High turnover of Tissue Factor enables efficient intracellular delivery of antibody-drug conjugates

Bart Ecg de Goeij, David Satijn, Claudia M Freitag, Richard Wubbolts, Wim K Bleeker, Alisher Khasanov, Tong Zhu, Gary Chen, David Miao, Patrick Hc van Berkel, Paul W H I Parren

    Research output: Contribution to journalArticleAcademicpeer-review

    Abstract

    Antibody drug conjugates (ADC) are emerging as powerful cancer treatments that combine antibody-mediated tumor targeting with the potent cytotoxic activity of toxins. We recently reported the development of a novel ADC that delivers the cytotoxic payload monomethyl auristatin E (MMAE) to tumor cells expressing tissue factor (TF). By carefully selecting a TF-specific antibody that interferes with TF:FVIIa-dependent intracellular signaling, but not with the pro-coagulant activity of TF, an ADC was developed (TF-011-MMAE/HuMax-TF-ADC) that efficiently kills tumor cells, with an acceptable toxicology profile. To gain more insight in the efficacy of TF-directed ADC treatment we compared the internalization characteristics and intracellular routing of TF with the epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2). Both in absence and presence of antibody, TF demonstrated more efficient internalization, lysosomal targeting and degradation than EGFR and HER2. By conjugating TF, EGFR and HER2 specific antibodies with duostatin-3, a toxin that induces potent cytotoxicity upon antibody-mediated internalization but lacks the ability to induce bystander killing, we were able to compare cytotoxicity of ADCs with different tumor specificities. TF-ADC demonstrated effective killing against tumor cell lines with variable levels of target expression. In xenograft models, TF-ADC was relatively potent in reducing tumor growth compared to EGFR- and HER2- ADCs. We hypothesize that the constant turnover of TF on tumor cells, makes this protein specifically suitable for an ADC approach.

    Original languageEnglish
    Pages (from-to)1130-1140
    Number of pages11
    JournalMolecular Cancer Therapeutics
    Volume14
    DOIs
    Publication statusPublished - 27 Feb 2015

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