Conjugation of glucosylated polymer chains to checkpoint blockade antibodies augments their efficacy and specificity for glioblastoma
Conjugation of glucosylated polymer chains to checkpoint blockade antibodies augments their efficacy and specificity for glioblastoma
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DOI：
10.1038/s41551-021-00803-z
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发表时间：
2021-10
影响因子：
28.1
通讯作者：
Tao Yang;Y. Mochida;Xueying Liu;Hang Zhou;Jinbing Xie;Y. Anraku;H. Kinoh;H. Cabral;K. Kataoka
中科院分区：
文献类型：
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作者：
Tao Yang;Y. Mochida;Xueying Liu;Hang Zhou;Jinbing Xie;Y. Anraku;H. Kinoh;H. Cabral;K. Kataoka
由于血液-肿瘤屏障和与健康组织的交叉反应，针对胶质母细胞瘤的免疫检查点阻断治疗效果不佳，且与免疫相关不良事件的风险很高。在这里，我们展示了与多个聚乙二醇链结合的抗程序性死亡配体1抗体对靶向葡萄糖转运蛋白1(在脑毛细血管中过表达)的作用，以及在还原的肿瘤微环境中的分离，增加了检查点阻断治疗胶质母细胞瘤的有效性和安全性。在携带原位胶质母细胞瘤的小鼠中，单剂葡萄糖化和多聚乙二醇化抗体可重振抗肿瘤免疫反应，诱导免疫记忆，保护动物免受肿瘤细胞的再次攻击，并抑制动物健康组织中的自身免疫反应。利用多价配体相互作用和肿瘤微环境的特性来促进血液-肿瘤屏障的跨越和提高药物特异性的药物递送制剂可能会增强其他基于抗体的治疗的有效性和安全性。
Because of the blood–tumour barrier and cross-reactivity with healthy tissues, immune checkpoint blockade therapy against glioblastoma has inadequate efficacy and is associated with a high risk of immune-related adverse events. Here we show that anti-programmed death-ligand 1 antibodies conjugated with multiple poly(ethylene glycol) (PEG) chains functionalized to target glucose transporter 1 (which is overexpressed in brain capillaries) and detaching in the reductive tumour microenvironment augment the potency and safety of checkpoint blockade therapy against glioblastoma. In mice bearing orthotopic glioblastoma tumours, a single dose of glucosylated and multi-PEGylated antibodies reinvigorated antitumour immune responses, induced immunological memory that protected the animals against rechallenge with tumour cells, and suppressed autoimmune responses in the animals’ healthy tissues. Drug-delivery formulations leveraging multivalent ligand interactions and the properties of the tumour microenvironment to facilitate the crossing of blood–tumour barriers and increase drug specificity may enhance the efficacy and safety of other antibody-based therapies.