Immune checkpoint inhibitors have drawn a consider attention as an effective cancer immunotherapy, and several monoclonal antibodies targeting the immune checkpoint receptors, such as human programmed cell death-1 (hPD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), are clinically used for treatment of various cancers. Here we present the development of a small-sized protein binder which specifically binds to hPD-1. The protein binder, which is composed of leucine-rich repeat (LRR) modules, was selected against hPD-1 through phage display, and its binding affinity was maturated up to 17 nM by modular evolution approach. The protein binder was shown to be highly specific for hPD-1, effectively inhibiting the interaction between hPD-1 and its ligand, hPD-L1. The protein binder restored T-cell function in vitro, and exhibited a strong anti-tumour activity in tumour mouse model, indicating that it acts as an effective checkpoint blockade. Based on the results, the developed protein binder specific for hPD-1 is likely to find a potential use in cancer immunotherapy.

中文翻译：

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一种对人 PD-1 特异的小型蛋白质结合剂可有效抑制肿瘤小鼠模型中的肿瘤生长。

免疫检查点抑制剂作为一种有效的癌症免疫疗法引起了人们的关注，一些针对免疫检查点受体的单克隆抗体，如人程序性细胞死亡-1 (hPD-1) 和细胞毒性 T 淋巴细胞相关蛋白 4 (CTLA-4) )，临床上用于治疗各种癌症。在这里，我们介绍了一种与 hPD-1 特异性结合的小型蛋白质结合剂的开发。蛋白质结合剂由富含亮氨酸的重复 (LRR) 模块组成，通过噬菌体展示针对 hPD-1 进行选择，其结合亲和力通过模块化进化方法成熟至 17 nM。蛋白质结合剂被证明对 hPD-1 具有高度特异性，可有效抑制 hPD-1 与其配体 hPD-L1 之间的相互作用。蛋白质结合剂在体外恢复了 T 细胞功能，并在肿瘤小鼠模型中表现出很强的抗肿瘤活性，表明它作为一种有效的检查点阻断剂。基于这些结果，开发的 hPD-1 特异性蛋白质结合剂很可能在癌症免疫治疗中找到潜在用途。