Sacituzumab govitecan, an antibody-drug conjugate targeting trophoblast cell-surface antigen 2, shows cytotoxic activity against poorly differentiated endometrial adenocarcinomas in vitro and in vivo

Giovanni Scambia, Elisabetta Perrone, Paola Manara, Salvatore Lopez, Stefania Bellone, Elena Bonazzoli, Aranzazu Manzano, Luca Zammataro, Anna Bianchi, Burak Zeybek, Natalia Buza, Joan Tymon-Rosario, Gary Altwerger, Chanhee Han, Gulden Menderes, Gloria S. Huang, Elena Ratner, Dan-Arin Silasi, Masoud Azodi, Pei HuiPeter E. Schwartz, Alessandro D. Santin

Risultato della ricerca: Contributo in rivistaArticolo in rivista

2 Citazioni (Scopus)

Abstract

Endometrial cancer is the most common gynecologic malignancy in developed countries. The antibody–drug conjugate (ADC) sacituzumab govitecan (SG) targets trophoblast cell-surface antigen-2 (Trop-2) – a cell-surface glycoprotein highly expressed in many epithelial tumors – and delivers the active metabolite of irinotecan SN-38 to Trop-2-positive tumor cells. We evaluated Trop-2 expression in endometrial endometrioid carcinoma (EC) tissues and the activity of SG against primary poorly differentiated EC cell lines and xenografts. Trop-2 expression was assessed in 143 formalin-fixed–paraffin-embedded tumors and seven primary tumor cell lines by immunohistochemistry and flow cytometry, respectively. Cell viability of primary tumor cell lines was assessed following exposure to SG, or control antibodies. Antibody-dependent cell cytotoxicity (ADCC) against Trop-2-positive and Trop-2-negative EC cell lines was measured in vitro using 4-h chromium release assays. A Trop-2-positive EC xenograft model was used to determine the in vivo activity of SG. Moderate-to-strong staining was detected in 84% (120/143) of EC samples, whereas 43% (3/7) of the primary EC cell lines tested overexpressed Trop-2. EC cell lines overexpressing Trop-2 were significantly more sensitive to SG compared to control ADC (P = 0.014 and P = 0.005). Both SG and the unconjugated parental antibody hRS7 mediated high ADCC against Trop-2-positive cell lines. Moreover, SG induced significant bystander killing of Trop-2-negative tumors cocultured with Trop-2-positive tumors. In the xenograft model, intravenous administration of SG twice weekly for three weeks was well tolerated and demonstrated impressive tumor growth inhibition against poorly differentiated, chemotherapy-resistant EC xenografts (P = 0.011). In summary, SG is a novel ADC with remarkable preclinical activity against poorly differentiated EC cell lines overexpressing Trop-2. These findings warrant future clinical trials.
Lingua originaleEnglish
pagine (da-a)645-656
Numero di pagine12
RivistaMolecular Oncology
Volume14
DOI
Stato di pubblicazionePubblicato - 2020

Keywords

  • IMMU-132
  • antibody–drug conjugate
  • endometrial carcinoma
  • sacituzumab govitecan
  • uterine cancer

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