Conjugation of glucosylated polymer chains to checkpoint blockade antibodies augments their efficacy and specificity for glioblastoma

被引:56
作者
Yang, Tao [1 ]
Mochida, Yuki [1 ]
Liu, Xueying [1 ]
Zhou, Hang [1 ]
Xie, Jinbing [1 ]
Anraku, Yasutaka [2 ]
Kinoh, Hiroaki [1 ]
Cabral, Horacio [2 ]
Kataoka, Kazunori [1 ,3 ]
机构
[1] Kawasaki Inst Ind Promot, Innovat Ctr NanoMed, Kawasaki, Kanagawa, Japan
[2] Univ Tokyo, Grad Sch Engn, Dept Bioengn, Tokyo, Japan
[3] Univ Tokyo, Inst Future Initiat, Tokyo, Japan
关键词
GROWTH-FACTOR RECEPTOR; OPEN-LABEL; CANCER; EGFR; HETEROGENEITY; MULTICENTER; GLUTATHIONE; EXPRESSION; AVELUMAB; DISEASE;
D O I
10.1038/s41551-021-00803-z
中图分类号
R318 [生物医学工程];
学科分类号
0831 ;
摘要
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. Monoclonal antibodies conjugated with multiple polymer chains functionalized to target glucose transporter 1 and detaching in the reductive tumour microenvironment augment the potency and safety of checkpoint blockade therapy for glioblastoma.
引用
收藏
页码:1274 / 1287
页数:23
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