In vitro and in vivo activity of DHES0815A, an antibody-drug conjugate targeting HER2/neu in uterine serous carcinoma

Abstract

<h3>Objectives:</h3> Uterine serous carcinoma (USC) is an aggressive histologic variant of endometrial cancer which portends a poor prognosis. DHES0815A is a novel antibody-drug-conjugate (ADC) which binds specifically to HER2-amplified USC tumors at a distinct epitope from that bound by trastuzumab, pertuzumab, and T-DM1 (trastuzumab emtansine) after which it delivers the toxic payload, PBD-MA, a DNA mono-alkylating agent. The objective of this study was to evaluate the preclinical activity of DHES0815A as a single agent against primary USC cell lines and xenografts. <h3>Methods:</h3> Twelve primary USC cell lines were assessed by immunohistochemistry (IHC) for HER2 protein expression and for <i>C-erbB2</i> gene amplification using fluorescent in situ hybridization (FISH) analysis. Cell viability in USC primary cell lines after exposure to DHES0815A, the non-targeted ADC, the unconjugated antibody MHES0488A, and T-DM1 were evaluated using flow cytometry-based-assays. <i>in vivo</i> activity of these respective agents was tested against HER2/neu overexpressing USC (ARK2) xenografts. <h3>Results:</h3> High HER2/neu protein expression by IHC and <i>C-erbB2</i> gene amplification by FISH was seen in 25% (3/12) of the primary USC cell lines. Primary tumor cell lines overexpressing HER2/neu were significantly more sensitive to DHES0815A when compared to the non-targeted control ADC (<i>p<0.05</i>). DHES0815A caused growth-inhibition and increased survival in HER2/neu overexpressing xenografts when compared to controls (<i>p<0.05</i>). The animals also tolerated DHES0815A treatment with no significant change in their body weight [Figure 1]. <h3>Conclusions:</h3> DHES0815A as a single agent is both highly selective and toxic to USC tumors overexpressing HER2/neu both <i>in vitro</i> and <i>in vivo.</i> HER2-directed ADCs, alone or in combination with other HER2/neu targeted agents may represent a novel and less toxic treatment option for patients with tumors harboring HER2/neu overexpression refractory to trastuzumab and traditional chemotherapy.