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

Gulden Menderes, Elena Bonazzoli, Stefania Bellone, Jonathan Black, Gary Altwerger, Alice Masserdotti, Francesca Pettinella, Luca Zammataro, Natalia Buza, Pei Hui, Serena Wong, Babak Litkouhi, Elena Ratner, Dan Arin Silasi, Gloria S. Huang, Masoud Azodi, Peter E. Schwartz, Alessandro D. Santin

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

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.

Original languageEnglish (US)
JournalGynecologic Oncology
DOIs
StateAccepted/In press - Feb 20 2017
Externally publishedYes

Keywords

  • Ado-trastuzumab emtansine
  • Antibody-drug conjugate
  • HER2
  • Ovarian serous carcinoma
  • SYD985
  • T-DM1

ASJC Scopus subject areas

  • Oncology
  • Obstetrics and Gynecology

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