Depatuxizumab

The epidermal growth factor receptor (EGFR) protein is highly expressed in a range of malignancies. Although therapeutic interventions directed toward EGFR have yielded therapeutic responses in cancer patients, side effects are common because of normal-tissue expression of wild-type EGFR. We developed a novel tumor-specific anti-EGFR chimeric antibody ch806 labeled with ²²⁵Ac and evaluated its in vitro properties and therapeutic efficacy in murine models of glioblastoma and colorectal cancer. Methods: ²²⁵Ac-ch806 was prepared using different chelators, yielding [²²⁵Ac]Ac-macropa-tzPEG₃Sq-ch806 and [²²⁵Ac]Ac-DOTA-dhPzPEG₄-ch806. Radiochemical yield, purity, apparent specific activity, and serum stability of ²²⁵Ac-ch806 were quantified. In vitro cell killing effect was examined. The biodistribution and therapeutic efficacy of ²²⁵Ac-ch806 were investigated in mice with U87MG.de2-7 and DiFi tumors. Pharmacodynamic analysis of tumors after therapy was performed, including DNA double-strand break immunofluorescence of γH2AX, as well as immunohistochemistry for proliferation, cell cycle arrest, and apoptosis. Results: [²²⁵Ac]Ac-macropa-tzPEG₃Sq-ch806 surpassed [²²⁵Ac]Ac-DOTA-dhPzPEG₄-ch806 in radiochemical yield, purity, apparent specific activity, and serum stability. [²²⁵Ac]Ac-macropa-tzPEG₃Sq-ch806 was therefore used for both in vitro and in vivo studies. It displayed a significant, specific, and dose-dependent in vitro cell-killing effect in U87MG.de2-7 cells. ²²⁵Ac-ch806 also displayed high tumor uptake and minimal uptake in normal tissues. ²²⁵Ac-ch806 significantly inhibited tumor growth and prolonged survival in both U87MG.de2-7 and DiFi models. Enhanced γH2AX staining was observed in ²²⁵Ac-ch806-treated tumors compared with controls. Reduced Ki-67 expression was evident in all ²²⁵Ac-ch806-treated tumors. Increased expression of p21 and cleaved caspase 3 was shown in U87MG.de2-7 and DiFi tumors treated with ²²⁵Ac-ch806. Conclusion: In glioblastoma and colorectal tumor models, ²²⁵Ac-ch806 significantly inhibited tumor growth via induction of double-strand breaks, thereby constraining cancer cell proliferation while inducing cell cycle arrest and apoptosis. These findings underscore the potential clinical applicability of ²²⁵Ac-ch806 as a potential therapy for EGFR-expressing solid tumors.

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. Depatuxizumab mafodotin (ABT-414), is an EGFR-targeting ADC comprised of the monoclonal antibody 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 (0–3.38 nM) resulted in dose-dependent cell death (IC50 values of 0.213 nM and 0.167 nM, 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. Although 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.