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N‐glycosylation of PD‐1 promotes binding of camrelizumab
EMBO Reports ( IF 6.5 ) Pub Date : 2020-10-15 , DOI: 10.15252/embr.202051444
Kefang Liu 1, 2, 3 , Shuguang Tan 2 , Wanjun Jin 4 , Jiawei Guan 2 , Qingling Wang 2 , Huan Sun 2 , Jianxun Qi 2 , Jinghua Yan 5 , Yan Chai 2 , Zhongfu Wang 4 , Chuxia Deng 1 , George F Gao 1, 2, 3
Affiliation  

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.

中文翻译:

PD-1的N-糖基化促进卡瑞利珠单抗的结合

PD-1 是一种高度糖基化的抑制性受体,主要在 T 细胞上表达。用单克隆抗体 (MAb) 靶向 PD-1 以阻断与其配体 PD-L1 的相互作用已成功用于治疗多种肿瘤。然而,PD-1 N-糖基化位点的多态性存在于人群中,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,我们展示了 PD-1 中不同的 N-聚糖组成,并显示了最近批准的 PD-1 特异性 MAb camrelizumab 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 相比显着降低。camrelizumab/PD-1复合物的结构表明,camrelizumab主要利用其重链与PD-1结合,而轻链空间抑制PD-L1与PD-1的结合。天冬酰胺 58 (N58) 的糖基化促进与 camrelizumab 的相互作用,而 camrelizumab 抑制 PD-L1 结合的效率对于糖基化缺陷的 PD-1 显着降低。这些结果增加了我们对糖基化如何影响免疫检查点治疗期间 PD-1 特异性 MAb 活性的理解。
更新日期:2020-12-10
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