AUTHOR=Perrone Emanuele , Lopez Salvatore , Zeybek Burak , Bellone Stefania , Bonazzoli Elena , Pelligra Silvia , Zammataro Luca , Manzano Aranzazu , Manara Paola , Bianchi Anna , Buza Natalia , Tymon-Rosario Joan , Altwerger Gary , Han Chanhee , Menderes Gulden , Ratner Elena , Silasi Dan-Arin , Azodi Masoud , Hui Pei , Schwartz Peter E. , Scambia Giovanni , Santin Alessandro D. 

TITLE=Preclinical Activity of Sacituzumab Govitecan, an Antibody-Drug Conjugate Targeting Trophoblast Cell-Surface Antigen 2 (Trop-2) Linked to the Active Metabolite of Irinotecan (SN-38), in Ovarian Cancer

JOURNAL=Frontiers in Oncology

VOLUME=10

YEAR=2020

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2020.00118

DOI=10.3389/fonc.2020.00118

ISSN=2234-943X

ABSTRACT=<p><bold>Background:</bold> Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy. Sacituzumab govitecan (SG) is a novel antibody-drug-conjugate (ADC) targeting trophoblast-antigen-2 (Trop-2), a cell surface glycoprotein highly expressed in many epithelial tumors, to deliver SN-38, the active metabolite of irinotecan. This study aimed to evaluate Trop-2 expression in EOC tissues and the preclinical activity of SG against primary EOC cell lines and xenografts.</p><p><bold>Methods:</bold> Trop-2 expression was assessed in 90 formalin-fixed-paraffin-embedded tumors and nine primary tumor cell lines by immunohistochemistry (IHC) and flow cytometry, respectively. Trop-2 expression and cell viability after exposure to SG in primary tumor cell lines, non-targeting control ADC, and SG-parental antibody hRS7 were evaluated using flow-cytometry-based-assays. Antibody-dependent-cell-cytotoxicity (ADCC) against Trop-2+ and Trop-2– EOC cell lines was tested <italic>in vitro</italic> using 4 h Chromium-release-assays. <italic>In vivo</italic> activity of SG was evaluated against Trop-2+ EOC xenografts.</p><p><bold>Results:</bold> Moderate-to-strong staining was seen in 47% (42/90) of ovarian tumors by IHC while 89% (8/9) of the primary EOC cell lines overexpressed Trop-2 by flow cytometry. EOC Trop-2+ were significantly more sensitive to SG compared to control ADC (<italic>p</italic> &lt; 0.05). Both SG and hRS7 mediated high ADCC activity against Trop-2+ cell lines. SG also induced significant bystander killing of Trop-2– tumor cells admixed with Trop-2+ EOC cells. In <italic>in vivo</italic> experiments SG treatment demonstrated impressive anti-tumor activity against chemotherapy-resistant EOC xenografts.</p><p><bold>Conclusion:</bold> SG demonstrates remarkable preclinical activity against biologically aggressive and chemotherapy-resistant EOC cell lines and a significant bystander effect against EOC cell lines with heterogenous Trop-2 expression. Clinical trials are warranted.</p>