Greenman Michelle, Bellone Stefania, Demirkiran Cem, Hartwich Tobias Max Philipp, Ettorre Victoria M, McNamara Blair, Sethi Namrata, Santin Niccolo G, Palmieri Luca, Yang-Hartwich Yang, Ratner Elena, Santin Alessandro D
Department of Obstetrics, Gynecology, and Reproductive Sciences Yale University School of Medicine, CT 06520, USA.
Humanitas Hospital San Pio X, Humanitas University, Rozzano, Milan, Italy.
Gynecol Oncol. 2025 Aug;199:64-71. doi: 10.1016/j.ygyno.2025.06.017. Epub 2025 Jun 28.
Uterine and ovarian carcinosarcomas (CS) are rare gynecologic tumors with a high recurrence rate and poor prognosis. Datopotamab-deruxtecan (Dato-DXd) is a novel antibody-drug-conjugate (ADC) targeting TROP2. We evaluated the preclinical activity of Dato-DXd in vitro against primary and metastatic CS cell lines with various TROP2 expression and in vivo against CS xenografts in mice.
TROP2 expression was determined using flow-cytometry. Cells were treated with Dato-DXd and a control ADC (CTL ADC) to evaluate IC values. Double-strand-DNA-breakage assay evaluated DNA damage while antibody-dependent-cell-cytotoxicity (ADCC) was evaluated using a 4-h chromium-release assay. Mice harboring CS xenografts were treated via retro-orbital Dato-DXd administration.
TROP2 expressing CS cell lines were highly sensitive to killing induced by Dato-DXd. In contrast, low-expressing CS cell lines had no significant difference in cell cytotoxicity. Dato-DXd induced ADCC in the presence of peripheral blood lymphocytes from healthy donors. When TROP2-negative cells were admixed with TROP2-overexpressing cells, a significant bystander effect with Dato-DXd was appreciated. In vivo, mouse xenografts overexpressing TROP2 treated with Dato-DXd demonstrated tumor growth suppression and longer overall survival compared to CTL ADC-treated xenografts.
Dato-DXd is active against primary and metastatic uterine and ovarian CS overexpressing TROP2 in vitro and in vivo. Our preclinical results warrant future clinical trials for patients with advanced/recurrent gynecologic CS resistant to chemotherapy.
子宫和卵巢癌肉瘤（CS）是罕见的妇科肿瘤，复发率高且预后不良。达妥昔单抗德鲁替康（Dato-DXd）是一种靶向TROP2的新型抗体药物偶联物（ADC）。我们评估了Dato-DXd在体外对具有不同TROP2表达的原发性和转移性CS细胞系的活性，以及在体内对小鼠CS异种移植瘤的活性。
使用流式细胞术测定TROP2表达。用Dato-DXd和对照ADC（CTL ADC）处理细胞以评估IC值。双链DNA断裂试验评估DNA损伤，而抗体依赖性细胞毒性（ADCC）则使用4小时铬释放试验进行评估。通过眶后注射Dato-DXd治疗携带CS异种移植瘤的小鼠。
表达TROP2的CS细胞系对Dato-DXd诱导的杀伤高度敏感。相比之下，低表达的CS细胞系在细胞毒性方面没有显著差异。Dato-DXd在健康供体的外周血淋巴细胞存在下诱导ADCC。当TROP2阴性细胞与TROP2过表达细胞混合时，可观察到Dato-DXd有显著的旁观者效应。在体内，与CTL ADC处理的异种移植瘤相比，用Dato-DXd处理的过表达TROP2的小鼠异种移植瘤表现出肿瘤生长抑制和更长的总生存期。
Dato-DXd在体外和体内对过表达TROP2的原发性和转移性子宫及卵巢CS具有活性。我们的临床前结果为晚期/复发性对化疗耐药的妇科CS患者的未来临床试验提供了依据。
