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

• DOI: 10.1016/j.xcrm.2024.101590
• Publication Date: 2024-06-05T16:18:01Z
• Authors: 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 P. Li; Jia Wei
• Keywords: Immunoconjugates; T-Lymphocytes; Programmed Cell Death 1 Receptor; CD8-Positive T-Lymphocytes; Lymphocyte Activation; Article; Mice, Inbred C57BL; Mice; Lymphocytes, Tumor-Infiltrating; Cell Line, Tumor; Tumor Microenvironment; Animals; Humans; Female; Oligopeptides; Immune Checkpoint Inhibitors

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.