Gu Zikuan, Xu Shuxin, Guo Zhanchen, Liu Zhen
State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University 163 Xianlin Avenue Nanjing 210023 China
Chem Sci. 2022 Aug 30;13(36):10897-10903. doi: 10.1039/d2sc03412c. eCollection 2022 Sep 21.
Blocking the PD-1/PD-L1 immune checkpoint has emerged as a promising strategy in cancer immunotherapy, in which monoclonal antibodies are predominately used as inhibitors. Despite their remarkable success, monoclonal antibody-based therapeutics suffer from drawbacks due to the use of antibodies, such as high cost, low stability and high frequency of immune-related adverse effects. Therefore, novel anti-PD-1/PD-L1 therapeutics that can address these issues are of significant importance. Herein, we report a molecularly imprinted polymer (MIP) based PD-1 nano inhibitor for blocking the PD-1/PD-L1 axis. The anti-PD-1 nanoMIP was rationally designed and engineered by epitope imprinting using the N-terminal epitope of PD-1 as the binding site. The anti-PD-1 nanoMIP showed good specificity and high affinity towards PD-1, yielding a disassociation constant at the 10 M level, much better than that between PD-1 and PD-L1. steric hindrance, this inhibitor could effectively block PD-1/PD-L1 interaction. Besides, it could effectively reactivate T cells and reverse the chemoresistance of tumor cells. Therefore, this present study not only provides a novel and promising immune checkpoint blockade inhibitor but also boosts further development of MIPs for cancer immunotherapy.
阻断PD-1/PD-L1免疫检查点已成为癌症免疫治疗中一种有前景的策略，其中单克隆抗体主要用作抑制剂。尽管取得了显著成功，但基于单克隆抗体的治疗方法由于使用抗体而存在缺点，如成本高、稳定性低和免疫相关不良反应频率高。因此，能够解决这些问题的新型抗PD-1/PD-L1治疗方法具有重要意义。在此，我们报道了一种基于分子印迹聚合物（MIP）的PD-1纳米抑制剂，用于阻断PD-1/PD-L1轴。通过以PD-1的N端表位为结合位点进行表位印迹，合理设计并构建了抗PD-1纳米MIP。抗PD-1纳米MIP对PD-1表现出良好的特异性和高亲和力，解离常数在10 M水平，远优于PD-1与PD-L1之间的解离常数。由于空间位阻，该抑制剂可有效阻断PD-1/PD-L1相互作用。此外，它还能有效重新激活T细胞并逆转肿瘤细胞的化疗耐药性。因此，本研究不仅提供了一种新型且有前景的免疫检查点阻断抑制剂，还推动了用于癌症免疫治疗的MIPs的进一步发展。
