趋化因子
效应器
肿瘤微环境
化学
癌症研究
细胞生物学
融合蛋白
CCL21型
免疫系统
趋化因子受体
生物
免疫学
生物化学
重组DNA
基因
作者
Tao Fang,Ran Li,Zeyang Li,Julia Cho,Jonathan S. Guzman,Roger D. Kamm,Hidde L. Ploegh
标识
DOI:10.1021/acs.molpharmaceut.9b00078
摘要
An optimal response to immune checkpoint blockade requires the presence of effector cells in the tumor microenvironment. We designed a PD-L1-targeted delivery strategy for chemokines, key molecules that drive leukocyte trafficking, to the tumor microenvironment, as a means of attracting the relevant leukocyte populations. This strategy combines a PD-L1-blocking single-domain antibody fragment (nanobody or VHH), a charge-engineered chemokine CCL21, and its subsequent characterization in a microfluidic device that resembles the tumor microenvironment. We show that the PD-L1-blocking VHH is a reliable fusion partner for the preparation of a functional chemokine fusion. Engineering the surface charge of CCL21 reduced its nonspecific binding to glycosaminoglycans, a property of chemokines that complicates their targeted delivery. Using a microfluidic assay, we show that it is possible to deliver a chemokine-VHH fusion to a PD-L1-positive environment and recruit effector cells.
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