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

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

  • Mol Cancer Ther. 2016 Aug;15(8):1900-9. doi: 10.1158/1535-7163.MCT-16-0163.
Jonathan Black 1,  Gulden Menderes 1,  Stefania Bellone 1,  Carlton L Schwab 1,  Elena Bonazzoli 1,  Francesca Ferrari 1,  Federica Predolini 1,  Christopher De Haydu 1,  Emiliano Cocco 1,  Natalia Buza 2,  Pei Hui 2,  Serena Wong 2,  Salvatore Lopez 3,  Elena Ratner 1,  Dan-Arin Silasi 1,  Masoud Azodi 1,  Babak Litkouhi 1,  Peter E Schwartz 1,  Peter Goedings 4,  Patrick H Beusker 4,  Miranda M C van der Lee 4,  C Marco Timmers 4,  Wim H A Dokter 4,  Alessandro D Santin 5
Affiliations

Affiliations

  • 1 Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut.
  • 2 Department of Pathology, Yale University School of Medicine, New Haven, Connecticut.
  • 3 Division of Gynecologic Oncology, University Campus Bio-Medico of Roma, Rome, Italy.
  • 4 Synthon Biopharmaceuticals BV., Nijmegen, the Netherlands.
  • 5 Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut. [email protected].
PMID: 27256376 DOI: 10.1158/1535-7163.MCT-16-0163
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.

Figures