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

Despite 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 (PD-1-(iRGD)2) through glycoengineering and bio-orthogonal reaction. PD-1-(iRGD)2 exhibited extra iRGD receptor dependent affinity to several cancer cell lines rather than normal cell lines. Via dual targeting, PD-1-(iRGD)2 engageed 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, PD-1-(iRGD)2 effectively reduced tumor growth with satisfactory biosafety. Moreover, results of flow cytometry and single-cell RNA-seq revealed that PD-1-(iRGD)2 remodeled the tumor microenvironment (TME) and expanded a unique population of "better effector" CD8+ tumor infiltrating T cells (TILs) expressing stem and memory associated genes including Tcf7, Il7r, Lef1 and Bach2. Conclusively, PD-1-(iRGD)2 could 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, PD-1-(iRGD)2 engages 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.