N-glycosylation of PD-1 promotes binding of camrelizumab
N-glycosylation of PD-1 promotes binding of camrelizumab
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DOI：
10.15252/embr.202051444
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发表时间：
2020-10-15
期刊：
影响因子：
7.7
通讯作者：
Gao, George F.
中科院分区：
文献类型：
--
作者：
Liu, Kefang;Tan, Shuguang;Gao, George F.
PD-1 is a highly glycosylated inhibitory receptor expressed mainly on T cells. Targeting ofPD-1 with monoclonal antibodies (MAbs) to block the interaction with its ligandPD-L1 has been successful for the treatment of multiple tumors. However, polymorphisms at N-glycosylation sites ofPD-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 inPD-1, and show that the binding affinity of camrelizumab, a recently approvedPD-1-specificMAb, to non-glycosylatedPD-1 proteins fromE. coliis substantially decreased compared with glycosylatedPD-1. The structure of the camrelizumab/PD-1 complex reveals that camrelizumab mainly utilizes its heavy chain to bind toPD-1, while the light chain sterically inhibits the binding ofPD-L1 toPD-1. Glycosylation of asparagine 58 (N58) promotes the interaction with camrelizumab, while the efficiency of camrelizumab to inhibit the binding ofPD-L1 is substantially reduced for glycosylation-deficientPD-1. These results increase our understanding of how glycosylation affects the activity ofPD-1-specificMAbs during immune checkpoint therapy.
