In vitro and in vivo activity of sacituzumab govitecan, an antibody-drug conjugate targeting trophoblast cell-surface antigen 2 (Trop-2) in uterine serous carcinoma. Gynecologic oncology

Chanhee Han, Emanuele Perrone, Burak Zeybek, Stefania Bellone, Joan Tymon-Rosario, Gary Altwerger, Gulden Menderes, Jacqueline Feinberg, Kaitlin Haines, Mariana Espinal Muller Karger, Anna Bianchi, Luca Zammataro, Aranzazu Manzano, Elena Bonazzoli, Paola Manara, Natalia Buza, Pei Hui, Elena Ratner, Dan-Arin Silasi, Gloria S. HuangMasoud Azodi, Peter E. Schwartz, Salvatore Lopez, Alessandro D. Santin

Research output: Contribution to journalArticlepeer-review

Abstract

OBJECTIVE: Uterine serous carcinoma (USC) is an aggressive variant of endometrial cancer with poor prognosis. Sacituzumab govitecan (SG) is a novel antibody-drug-conjugate (ADC) targeting trophoblast cell-surface antigen 2 (Trop-2), a transmembrane-calcium-signal-transducer, to deliver SN-38, the active metabolite of irinotecan. The objective of this study was to evaluate the expression of Trop-2 in USC and the preclinical activity of SG against primary USC cell-lines and xenografts. METHODS: We used immunohistochemistry (IHC) and flow-cytometry-based assays to evaluate Trop-2 expression and cell-viability in USC tissue and primary tumor-cell-lines after exposure to SG, non-targeting control ADC, and naked antibody hRS7-IgG. Antibody-dependent-cell-cytotoxicity (ADCC) against Trop-2+ and Trop-2- USC cell-lines was evaluated in vitro using 4-hr-Chromium-release-assays. In vivo activity of SG was tested against Trop-2+ USC xenografts by intravenous administration of SG, control ADC, and hRS7. RESULTS: Trop-2 expression by IHC was detected in 95.1% of USC samples (99/104). Primary tumor cell-lines overexpressing Trop-2 were significantly more sensitive to SG when compared to control ADC (p
Original languageEnglish
Pages (from-to)430-438
Number of pages9
JournalGynecologic Oncology
Volume156
Issue number2
DOIs
Publication statusPublished - 2020

Keywords

  • Female
  • Humans
  • Random Allocation
  • Cell Line, Tumor
  • Molecular Targeted Therapy
  • Immunohistochemistry
  • Tissue Array Analysis
  • Flow Cytometry
  • Animals
  • Mice
  • Xenograft Model Antitumor Assays
  • Mice, SCID
  • *antibody drug conjugate (ADC)
  • *IMMU-132
  • *Sacituzumab govitecan
  • *Uterine cancer
  • *Uterine serous carcinoma
  • Antibodies, Monoclonal, Humanized/immunology/*pharmacology
  • Antibody-Dependent Cell Cytotoxicity
  • Antigens, Neoplasm/biosynthesis/*immunology
  • Camptothecin/*analogs & derivatives/immunology/pharmacology
  • Cell Adhesion Molecules/biosynthesis/*immunology
  • Cystadenocarcinoma, Serous
  • Immunoconjugates/immunology/*pharmacology
  • Uterine Neoplasms/*drug therapy/immunology/metabolism

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