SYD985, a novel duocarmycin-based HER2-targeting antibody-drug conjugate, shows promising antitumor activity in epithelial ovarian carcinoma with HER2/Neu expression

Authors

Gulden Menderes, 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.
Stefania Bellone, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, CT 06520, USA.
Jonathan Black, 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.
Alice Masserdotti, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, CT 06520, USA.
Francesca Pettinella, 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.
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.
Serena Wong, Department of Pathology, Yale University School of Medicine, CT 06520, USA.
Babak Litkouhi, Department of Obstetrics, Gynecology, and Reproductive Sciences, 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.
Peter E. Schwartz, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, CT 06520, USA.
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

BACKGROUND: Epithelial ovarian cancer (EOC) is an aggressive and heterogeneous disease. <10% of EOC demonstrate HER2/neu 3+ receptor over-expression. However, moderate to low (i.e., 2+ and 1+) HER2/neu expression is reported in up to 50% of EOC. The objective of this study was to compare the anti-tumor activity of SYD985, a novel HER2-targeting antibody-drug conjugate (ADC), to trastuzumab emtansine (T-DM1) in EOC models with differential HER2/neu expression. METHODS: The cytotoxicity of SYD985 and T-DM1 was evaluated using ten primary EOC cell lines with 0/1+, 2+, and 3+ HER2/neu expression in antibody-dependent cellular cytotoxicity (ADCC), proliferation, viability and bystander killing experiments. Finally, the in vivo activity of SYD985 and T-DM1 was also studied in ovarian cancer xenografts. RESULTS: SYD985 and T-DM1 induced similar ADCC in the presence of peripheral blood lymphocytes (PBL) against EOC cell lines with differential HER2/neu expression. In contrast, SYD985 was 3 to 42 fold more cytotoxic in the absence of PBL when compared to T-DM1 (p<0.0001). Unlike T-DM1, SYD985 induced efficient bystander killing of HER2/neu 0/1+ tumor cells when admixed with HER2/neu 3+ EOC cells. In vivo studies confirmed that SYD985 is significantly more active than T-DM1 against HER2/neu 3+ EOC xenografts. CONCLUSIONS: SYD985 is a novel ADC with remarkable activity against EOC with strong (3+) as well as moderate to low (i.e., 2+ and 1+) HER2/neu expression. SYD985 is more potent than T-DM1 in comparative experiments and unlike T-DM1, it is active against EOC demonstrating moderate/low or heterogeneous HER2/neu expression.

First Page

179

Last Page

186

DOI

10.1016/j.ygyno.2017.04.023

Publication Date

7-1-2017

Recommended Citation

Menderes, Gulden; Bonazzoli, Elena; Bellone, Stefania; Black, Jonathan; Altwerger, Gary; Masserdotti, Alice; Pettinella, Francesca; Zammataro, Luca; Buza, Natalia; Hui, Pei; Wong, Serena; Litkouhi, Babak; Ratner, Elena; Silasi, Dan-Arin; Huang, Gloria S.; Azodi, Masoud; Schwartz, Peter E.; and Santin, Alessandro D., "SYD985, a novel duocarmycin-based HER2-targeting antibody-drug conjugate, shows promising antitumor activity in epithelial ovarian carcinoma with HER2/Neu expression" (2017). Obstetrics and Gynecology. 183.
https://scholar.bridgeporthospital.org/obgyn/183

Identifier

28473206 (pubmed); NIHMS873267 (mid); PMC5533304 (pmc); 10.1016/j.ygyno.2017.04.023 (doi); S0090-8258(17)30804-1 (pii)