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戈沙妥珠单抗（Sacituzumab Govitecan）的临床前活性研究，这是一种靶向滋养层细胞表面抗原2（Trop-2）并与伊立替康活性代谢物（SN-38）偶联的抗体药物偶联物在卵巢癌中的研究。

Preclinical Activity of Sacituzumab Govitecan, an Antibody-Drug Conjugate Targeting Trophoblast Cell-Surface Antigen 2 (Trop-2) Linked to the Active Metabolite of Irinotecan (SN-38), in Ovarian Cancer.

作者信息

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

机构信息

Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT, United States.

Department of Woman and Child Health Sciences, Universita' Cattolica del Sacro Cuore, Rome, Italy.

出版信息

Front Oncol. 2020 Feb 12;10:118. doi: 10.3389/fonc.2020.00118. eCollection 2020.

DOI:10.3389/fonc.2020.00118
PMID:32117765
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7028697/
Abstract

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. 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 using 4 h Chromium-release-assays. activity of SG was evaluated against Trop-2+ EOC xenografts. 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 ( < 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 experiments SG treatment demonstrated impressive anti-tumor activity against chemotherapy-resistant EOC xenografts. 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.

摘要

上皮性卵巢癌（EOC）是最致命的妇科恶性肿瘤。戈沙妥珠单抗（SG）是一种新型抗体药物偶联物（ADC），靶向滋养层抗原2（Trop-2），这是一种在许多上皮肿瘤中高度表达的细胞表面糖蛋白，用于递送伊立替康的活性代谢产物SN-38。本研究旨在评估EOC组织中Trop-2的表达以及SG对原发性EOC细胞系和异种移植物的临床前活性。分别通过免疫组织化学（IHC）和流式细胞术评估了90例福尔马林固定石蜡包埋肿瘤和9种原发性肿瘤细胞系中的Trop-2表达。使用基于流式细胞术的检测方法评估原发性肿瘤细胞系、非靶向对照ADC和SG亲本抗体hRS7暴露于SG后的Trop-2表达和细胞活力。使用4小时铬释放试验检测针对Trop-2+和Trop-2-EOC细胞系的抗体依赖性细胞毒性（ADCC）。评估了SG对Trop-2+ EOC异种移植物的活性。通过IHC在47%（42/90）的卵巢肿瘤中观察到中度至强染色，而通过流式细胞术89%（8/9）的原发性EOC细胞系过表达Trop-2。与对照ADC相比，EOC Trop-2+对SG的敏感性显著更高（<0.05）。SG和hRS7均介导针对Trop-2+细胞系的高ADCC活性。SG还诱导与Trop-2+ EOC细胞混合的Trop-2-肿瘤细胞产生显著的旁观者杀伤作用。在实验中，SG治疗对化疗耐药的EOC异种移植物显示出令人印象深刻的抗肿瘤活性。SG对具有生物学侵袭性和化疗耐药性的EOC细胞系显示出显著的临床前活性，并且对具有异质性Trop-2表达的EOC细胞系具有显著的旁观者效应。有必要进行临床试验。

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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/98f1/7028697/62620c9d9d68/fonc-10-00118-g0002.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/98f1/7028697/7307b3bdafc6/fonc-10-00118-g0007.jpg

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卵巢癌的个性化治疗：晚期复发性卵巢癌的疾病监测、生物标志物表达及靶向治疗综述
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