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

Jonathan Black, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut.
Gulden Menderes, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut.
Stefania Bellone, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut.
Carlton L. Schwab, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut.
Elena Bonazzoli, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut.
Francesca Ferrari, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut.
Federica Predolini, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut.
Christopher De Haydu, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut.
Emiliano Cocco, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut.
Natalia Buza, Department of Pathology, Yale University School of Medicine, New Haven, Connecticut.
Pei Hui, Department of Pathology, Yale University School of Medicine, New Haven, Connecticut.
Serena Wong, Department of Pathology, Yale University School of Medicine, New Haven, Connecticut.
Salvatore Lopez, Division of Gynecologic Oncology, University Campus Bio-Medico of Roma, Rome, Italy.
Elena Ratner, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut.
Dan-Arin Silasi, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut.
Masoud Azodi, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut.
Babak Litkouhi, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut.
Peter E. Schwartz, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut.
Peter Goedings, Synthon Biopharmaceuticals BV., Nijmegen, the Netherlands.
Patrick H. Beusker, Synthon Biopharmaceuticals BV., Nijmegen, the Netherlands.
Miranda M. van der Lee, Synthon Biopharmaceuticals BV., Nijmegen, the Netherlands.
C Marco Timmers, Synthon Biopharmaceuticals BV., Nijmegen, the Netherlands.
Wim H. Dokter, Synthon Biopharmaceuticals BV., Nijmegen, the Netherlands.
Alessandro D. Santin, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut. alessandro.santin@yale.edu.

Document Type

Article

Publication Title

Molecular cancer therapeutics

Abstract

Uterine serous carcinoma (USC) is an aggressive form of endometrial cancer. Up to 35% of USC may overexpress the HER2/neu oncogene at strong (i.e., 3+) levels by IHC while an additional 40% to 50% express HER2/neu at moderate (2+) or low (1+) levels. We investigated the efficacy of SYD985, (Synthon Biopharmaceuticals), a novel HER2-targeting antibody-drug conjugate (ADC) composed of the mAb trastuzumab linked to a highly potent DNA-alkylating agent (i.e., duocarmycin) in USC. We also compared the antitumor activity of SYD985 in head-to-head experiments to trastuzumab emtansine (T-DM1), a FDA-approved ADC, against multiple primary USC cell lines expressing different levels of HER2/neu in in vitro and in vivo experiments. Using antibody-dependent cellular cytotoxicity (ADCC), proliferation, viability, and bystander killing assays as well as propidium iodide-based flow cytometry assays and multiple in vivo USC mouse xenograft models, we demonstrate for the first time that SYD985 is a novel ADC with activity against USC with strong (3+) as well as low to moderate (i.e., 1+/2+) HER2/neu expression. SYD985 is 10- to 70-fold more potent than T-DM1 in comparative experiments and, unlike T-DM1, it is active against USC demonstrating moderate/low or heterogeneous HER2/neu expression. Clinical studies with SYD985 in patients harboring chemotherapy-resistant USC with low, moderate, and high HER2 expression are warranted. Mol Cancer Ther; 15(8); 1900-9. ©2016 AACR.

First Page

1900

Last Page

9

DOI

10.1158/1535-7163.MCT-16-0163

Publication Date

8-1-2016

Identifier

27256376 (pubmed); 10.1158/1535-7163.MCT-16-0163 (doi); 1535-7163.MCT-16-0163 (pii)

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