Anti-PD-1-iRGD Peptide Conjugate Boosts Antitumor Efficacy via Engagement Augmentation and Penetration Enhancement of T cells

Abstract

AbstractDespite the important breakthroughs of immune-checkpoint inhibitors (ICIs) in recent years, the overall objective response rate (ORR) remains limited in various cancers. Here, we synthesized programmed cell death protein-1 (PD-1) antibody iRGD conjugate (αPD-1-(iRGD)2) through glycoengineering and bio-orthogonal reaction. αPD-1-(iRGD)2exhibited extra iRGD receptor dependent affinity to several cancer cell lines rather than normal cell lines. Via dual targeting, αPD-1-(iRGD)2engageed tumor cells and T cells thus mediating T cell activation and facilitating tumor elimination. Besides, the attachment of iRGD impressively improved the penetrability of both PD-1 antibody and PD-1+T cells. In multiple syngeneic mouse models, αPD-1-(iRGD)2effectively reduced tumor growth with satisfactory biosafety. Moreover, results of flow cytometry and single-cell RNA-seq revealed that αPD-1-(iRGD)2remodeled the tumor microenvironment (TME) and expanded a unique population of “better effector” CD8+tumor infiltrating T cells (TILs) expressing stem and memory associated genes includingTcf7,Il7r,Lef1andBach2. Conclusively, αPD-1-(iRGD)2could be a novel and promising therapeutic approach for cancer immunotherapy.Statement of significanceDesigned against the clinical dilemma of unsatisfied response rate after contemporary cancer immunotherapy, αPD-1-(iRGD)2engages T cells and tumor cells, promotes T cell infiltration and expands a unique population of “better effectors” with enhanced therapeutic potential for the treatment of cancer.