Faculty of Health Sciences, University of Macau, Macau SAR, China.
CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.
EMBO Rep. 2020 Dec 3;21(12):e51444. doi: 10.15252/embr.202051444. Epub 2020 Oct 15.
PD-1 is a highly glycosylated inhibitory receptor expressed mainly on T cells. Targeting of PD-1 with monoclonal antibodies (MAbs) to block the interaction with its ligand PD-L1 has been successful for the treatment of multiple tumors. However, polymorphisms at N-glycosylation sites of PD-1 exist in the human population that might affect antibody binding, and dysregulated glycosylation has been observed in the tumor microenvironment. Here, we demonstrate varied N-glycan composition in PD-1, and show that the binding affinity of camrelizumab, a recently approved PD-1-specific MAb, to non-glycosylated PD-1 proteins from E. coli is substantially decreased compared with glycosylated PD-1. The structure of the camrelizumab/PD-1 complex reveals that camrelizumab mainly utilizes its heavy chain to bind to PD-1, while the light chain sterically inhibits the binding of PD-L1 to PD-1. Glycosylation of asparagine 58 (N58) promotes the interaction with camrelizumab, while the efficiency of camrelizumab to inhibit the binding of PD-L1 is substantially reduced for glycosylation-deficient PD-1. These results increase our understanding of how glycosylation affects the activity of PD-1-specific MAbs during immune checkpoint therapy.
PD-1 是一种高度糖基化的抑制性受体，主要表达于 T 细胞上。用单克隆抗体（mAb）靶向 PD-1 以阻断其与配体 PD-L1 的相互作用，已成功用于多种肿瘤的治疗。然而，PD-1 的 N-糖基化位点存在多态性，可能影响抗体结合，并且在肿瘤微环境中观察到糖基化失调。在这里，我们证明了 PD-1 中存在不同的 N-聚糖组成，并表明最近批准的 PD-1 特异性 mAb 卡瑞利珠单抗与来自大肠杆菌的非糖基化 PD-1 蛋白的结合亲和力与糖基化 PD-1 相比显著降低。卡瑞利珠单抗/PD-1 复合物的结构表明，卡瑞利珠单抗主要利用其重链与 PD-1 结合，而轻链则在空间上抑制 PD-L1 与 PD-1 的结合。天冬酰胺 58（N58）的糖基化促进了与卡瑞利珠单抗的相互作用，而对于糖基化缺陷的 PD-1，卡瑞利珠单抗抑制 PD-L1 结合的效率则显著降低。这些结果增加了我们对糖基化如何在免疫检查点治疗期间影响 PD-1 特异性 mAb 活性的理解。
