Efficacy of Depatuxizumab Mafodotin (ABT-414) in preclinical models of head and neck cancer.

Abstract

Epidermal growth factor receptor (EGFR) is highly expressed in 80-90% of head and neck squamous cell carcinomas (HNSCCs), making it an ideal target for antibody-drug conjugates (ADCs). Depatuxizumab mafodotin (ABT-414), is an EGFR-targeting ADC comprised of the monoclonal antibody (mAb) ABT-806 conjugated to monomethyl auristatin F, a tubulin polymerization inhibitor. This study assessed the in vivo efficacy of ABT-414 in HNSCC. The effects of ABT-414 on HNSCCs were determined using in vitro cytotoxicity assays and in vivo flank xenograft mouse models. The distribution of ABT-414 was assessed ex vivo via optical imaging methods using a conjugate of ABT-414 to the near-infrared agent IRDye800. In vitro treatment of high EGFR-expressing human HNSCC cell lines (UMSCC47 and FaDu) with ABT-414 (0-3.38nM) resulted in dose-dependent cell death (IC50 values of 0.213nM and 0.167nM, respectively). ABT-414 treatment of the FaDu mouse xenografts displayed antitumor activity (p= 0.023) without a change in body mass (p= 0.1335), whereas treatment of UMSCC47 did not generate a significant response (p = 0.1761). Fluorescence imaging revealed ABT-414-IRDye800 accumulation in the tumors of both FaDu and UMSCC47 cell lines, with a signal-to-background ratio of >10. ABT-414 treatment yielded antitumor activity in FaDu tumors, but not in UMSCC47, highlighting the potential for ABT-414 efficacy in high EGFR-expressing tumors. While ABT-414-IRDye800 localized tumors in both cell lines, the differing antitumor responses highlight the need for further investigation into the role of the tumor microenvironment in drug delivery.