Glycoengineering-based anti-PD-1-iRGD peptide conjugate boosts antitumor efficacy through T cell engagement

作者：Yunfeng Pan, Qi Xue, Yi Yang, Tao Shi, Hanbing Wang, Xueru Song, Yuting Luo, Wenqi Liu, Shiji Ren, Yiran Cai, Yang Nie, Zhentao Song, Baorui Liu, Jie Li, Jia Wei · 发表于：Cell Reports Medicine · 年份：2024 · DOI：10.1016/j.xcrm.2024.101590 · 被引用次数：12 · 研究领域：CAR-T cell therapy research、Cancer Immunotherapy and Biomarkers、Immunotherapy and Immune Responses

Despite the important breakthroughs of immune checkpoint inhibitors in recent years, the objective response rates remain limited. Here, we synthesize programmed cell death protein-1 (PD-1) antibody-iRGD cyclic peptide conjugate (αPD-1-(iRGD) 2 ) through glycoengineering methods. In addition to enhancing tissue penetration, αPD-1-(iRGD) 2 simultaneously engages tumor cells and PD-1 + T cells via dual targeting, thus mediating tumor-specific T cell activation and proliferation with mild effects on non-specific T cells. In multiple syngeneic mouse models, αPD-1-(iRGD) 2 effectively reduces tumor growth with satisfactory biosafety. Moreover, results of flow cytometry and single-cell RNA-seq reveal that αPD-1-(iRGD) 2 remodels the tumor microenvironment and expands a population of "better effector" CD8 + tumor infiltrating T cells expressing stem- and memory-associated genes, including Tcf7 , Il7r , Lef1 , and Bach2 . Conclusively, αPD-1-(iRGD) 2 is a promising antibody conjugate therapeutic beyond antibody-drug conjugate for cancer immunotherapy.