PD1/PDL1 pathway plays a critical role in cancer immune responses. The immune checkpoint inhibitors of PD1/PDL1 have been well explored and developed for immunotherapies of solid tumors. Recently, various monoclonal antibodies targeting the PD1/PDL1 pathway have emerged and achieved remarkable success in clinical trials. However, challenges with these monoclonal antibodies have appeared during cancer therapies, including predictors of response, patient selection, and innate resistance. Thus, a competitive antagonist of native PD1/PDL1, with smaller size and lower side-effect, is required for future cancer therapies. In this study, we utilized a protein evolution system of phage-assisted continuous evolution (PACE) to evolve PD1 continuously. Our results indicated that the newly evolved PD1 bound to PDL1 with higher affinity. The interactome analysis further suggested that these evolved PD1s exhibited higher specificity with PDL1. Therefore, these evolved PD1s may be applied as a new tool for tumor immunotherapy.

PD1 / PDL1途径在癌症免疫反应中起关键作用。PD1 / PDL1的免疫检查点抑制剂已被广泛研究和开发用于实体瘤的免疫治疗。最近，已经出现了针对PD1 / PDL1途径的各种单克隆抗体，并在临床试验中取得了显著成功。然而，在癌症治疗期间，这些单克隆抗体的挑战已经出现，包括反应的预测因子，患者选择和先天性抵抗力。因此，未来的癌症治疗需要具有较小尺寸和较低副作用的天然PD1 / PDL1竞争性拮抗剂。在这项研究中，我们利用噬菌体辅助连续进化（PACE）的蛋白质进化系统来连续进化PD1。我们的结果表明，新进化的PD1以更高的亲和力与PDL1结合。相互作用组分析进一步表明，这些进化的PD1对PDL1表现出更高的特异性。因此，这些进化的PD1s可以用作肿瘤免疫治疗的新工具。