Trastuzumab deruxtecan (DS-8201a), a HER2-targeting antibody–drug conjugate with a topoisomerase I inhibitor exatecan derivative (DX-8951 derivative, DXd), has been reported to exert potent antitumor effects in xenograft mouse models and clinical trials. In this study, the immune system–activating ability of DS-8201a was assessed. DS-8201a significantly suppressed tumor growth in an immunocompetent mouse model with human HER2-expressing CT26.WT (CT26.WT-hHER2) cells. Cured immunocompetent mice rejected not only rechallenged CT26.WT-hHER2 cells, but also CT26.WT-mock cells. Splenocytes from the cured mice responded to both CT26.WT-hHER2 and CT26.WT-mock cells. Further analyses revealed that DXd upregulated CD86 expression on bone marrow–derived dendritic cells (DC) in vitro and that DS-8201a increased tumor-infiltrating DCs and upregulated their CD86 expression in vivo. DS-8201a also increased tumor-infiltrating CD8+ T cells and enhanced PD-L1 and MHC class I expression on tumor cells. Furthermore, combination therapy with DS-8201a and anti–PD-1 antibody was more effective than either monotherapy. In conclusion, DS-8201a enhanced antitumor immunity, as evidenced by the increased expression of DC markers, augmented expression of MHC class I in tumor cells, and rejection of rechallenged tumor cells by adaptive immune cells, suggesting that DS-8201a enhanced tumor recognition by T cells. Furthermore, DS-8201a treatment benefited from combination with anti–PD-1 antibody, possibly due to increased T-cell activity and upregulated PD-L1 expression induced by DS-8201a. Mol Cancer Ther; 17(7); 1494–503. ©2018 AACR.

中文翻译：

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HER2 靶向抗体药物偶联物曲妥珠单抗 deruxtecan (DS-8201a) 可增强小鼠模型的抗肿瘤免疫力

Trastuzumab deruxtecan (DS-8201a) 是一种靶向 HER2 的抗体-药物偶联物，与拓扑异构酶 I 抑制剂 exatecan 衍生物（DX-8951 衍生物，DXd）结合，据报道在异种移植小鼠模型和临床试验中发挥强大的抗肿瘤作用。在这项研究中，评估了 DS-8201a 的免疫系统激活能力。DS-8201a 在具有表达人类 HER2 的 CT26.WT (CT26.WT-hHER2) 细胞的免疫活性小鼠模型中显着抑制肿瘤生长。治愈的免疫活性小鼠不仅排斥再攻击的 CT26.WT-hHER2 细胞，而且排斥 CT26.WT-模拟细胞。来自治愈小鼠的脾细胞对 CT26.WT-hHER2 和 CT26.WT-模拟细胞都有反应。进一步的分析表明，DXd 在体外上调了骨髓来源的树突细胞 (DC) 上的 CD86 表达，而 DS-8201a 增加了肿瘤浸润 DC 并在体内上调了它们的 CD86 表达。DS-8201a 还增加了肿瘤浸润性 CD8+ T 细胞并增强了肿瘤细胞上的 PD-L1 和 MHC I 类表达。此外，DS-8201a 和抗 PD-1 抗体的联合治疗比单一疗法更有效。总之，DS-8201a 增强了抗肿瘤免疫，如 DC 标志物表达增加、肿瘤细胞中 MHC I 类表达增强以及适应性免疫细胞对重新攻击的肿瘤细胞的排斥所证明的，表明 DS-8201a 增强了肿瘤识别T细胞。此外，DS-8201a 治疗受益于与抗 PD-1 抗体的组合，可能是由于 DS-8201a 诱导的 T 细胞活性增加和 PD-L1 表达上调。摩尔癌症治疗; 17(7); 1494-503。©2018 AACR。