Pan-HER - an antibody mixture targeting EGFR, HER2, and HER3 abrogates preformed and ligand-induced EGFR homo- and heterodimers: Pan-HER abrogates EGFR dimers

Sofie Ellebaek, Susanne Brix Pedersen, Michael Grandal, Johan Lantto, Ivan D. Horak, Michael Kragh, Thomas Tuxen Poulsen

    Research output: Contribution to journalJournal articleResearchpeer-review

    371 Downloads (Pure)

    Abstract

    The human epidermal growth factor receptor (HER)-family is involved in development of many epithelial cancers. Therefore, HER-family members constitute important targets for anti-cancer therapeutics such as monoclonal antibodies (mAbs). A limitation to the success of single HER-targeting mAbs is development of acquired resistance through mechanisms such as alterated receptor dimerization patterns and dependencies. Pan-HER is a mixture of six mAbs simultaneously targeting epidermal growth factor receptor (EGFR), HER2, and HER3 with two mAbs against each receptor. Pan-HER has previously demonstrated broader efficacy than targeting single or dual receptor combinations also in resistant settings. In light of this broad efficacy, we decided to investigate the effect of Pan-HER compared with single HER-targeting with single and dual mAbs on HER-family cross-talk and dimerization focusing on EGFR. The effect of Pan-HER on cell proliferation and HER-family receptor degradation was superior to treatment with single mAbs targeting either single receptor, and similar to targeting a single receptor with two non-overlapping antibodies. Furthermore, changes in EGFR-dimerization patterns after treatment with Pan-HER were investigated by in situ proximity ligation assay and co-immunoprecipitation, demonstrating that Pan-HER and the EGFR-targeting mAb mixture efficiently down-regulate basal EGFR homo- and heterodimerization in two tested cell lines, whereas single mAbs had limited effects. Pan-HER and the EGFR-targeting mAb mixture also blocked EGF-binding and thereby ligand-induced changes in EGFR-dimerization levels. These results suggest that Pan-HER reduces the cellular capability to switch HER-dependency and dimerization pattern in response to treatment and thus hold promise for future clinical development of Pan-HER in resistant settings. This article is protected by copyright. All rights reserved.
    Original languageEnglish
    JournalInternational Journal of Cancer
    Volume139
    Issue number9
    Pages (from-to)2095-2105
    Number of pages11
    ISSN0020-7136
    DOIs
    Publication statusPublished - 2016

    Keywords

    • Antibodies
    • HER-family
    • EGFR
    • Dimerization

    Fingerprint

    Dive into the research topics of 'Pan-HER - an antibody mixture targeting EGFR, HER2, and HER3 abrogates preformed and ligand-induced EGFR homo- and heterodimers: Pan-HER abrogates EGFR dimers'. Together they form a unique fingerprint.

    Cite this