程序性死亡 1 (PD-1) 和程序性死亡配体 1 (PD-L1) 是对免疫治疗产生重大影响的关键免疫检查点 (IC)。肿瘤对单 IC 靶向药物的耐药性增加了人们对双靶点药物的兴趣，双靶点药物已显示出癌症治疗的可行性。在本研究中，我们旨在开发针对PD-1/PD-L1通路的双靶点肽药物，并评估其与功能性抗体相比在增强人T细胞对舌鳞癌细胞系的细胞毒性方面的功效。通过序列分析和肽截短，我们修饰了一个针对 PD-1 的现有肽，名为 nABPD-1。随后，我们获得了两种新型肽，分别命名为nABPD-2和nABPD-3，其中与nABPD-1相比，nABPD-2对人PD-1蛋白的亲和力增强。重要的是，nABPD-2 表现出双靶向能力，对 PD-L1 和 PD-1 均具有高亲和力。此外，nABPD-2有效促进人类T细胞对舌鳞状细胞癌细胞系的细胞毒性，超过单独的抗PD-1或抗PD-L1功能性抗体的功效。考虑到 nABPD-2 的生产成本和剂量要求较低，它有可能用于治疗应用。版权所有 © 2024 Elsevier B.V. 保留所有权利。

Programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1) are key immune checkpoints (ICs) that critically influence immunotherapy. Tumor resistance to single IC-targeting drugs has increased interest in dual-target drugs, which have shown feasibility for cancer treatment. In this study, we aimed to develop dual-target peptide drugs targeting the PD-1/PD-L1 pathway and to evaluate their efficacy compared to functional antibodies in enhancing the cytotoxicity of human T cells against tongue squamous carcinoma cell lines. Through sequence analysis and peptide truncation, we modified a pre-existing peptide named nABPD-1 targeting PD-1. Subsequently, we obtained two novel peptides named nABPD-2 and nABPD-3, with nABPD-2 showing an enhanced affinity for human PD-1 protein compared to nABPD-1. Importantly, nABPD-2 exhibited dual-targeting capability, possessing a high affinity for both PD-L1 and PD-1. Furthermore, nABPD-2 effectively promoted the cytotoxicity of human T cells against tongue squamous carcinoma cell lines, surpassing the efficacy of anti-PD-1 or anti-PD-L1 functional antibodies alone. Considering that nABPD-2 has lower production costs and dose requirements, it can potentially be used in therapeutic applications.Copyright © 2024 Elsevier B.V. All rights reserved.