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.
Highlights
Endometrial endometrioid carcinoma (EC) is the most prevalent gynecologic malignancy in the United States, with approximately 61 880 newly diagnosed cases and 12 160 deaths in 2019
Moderate-tostrong trophoblast cell-surface antigen 2 (Trop-2) expression was found in 84% (120/143) of the EC samples evaluated by IHC and 43% of the primary EC cell lines assessed by flow cytometry
We demonstrated that the mechanism by which Sacituzumab govitecan or IMMU-132 (SG) induces tumor cell killing is due to the internalization of the nontargeting control antibody–drug conjugate (ADC) and the consequent intracellular release of the toxic payload SN-38 but it may be potentially mediated by immune system cells (i.e., NK cells)
Summary
Endometrial endometrioid carcinoma (EC) is the most prevalent gynecologic malignancy in the United States, with approximately 61 880 newly diagnosed cases and 12 160 deaths in 2019. Up to 35% of EC patients are diagnosed with a more aggressive histopathology, such as poorly differentiated endometrioid, and serous or clear cell carcinoma (Bokhman, 1983; Rose et al, 2017). These patients account for the majority who present with stage III or IV disease that are typically nonresponsive to the gold standard chemotherapy treatment involving carboplatin plus paclitaxel, which portends a poor prognosis (Creutzberg et al, 2004; Rose et al, 2017; Young et al, 2015). The identification of novel treatment modalities for patients diagnosed with biologically aggressive EC remains an unmet medical need
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