Bystander killing effect of DS-8201a, a novel anti-human epidermal growth factor receptor 2 antibody-drug conjugate, in tumors with human epidermal growth factor receptor 2 heterogeneity.
Bystander killing effect of DS-8201a, a novel anti-human epidermal growth factor receptor 2 antibody-drug conjugate, in tumors with human epidermal growth factor receptor 2 heterogeneity.
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DOI：
10.1111/cas.12966
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发表时间：
2016-07
期刊：
影响因子：
5.7
通讯作者：
Agatsuma T
中科院分区：
文献类型：
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作者：
Ogitani Y;Hagihara K;Oitate M;Naito H;Agatsuma T
抗体-药物缀合物选择性地且有效地将抗癌剂递送至肿瘤组织，并且具有显著的抗肿瘤功效和宽的治疗窗。DS-8201 a是一种人表皮生长因子受体2（HER 2）靶向抗体-药物偶联物，使用新型连接体-有效负载系统与强效拓扑异构酶I抑制剂依沙替康衍生物（DX-8951衍生物，DXd）制备。它对高和低HER 2表达的曲妥珠单抗-美坦新偶联物（T-DM 1）不敏感的患者源性异种移植物模型有效。在本研究中，评价了DS-8201 a的旁观者杀伤效应，并与T-DM 1进行了比较。我们证实DS-8201 a的有效载荷DXd（1）具有高度膜渗透性，而T-DM 1的有效载荷Lys-SMCC-DM 1具有较低的渗透性。在HER 2阳性KPL-4细胞和阴性MDA-MB-468细胞的体外共培养条件下，DS-8201 a可杀死这两种细胞，而T-DM 1和具有低渗透性有效负载的抗体-药物偶联物抗HER 2-DXd（2）则不会。通过使用体内成像系统，使用接种HER 2阳性NCI-N87细胞和HER 2阴性MDA-MB-468-Luc细胞的混合物的小鼠进行体内评价。在体内，DS-8201 a降低了小鼠的荧光素酶信号，表明抑制了MDA-MB-468-Luc群体;然而，T-DM 1和抗HER 2-DXd（2）没有。此外，已证实DS-8201 a对接种在NCI-N87肿瘤对侧的MDA-MB-468-Luc肿瘤无效，表明DS-8201 a的旁观者杀伤效应仅在邻近HER 2阳性细胞的细胞中观察到，表明全身毒性问题较低。这些结果表明，DS-8201 a由于具有高度膜渗透性的有效负载而具有强效旁观者效应，并且在治疗对T-DM 1无应答的HER 2异质性肿瘤方面具有益处。
Antibody–drug conjugates deliver anticancer agents selectively and efficiently to tumor tissue and have significant antitumor efficacy with a wide therapeutic window. DS‐8201a is a human epidermal growth factor receptor 2 (HER2)‐targeting antibody–drug conjugate prepared using a novel linker‐payload system with a potent topoisomerase I inhibitor, exatecan derivative (DX‐8951 derivative, DXd). It was effective against trastuzumab emtansine (T‐DM1)‐insensitive patient‐derived xenograft models with both high and low HER2 expression. In this study, the bystander killing effect of DS‐8201a was evaluated and compared with that of T‐DM1. We confirmed that the payload of DS‐8201a, DXd (1), was highly membrane‐permeable whereas that of T‐DM1, Lys‐SMCC‐DM1, had a low level of permeability. Under a coculture condition of HER2‐positive KPL‐4 cells and negative MDA‐MB‐468 cells in vitro, DS‐8201a killed both cells, whereas T‐DM1 and an antibody–drug conjugate with a low permeable payload, anti‐HER2‐DXd (2), did not. In vivo evaluation was carried out using mice inoculated with a mixture of HER2‐positive NCI‐N87 cells and HER2‐negative MDA‐MB‐468‐Luc cells by using an in vivo imaging system. In vivo, DS‐8201a reduced the luciferase signal of the mice, indicating suppression of the MDA‐MB‐468‐Luc population; however, T‐DM1 and anti‐HER2‐DXd (2) did not. Furthermore, it was confirmed that DS‐8201a was not effective against MDA‐MB‐468‐Luc tumors inoculated at the opposite side of the NCI‐N87 tumor, suggesting that the bystander killing effect of DS‐8201a is observed only in cells neighboring HER2‐positive cells, indicating low concern in terms of systemic toxicity. These results indicated that DS‐8201a has a potent bystander effect due to a highly membrane‐permeable payload and is beneficial in treating tumors with HER2 heterogeneity that are unresponsive to T‐DM1.