoted enhanced cancer cell growth inhibition by affibodies as single agents and as part of combination therapy approaches. Mechanistic investigations revealed that engineered multivalency enhanced affibody-mediated HER3 downregulation in multiple cancer cell types. Overall, these-rusults highlight the promise of engineered multivalency as a generaL strategy for enhanced efficacy of HER3-targeted therapeutics against a variety of cancers.

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External Sources

  1. View Full Text
  2. DOI: 10.1021/acs.molpharmaceut.6b00919
  3. View record in Web of Science®
  4. WOS: 000398426100008

Library Notes

  1. Fiscal Year: FY2016-2017
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