Potential therapeutic activity of adecatumumab (MT201), a fully human monoclonal antibody, against epithelial cell adhesion molecule (EpCAM) in uterine serous papillary carcinoma

Abstract

e16502 Background: Uterine serous papillary carcinoma (USPC) represents a variant of endometrial cancer characterized by a highly aggressive biologic behavior and inborn resistance to chemotherapy. MT201 is a fully human monoclonal antibody recently developed against epithelial cell adhesion molecule (EpCAM). In this study we have evaluated the potential of MT201 as a novel therapeutic strategy against USPC. Methods: EpCAM expression was evaluated by real time-PCR and immunohistochemistry (IHC) in a total of 54 USPC fresh-frozen biopsies and paraffin embedded tissues. EpCAM surface expression was evaluated by flow cytometry in 6 freshly established USPC cell lines derived from advanced stage USPC patients. Sensitivity to MT201 antibody dependent cellular cytotoxicity (ADCC) and complement dependent cytotoxicity (CDC) was tested in standard 4-hour chromium (51Cr) release cytotoxicity assays. Results: EpCAM transcript was significantly overexpressed in fresh frozen USPC when compared to fresh-frozen normal endometrial cells (NEC) [i.e., mean (minimum-maximum) copy number of 515.4 (31.5–1568.3) in tumor samples versus 8.1 (1.0–25.5) in flash-frozen NEC (p < 0.001)]. By IHC, EpCAM protein expression was found in 96% (26 out of 27) USPC samples and this expression was significantly higher when compared to normal endometrial cells (p < 0.01). High surface expression of EpCAM by flow cytometry was found in 83% (5 out of 6) of the primary USPC cell lines available to this study. Importantly, while primary USPC cell lines were highly resistant to natural killer dependent cytotoxicity in vitro, EpCAM positive cell lines were found highly sensitive to MT201-mediated ADCC. Human serum IgG did inhibit MT201-mediated cytotoxicity against USPC in vitro. Conclusions: These results demonstrate for the first time high EpCAM expression in uterine serous carcinoma at mRNA and protein levels and high sensitivity to MT201-mediated cytotoxicity in vitro by primary USPC cell lines. MT201 might be a novel and attractive therapeutic strategy in patients harboring advanced, recurrent or metastatic USPC refractory to standard treatment modalities. No significant financial relationships to disclose.