上皮性卵巢癌（EOC）与最高的妇科癌症死亡率相关。开发新颖、有效的靶向治疗组合仍然是一个未得到满足的医疗需求。我们评估了 datopotamab deruxtecan (Dato-Dxd) 的临床前活性，datopotamab deruxtecan (Dato-Dxd) 是一种新型 TROP2 靶向抗体药物偶联物 (ADC)，在具有可变 TROP2 表达的卵巢癌细胞系和异种移植物中的临床前活性。使用流式细胞术评估 Dato-DXd 的体外细胞活力基于针对一组具有可变 TROP2 表达的 EOC 原代细胞系的测定。使用荧光抗磷酸组蛋白 H2A.X 抗体通过流式细胞术检测 dsDNA 断裂。在 TROP2 过表达异种移植物中测试了 Dato-DXd 的体内抗肿瘤活性。与 TROP2 阴性肿瘤相比，TROP2 过表达 (3) 和中等 (2) 表达的 EOC 细胞系表现出对 Dato-DXd 更高的敏感性。与暴露于非结合缀合物的肿瘤细胞相比，暴露于 TROP2 EOC 的 Dato-DXd 表现出 dsDNA 断裂和膜联蛋白-V 阳性（凋亡标记）增加（分别为 p = 0.001 和 p = 0.016）。在外周血淋巴细胞存在的情况下，Dato-DXd 诱导显着的抗体依赖性细胞毒性 (ADCC)。虽然检测到针对具有低 TROP2 表达的 EOC 细胞系的活性可忽略不计，但当这些细胞与 TROP2 3 肿瘤细胞在体外混合时，Dato-DXd 对具有低/可忽略 TROP2 的肿瘤细胞表现出显着的旁观者杀伤作用。 Dato-DXd 对 EOC 细胞系衍生的异种移植模型表现出肿瘤生长抑制作用，这些模型在 3 个水平上过度表达 TROP2，与对照相比延长了生存期，且毒性最小。Dato-DXd 对 TROP2 过度表达的卵巢癌表现出有希望的临床前活性。未来有必要在卵巢癌患者中进行临床试验。版权所有 © 2024 Elsevier Inc. 保留所有权利。

Epithelial ovarian cancer (EOC) is associated with the highest gynecologic cancer mortality. The development of novel, effective combinations of targeted therapeutics remains an unmet medical need. We evaluated the preclinical activity of datopotamab deruxtecan (Dato-Dxd), a novel TROP2 targeting antibody drug conjugate (ADC) in ovarian cancer cell lines and xenografts with variable TROP2 expression.In vitro cell viability with Dato-DXd was assessed using flow-cytometry based assays against a panel of EOC primary cell lines with variable TROP2 expression. Fluorescent anti-phospho-histone H2A.X antibody was used to detect dsDNA breaks by flow-cytometry. The in vivo antitumor activity of Dato-DXd was tested in TROP2 overexpressing xenografts.TROP2 overexpressing (3+) and moderate (2+) expressing EOC cell lines demonstrated higher sensitivity to Dato-DXd when compared to TROP2 negative tumors. Dato-DXd exposed TROP2+ EOC demonstrated increased dsDNA breaks and Annexin-V positivity (a marker of apoptosis) when compared to tumor cells exposed to the non-binding conjugate (p = 0.001 and p = 0.016, respectively). Dato-DXd induced significant antibody-dependent cellular cytotoxicity (ADCC) in the presence of peripheral-blood-lymphocytes. While negligible activity was detected against EOC cell lines with low TROP2 expression, Dato-DXd demonstrated significant bystander killing against tumor cells with low/negligible TROP2 when such cells were admixed with TROP2 3+ tumor cells in vitro. Dato-DXd showed tumor growth suppression against EOC cell line derived xenograft models that overexpress TROP2 at 3+ levels, prolonging survival when compared to controls, with minimal toxicity.Dato-DXd shows promising preclinical activity against TROP2 overexpressing ovarian cancers. Future clinical trials in ovarian cancer patients are warranted.Copyright © 2024 Elsevier Inc. All rights reserved.