SYD985, a Novel Duocarmycin-Based HER2-Targeting Antibody-Drug Conjugate, Shows Antitumor Activity in Uterine and Ovarian Carcinosarcoma with HER2/Neu Expression

Gulden Menderes, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, Connecticut.
Elena Bonazzoli, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, Connecticut.
Stefania Bellone, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, Connecticut.
Jonathan Black, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, Connecticut.
Federica Predolini, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, Connecticut.
Francesca Pettinella, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, Connecticut.
Alice Masserdotti, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, Connecticut.
Luca Zammataro, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, Connecticut.
Gary Altwerger, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, Connecticut.
Natalia Buza, Department of Pathology, Yale University School of Medicine, Connecticut.
Pei Hui, Department of Pathology, Yale University School of Medicine, Connecticut.
Serena Wong, Department of Pathology, Yale University School of Medicine, Connecticut.
Babak Litkouhi, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, Connecticut.
Elena Ratner, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, Connecticut.
Dan-Arin Silasi, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, Connecticut.
Masoud Azodi, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, Connecticut.Follow
Peter E. Schwartz, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, Connecticut.
Alessandro D. Santin, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, Connecticut. alessandro.santin@yale.edu.

Document Type

Article

Publication Title

Clinical cancer research : an official journal of the American Association for Cancer Research

Abstract

Carcinosarcomas (CS) are highly aggressive gynecologic malignancies containing both carcinomatous and sarcomatous elements with heterogeneous HER2/neu expression. We compared the efficacy of SYD985 (Synthon Biopharmaceuticals BV), a novel HER2-targeting antibody-drug conjugate (ADC), to trastuzumab emtansine (T-DM1, Genentech-Roche) against primary uterine and ovarian CS. Eight primary CS cell lines were evaluated for HER2/neu surface expression by IHC and gene amplification by FISH assays. The in vitro experiments included cytotoxicity, antibody-dependent cellular cytotoxicity (ADCC), proliferation, viability, and bystander killing. In vivo activity was studied in mouse xenograft and patient-derived xenograft (PDX) models. SYD985 and T-DM1 induced similar levels of ADCC against CS cell lines with low and high HER2/neu expression when challanged in the presence of effector cells. In contrast, SYD985 was 7- to 54-fold more potent than T-DM1 in the absence of effector cells. SYD985, unlike T-DM1, was active against CS demonstrating low or heterogeneous HER2/neu expression. Specifically, the mean IC values were 0.060 μg/mL and 3.221 μg/mL (P < 0.0001) against HER2/neu 0/1+ cell lines and 0.013 μg/mL and 0.096 μg/mL (P < 0.0001) against HER2/neu 3+ cell lines for SYD985 versus T-DM1, respectively. Importantly, unlike T-DM1, SYD985 induced efficient bystander killing of HER2/neu 0/1+ tumor cells admixed with HER2/neu 3+ cells. In vivo studies confirmed that SYD985 is more active than T-DM1 in CS and highly effective against HER2/neu expressing xenografts and PDX. SYD985 may represent a novel and highly effective ADC against HER2-expressing CS. Clinical studies with SYD985 in patients harboring chemotherapy-resistant CS with low/moderate and high HER2 expression are warranted. Clin Cancer Res; 23(19); 5836-45. ©2017 AACR.

First Page

5836

Last Page

5845

DOI

10.1158/1078-0432.CCR-16-2862

Publication Date

10-1-2017

Identifier

28679774 (pubmed); NIHMS890751 (mid); PMC5626613 (pmc); 10.1158/1078-0432.CCR-16-2862 (doi); 1078-0432.CCR-16-2862 (pii)

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