西格莱克
癌症研究
免疫系统
免疫检查点
可药性
免疫疗法
下调和上调
基诺美
癌症
生物
免疫学
癌症免疫疗法
医学
信号转导
细胞生物学
内科学
生物化学
基因
作者
Melissa A. Gray,Michal A. Stanczak,Natália Rodrigues Mantuano,Han Xiao,Johan F. A. Pijnenborg,Stacy A. Malaker,Caitlyn L. Miller,Payton A. Weidenbacher,Julia T. Tanzo,Green Ahn,Elliot C. Woods,Heinz Läubli,Carolyn R. Bertozzi
标识
DOI:10.1038/s41589-020-0622-x
摘要
Currently approved immune checkpoint inhibitor therapies targeting the PD-1 and CTLA-4 receptor pathways are powerful treatment options for certain cancers; however, most patients across cancer types still fail to respond. Consequently, there is interest in discovering and blocking alternative pathways that mediate immune suppression. One such mechanism is an upregulation of sialoglycans in malignancy, which has been recently shown to inhibit immune cell activation through multiple mechanisms and therefore represents a targetable glycoimmune checkpoint. Since these glycans are not canonically druggable, we designed an αHER2 antibody-sialidase conjugate that potently and selectively strips diverse sialoglycans from breast cancer cells. In syngeneic breast cancer models, desialylation enhanced immune cell infiltration and activation and prolonged the survival of mice, an effect that was dependent on expression of the Siglec-E checkpoint receptor found on tumor-infiltrating myeloid cells. Thus, antibody-sialidase conjugates represent a promising modality for glycoimmune checkpoint therapy.
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