Anti-tumor activity and biomarker analysis for TROP2-antibody drug conjugate Datopotamab deruxtecan in patient-derived breast cancer xenograft models

Datopotamab deruxtecan (Dato-DXd), is a humanized anti-TROP2 IgG1 monoclonal antibody linked to a potent topoisomerase I inhibitor payload (DXd). Dato-DXd has already shown antitumor activity in breast cancer; however, the determinants of response, including the importance of TROP2 expression, remain unclear. We tested the activity of Dato-DXd in a panel of breast cancer patient-derived xenografts (BCXs) varying in TROP2 expression.The antitumor activity of Dato-DXd and isotype-control-DXd (IgG-DXd) was assessed against 11 BCXs varying in TROP2 expression, 10 representing tumors post-neoadjuvant chemotherapy. Pharmacodynamic effects were assessed at 24 and 72 hours. The effects of TROP2 expression on Dato-DXd activity was assessed in vitro and in vivo using viral overexpression in BCX-derived cell lines.

达妥昔单抗德鲁替康（Datopotamab deruxtecan，简称Dato-DXd）是一款人源化抗滋养层细胞表面抗原2（TROP2）IgG1单克隆抗体，与强效拓扑异构酶I抑制剂载荷（DXd）偶联。Dato-DXd已在乳腺癌中展现出抗肿瘤活性，但肿瘤应答的决定因素（包括TROP2表达的重要性）仍不明确。本研究在一组TROP2表达水平各异的乳腺癌患者来源异种移植瘤（breast cancer patient-derived xenografts，简称BCXs）模型队列中，检测了Dato-DXd的抗肿瘤活性。我们针对11株TROP2表达水平各异的BCX模型（其中10株来源于新辅助化疗后的肿瘤组织），评估了Dato-DXd与同型对照-DXd（IgG-DXd）的抗肿瘤活性，并于给药后24小时及72小时分别检测了药效学效应。此外，通过在BCX来源细胞系中开展病毒介导的过表达实验，我们在体外与体内环境中评估了TROP2表达对Dato-DXd抗肿瘤活性的影响。