A Bispecific Peptide-Polymer Conjugate Bridging Target-Effector Cells to Enhance Immunotherapy

Peptide-based immune checkpoint inhibitors exhibit remarkable therapeutic benefits although their application is hindered by quick blood clearance and low affinity with receptors. The modification of the peptides into artificial antibodies is an ideal platform to solve these problems, and one of the optional pathways is the conjugation of peptides with a polymer. More importantly, the bridging effect, mediated by bispecific artificial antibodies, could promote the interaction of cancer cells and T cells, which will benefit cancer immunotherapy. Herein, a bispecific peptide-polymer conjugate (^octa PEG-PD1-PDL1) is prepared by simultaneously conjugating PD1-binding and PDL1-binding peptides onto 8-arm-PEG. ^octa PEG-PD1-PDL1 bridges T cells and cancer cells and thus enhances T cell-mediated cytotoxicity against cancer cells. Meanwhile, the tumor-targeting ^octa PEG-PD1-PDL1 increases the infiltration of cytotoxic T lymphocytes in tumors and reduces their exhaustion. It effectively activates the tumor immune microenvironment and exerts a potent antitumor effect against CT26 tumor models with a tumor inhibition rate of 88.9%. This work provides a novel strategy to enhance tumor immunotherapy through conjugating bispecific peptides onto a hyperbranched polymer to effectively engage target-effector cells.