Trastuzumab deruxtecan (DS-8201a), a HER2-targeting antibody-drug conjugate with topoisomerase I inhibitor payload, shows antitumor activity in uterine and ovarian carcinosarcoma with HER2/neu expression

Authors

Dennis Mauricio, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520, United States of America.
Stefania Bellone, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520, United States of America.
Levent Mutlu, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520, United States of America.
Blair McNamara, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520, United States of America.
Diego D. Manavella, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520, United States of America.
Cem Demirkiran, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520, United States of America.
Miguel Skyler Verzosa, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520, United States of America.
Natalia Buza, Department of Pathology, Yale University School of Medicine, New Haven, CT 06520, United States of America.
Pei Hui, Department of Pathology, Yale University School of Medicine, New Haven, CT 06520, United States of America.
Tobias Max Hartwich, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520, United States of America.
Justin Harold, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520, United States of America.
Yang Yang-Hartwich, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520, United States of America.
Margherita Zipponi, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520, United States of America.
Gary Altwerger, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520, United States of America.
Elena Ratner, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520, United States of America.
Gloria S. Huang, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520, United States of America.
Mitchell Clark, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520, United States of America.
Vaagn Andikyan, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520, United States of America.
Masoud Azodi, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520, United States of America.Follow
Peter E. Schwartz, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520, United States of America.
Alessandro D. Santin, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520, United States of America. Electronic address: alessandro.santin@yale.edu.

Document Type

Article

Publication Title

Gynecologic oncology

Abstract

OBJECTIVES: Carcinosarcomas are highly aggressive gynecologic malignancies containing both carcinomatous and sarcomatous elements with heterogeneous HER2/neu expression and limited therapeutic options. We compared the efficacy of trastuzumab deruxtecan (DS-8201a), a novel HER2/neu-targeting antibody-drug conjugate (ADC) to an ADC isotype control (MAAA-9199) against primary uterine and ovarian carcinosarcomas in vitro and in vivo. METHODS: Twelve primary carcinosarcoma (CS) cell lines were evaluated for HER2/neu surface expression by immunohistochemistry (IHC) and by flow cytometry, and gene amplification by fluorescence in situ hybridization (FISH) assays. The in vitro experiments included cytotoxicity and bystander killing effect assays on three cell lines of variable HER2/neu expression. In vivo activity was studied in a mouse CS xenograft model of 3+ HER2/neu uterine CS. RESULTS: In vitro studies showed that DS-8201a was highly effective against uterine and ovarian CS cell lines demonstrating 3+ HER2/neu expression compared to MAAA-9199 control; there was no significant improvement in the 0 HER2/neu CS cell line. However, DS-8201a induced efficient bystander killing of 0 HER2/neu tumor cells when admixed with 3+ HER2/neu cells. In vivo studies confirmed that DS-8201a was more effective than MAAA-9199 in 3+ HER2/neu-expressing CS xenografts. CONCLUSION: DS-8201a may represent a novel and highly effective ADC against HER2/neu-expressing CS.

First Page

38

Last Page

45

DOI

10.1016/j.ygyno.2022.12.018

Publication Date

3-1-2023

Recommended Citation

Mauricio, Dennis; Bellone, Stefania; Mutlu, Levent; McNamara, Blair; Manavella, Diego D.; Demirkiran, Cem; Verzosa, Miguel Skyler; Buza, Natalia; Hui, Pei; Hartwich, Tobias Max; Harold, Justin; Yang-Hartwich, Yang; Zipponi, Margherita; Altwerger, Gary; Ratner, Elena; Huang, Gloria S.; Clark, Mitchell; Andikyan, Vaagn; Azodi, Masoud; Schwartz, Peter E.; and Santin, Alessandro D., "Trastuzumab deruxtecan (DS-8201a), a HER2-targeting antibody-drug conjugate with topoisomerase I inhibitor payload, shows antitumor activity in uterine and ovarian carcinosarcoma with HER2/neu expression" (2023). Obstetrics and Gynecology. 190.
https://scholar.bridgeporthospital.org/obgyn/190

Identifier

36610380 (pubmed); NIHMS1863149 (mid); PMC10445234 (pmc); 10.1016/j.ygyno.2022.12.018 (doi); S0090-8258(22)02018-2 (pii)