1School of Life Sciences, Anhui University, 230601 Hefei, Anhui China.
2Institutes of Physical Science and Information Technology, Anhui University, 230601 Hefei, Anhui China.
Commun Biol. 2019 Oct 25;2:392. doi: 10.1038/s42003-019-0642-9. eCollection 2019.
Programmed cell death 1 (PD-1) is inhibitory receptor and immune checkpoint protein. Blocking the interaction of PD-1 and its ligands PD-L1/ L2 is able to active T-cell-mediated antitumor response. Monoclonal antibody-based drugs targeting PD-1 pathway have exhibited great promise in cancer therapy. Here we show that MW11-h317, an anti-PD-1 monoclonal antibody, displays high affinity for PD-1 and blocks PD-1 interactions with PD-L1/L2. MW11-h317 can effectively induce T-cell-mediated immune response and inhibit tumor growth in mouse model. Crystal structure of PD-1/MW11-h317 Fab complex reveals that both the loops and glycosylation of PD-1 are involved in recognition and binding, in which Asn58 glycosylation plays a critical role. The unique glycan epitope in PD-1 to MW11-h317 is different from the first two approved clinical PD-1 antibodies, nivolumab and pembrolizumab. These results suggest MW11-h317 as a therapeutic monoclonal antibody of PD-1 glycosylation-targeting which may become efficient alternative for cancer therapy.
程序性细胞死亡蛋白 1（PD-1）是抑制性受体和免疫检查点蛋白。阻断 PD-1 与其配体 PD-L1/L2 的相互作用能够激活 T 细胞介导的抗肿瘤反应。针对 PD-1 通路的单克隆抗体药物在癌症治疗中显示出巨大的潜力。在这里，我们展示了 MW11-h317，一种抗 PD-1 单克隆抗体，对 PD-1 具有高亲和力，并阻断 PD-1 与 PD-L1/L2 的相互作用。MW11-h317 可以有效地诱导 T 细胞介导的免疫反应，并抑制小鼠模型中的肿瘤生长。PD-1/MW11-h317 Fab 复合物的晶体结构表明，PD-1 的环和糖基化都参与了识别和结合，其中 Asn58 糖基化起着关键作用。PD-1 与 MW11-h317 的独特聚糖表位与前两种批准的临床 PD-1 抗体，nivolumab 和 pembrolizumab 不同。这些结果表明 MW11-h317 是一种针对 PD-1 糖基化的治疗性单克隆抗体，可能成为癌症治疗的有效替代方法。
