7CU5

N-Glycosylation of PD-1 and glycosylation dependent binding of PD-1 specific monoclonal antibody camrelizumab

Summary for 7CU5

• Entry DOI: 10.2210/pdb7cu5/pdb
• Descriptor: camrelizumab-scFv, Programmed cell death protein 1, alpha-D-mannopyranose-(1-6)-alpha-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-[alpha-L-fucopyranose-(1-6)]2-acetamido-2-deoxy-beta-D-glucopyranose, ... (6 entities in total)
• Functional Keywords: camrelizumab, glycosylation, pd-1., immune system
• Biological source: Homo sapiens; More
• Total number of polymer chains: 4
• Total formula weight: 79833.54

Authors

Liu, K.F.,Tan, S.G.,Jin, W.J.,Guan, J.W.,Wang, W.L.,Sun, H.,Qi, J.X.,Yan, J.H.,Chai, Y.,Wang, Z.F.,Chu, X.D.,Gao, G.F. (deposition date: 2020-08-21, release date: 2020-10-14, Last modification date: 2024-10-30)

Primary citation

Liu, K.,Tan, S.,Jin, W.,Guan, J.,Wang, Q.,Sun, H.,Qi, J.,Yan, J.,Chai, Y.,Wang, Z.,Deng, C.,Gao, G.F.
N-glycosylation of PD-1 promotes binding of camrelizumab.
Embo Rep., 21:e51444-e51444, 2020

PubMed Abstract: 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.

PubMed: 33063473
DOI: 10.15252/embr.202051444

Experimental method

X-RAY DIFFRACTION (2.81 Å)