In vitro and in vivo activity of sacituzumab govitecan, an antibody-drug conjugate targeting trophoblast cell-surface antigen 2 (Trop-2) in uterine serous carcinoma

Chanhee Han, Department of Obstetrics, Gynecology, and Reproductive Sciences Yale University School of Medicine, CT, 06520, USA.
Emanuele Perrone, Department of Obstetrics, Gynecology, and Reproductive Sciences Yale University School of Medicine, CT, 06520, USA; Department of Obstetrics and Gynecology, Università Cattolica del Sacro Cuore, Roma, Italy.
Burak Zeybek, Department of Obstetrics, Gynecology, and Reproductive Sciences Yale University School of Medicine, CT, 06520, USA.
Stefania Bellone, Department of Obstetrics, Gynecology, and Reproductive Sciences Yale University School of Medicine, CT, 06520, USA.
Joan Tymon-Rosario, Department of Obstetrics, Gynecology, and Reproductive Sciences Yale University School of Medicine, CT, 06520, USA.
Gary Altwerger, Department of Obstetrics, Gynecology, and Reproductive Sciences Yale University School of Medicine, CT, 06520, USA.
Gulden Menderes, Department of Obstetrics, Gynecology, and Reproductive Sciences Yale University School of Medicine, CT, 06520, USA.
Jacqueline Feinberg, Department of Obstetrics, Gynecology, and Reproductive Sciences Yale University School of Medicine, CT, 06520, USA.
Kaitlin Haines, Department of Obstetrics, Gynecology, and Reproductive Sciences Yale University School of Medicine, CT, 06520, USA.
Mariana Espinal Muller Karger, Department of Obstetrics, Gynecology, and Reproductive Sciences Yale University School of Medicine, CT, 06520, USA.
Anna Bianchi, Department of Obstetrics, Gynecology, and Reproductive Sciences Yale University School of Medicine, CT, 06520, USA.
Luca Zammataro, Department of Obstetrics, Gynecology, and Reproductive Sciences Yale University School of Medicine, CT, 06520, USA.
Aranzazu Manzano, Department of Obstetrics, Gynecology, and Reproductive Sciences Yale University School of Medicine, CT, 06520, USA.
Elena Bonazzoli, Department of Obstetrics, Gynecology, and Reproductive Sciences Yale University School of Medicine, CT, 06520, USA.
Paola Manara, Department of Obstetrics, Gynecology, and Reproductive Sciences Yale University School of Medicine, CT, 06520, USA.
Natalia Buza, Department of Pathology, Yale University School of Medicine, CT, 06520, USA.
Pei Hui, Department of Pathology, Yale University School of Medicine, CT, 06520, USA.
Elena Ratner, Department of Obstetrics, Gynecology, and Reproductive Sciences Yale University School of Medicine, CT, 06520, USA.
Dan-Arin Silasi, Department of Obstetrics, Gynecology, and Reproductive Sciences Yale University School of Medicine, CT, 06520, USA.
Gloria S. Huang, Department of Obstetrics, Gynecology, and Reproductive Sciences Yale University School of Medicine, CT, 06520, USA.
Masoud Azodi, Department of Obstetrics, Gynecology, and Reproductive Sciences Yale University School of Medicine, CT, 06520, USA.Follow
Peter E. Schwartz, Department of Obstetrics, Gynecology, and Reproductive Sciences Yale University School of Medicine, CT, 06520, USA.
Salvatore Lopez, Department of Obstetrics, Gynecology, and Reproductive Sciences Yale University School of Medicine, CT, 06520, USA; Department of Experimental and Clinical Medicine, Magna Graecia University, Catanzaro, Italy; Department of Gynecology Oncology, Istituto Nazionale dei Tumori di Milano, 20133, Milan, Italy.
Alessandro D. Santin, Department of Obstetrics, Gynecology, and Reproductive Sciences Yale University School of Medicine, CT, 06520, USA. Electronic address: alessandro.santin@yale.edu.

Document Type

Article

Publication Title

Gynecologic oncology

Abstract

OBJECTIVE: Uterine serous carcinoma (USC) is an aggressive variant of endometrial cancer with poor prognosis. Sacituzumab govitecan (SG) is a novel antibody-drug-conjugate (ADC) targeting trophoblast cell-surface antigen 2 (Trop-2), a transmembrane-calcium-signal-transducer, to deliver SN-38, the active metabolite of irinotecan. The objective of this study was to evaluate the expression of Trop-2 in USC and the preclinical activity of SG against primary USC cell-lines and xenografts. METHODS: We used immunohistochemistry (IHC) and flow-cytometry-based assays to evaluate Trop-2 expression and cell-viability in USC tissue and primary tumor-cell-lines after exposure to SG, non-targeting control ADC, and naked antibody hRS7-IgG. Antibody-dependent-cell-cytotoxicity (ADCC) against Trop-2+ and Trop-2- USC cell-lines was evaluated in vitro using 4-hr-Chromium-release-assays. In vivo activity of SG was tested against Trop-2+ USC xenografts by intravenous administration of SG, control ADC, and hRS7. RESULTS: Trop-2 expression by IHC was detected in 95.1% of USC samples (99/104). Primary tumor cell-lines overexpressing Trop-2 were significantly more sensitive to SG when compared to control ADC (p <0.05). Both SG and hRS7 mediated ADCC in Trop2+ USC cell-lines while no cytotoxicity was detected against Trop-2- cells. SG induced significant bystander killing of Trop-2- tumors when admixed with Trop-2+ tumors. SG caused growth-inhibition and increased survival in SG treated mice harboring Trop-2+ xenografts when compared to controls (p <0.05). CONCLUSIONS: SG is remarkably active against USC overexpressing Trop-2 in vitro and in vivo. Our results combined with SG clinical responses recently reported against multiple chemotherapy resistant human tumors further support clinical development of SG in USC patients with advanced/recurrent disease.

First Page

430

Last Page

438

DOI

10.1016/j.ygyno.2019.11.018

Publication Date

2-1-2020

Identifier

31839338 (pubmed); 10.1016/j.ygyno.2019.11.018 (doi); S0090-8258(19)31669-5 (pii)

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