Abstract
Background: Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy. Sacituzumab govitecan (SG) is a novel antibody-drug-conjugate (ADC) targeting trophoblast-antigen-2 (Trop-2), a cell surface glycoprotein highly expressed in many epithelial tumors, to deliver SN-38, the active metabolite of irinotecan. This study aimed to evaluate Trop-2 expression in EOC tissues and the preclinical activity of SG against primary EOC cell lines and xenografts.Methods: Trop-2 expression was assessed in 90 formalin-fixed-paraffin-embedded tumors and nine primary tumor cell lines by immunohistochemistry (IHC) and flow cytometry, respectively. Trop-2 expression and cell viability after exposure to SG in primary tumor cell lines, non-targeting control ADC, and SG-parental antibody hRS7 were evaluated using flow-cytometry-based-assays. Antibody-dependent-cell-cytotoxicity (ADCC) against Trop-2+ and Trop-2– EOC cell lines was tested in vitro using 4 h Chromium-release-assays. In vivo activity of SG was evaluated against Trop-2+ EOC xenografts.Results: Moderate-to-strong staining was seen in 47% (42/90) of ovarian tumors by IHC while 89% (8/9) of the primary EOC cell lines overexpressed Trop-2 by flow cytometry. EOC Trop-2+ were significantly more sensitive to SG compared to control ADC (p < 0.05). Both SG and hRS7 mediated high ADCC activity against Trop-2+ cell lines. SG also induced significant bystander killing of Trop-2– tumor cells admixed with Trop-2+ EOC cells. In in vivo experiments SG treatment demonstrated impressive anti-tumor activity against chemotherapy-resistant EOC xenografts.Conclusion: SG demonstrates remarkable preclinical activity against biologically aggressive and chemotherapy-resistant EOC cell lines and a significant bystander effect against EOC cell lines with heterogenous Trop-2 expression. Clinical trials are warranted.
Highlights
Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy
Eighty-nine percent of the EOC cell lines were determined to have more than 2+ Trop-2 expression by flow cytometry (Table 1)
Since Trop-2 is differentially expressed on the surface of a variety of human epithelial tumors when compared to normal cells, it may represent a promising target for targeted therapeutics such as Antibody drug conjugates (ADC)
Summary
Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy. Sacituzumab govitecan (SG) is a novel antibody-drug-conjugate (ADC) targeting trophoblast-antigen-2 (Trop-2), a cell surface glycoprotein highly expressed in many epithelial tumors, to deliver SN-38, the active metabolite of irinotecan. Epithelial ovarian cancer (EOC) remains the most lethal gynecologic malignancy. The development of novel treatment modalities for patients diagnosed with advanced/recurrent EOC are eagerly awaited. Antibody drug conjugates (ADC) represent a novel and promising therapeutic approach for cancer patients which combine antibody targeting of differentially expressed surface proteins/receptors with a toxic payload to allow selective delivery of chemotherapeutic agents to tumor cells. ADC may optimize tumor targeting in vivo while potentially minimizing the side effects of highly toxic chemotherapy agents [4, 5]. One of the main challenges in ADC development is the generation of linkers able to maintain the integrity of ADC in human system and allowing the release of the toxic payload after internalization or in close proximity, of the targetcells [5,6,7]
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