A bispecific peptide-polymer conjugate bridging target-effector cells to enhance immunotherapy.

Abstract

Peptide-based immune checkpoint inhibitors exhibited remarkable therapeutic benefits although their application was hindered by quick blood clearance and low affinity with receptors. The modification of the peptides into artificial antibodies was an ideal platform to solve these problems, and one of the optional pathways was 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, we prepared a bispecific peptide-polymer conjugate (octa PEG-PD1-PDL1) by simultaneously conjugating PD1-binding and PDL1-binding peptides onto 8-arm-PEG. octa PEG-PD1-PDL1 bridged T cells and cancer cells and thus enhanced T cell-mediated cytotoxicity against cancer cells. Meanwhile, the tumor-targeting octa PEG-PD1-PDL1 increased the infiltration of cytotoxic T lymphocytes in tumors and reduced their exhaustion. It effectively activated the tumor immune microenvironment and exerted a potent antitumor effect against CT26 tumor models with a tumor inhibition rate of 88.9%. This work provided a novel strategy to enhance tumor immunotherapy through conjugating bispecific peptides onto a hyperbranched polymer to effectively engage target-effector cells. This article is protected by copyright. All rights reserved.