N-glycosylation of PD-1 promotes binding of camrelizumab

Area of Science:

• Immunology
• Structural Biology
• Glycobiology

Background:

• Programmed cell death protein 1 (PD-1) is an inhibitory receptor on T cells, a key target in cancer immunotherapy.
• Monoclonal antibodies (MAbs) targeting PD-1/PD-L1 interaction are effective cancer treatments.
• Genetic variations and tumor microenvironment alterations in PD-1 glycosylation may affect MAb efficacy.

Purpose of the Study:

• To investigate the role of PD-1 N-glycosylation in the binding affinity and inhibitory function of the PD-1-specific MAb, camrelizumab.
• To elucidate the structural basis of camrelizumab interaction with glycosylated PD-1.

Main Methods:

• Analysis of N-glycan composition of PD-1.
• Comparison of camrelizumab binding affinity to glycosylated and non-glycosylated PD-1.
• Structural determination of the camrelizumab/PD-1 complex.
• Assessment of camrelizumab's efficiency in inhibiting PD-L1 binding to glycosylation-deficient PD-1.

Main Results:

• PD-1 exhibits varied N-glycan compositions.
• Camrelizumab binding affinity to non-glycosylated PD-1 is significantly reduced compared to glycosylated PD-1.
• Camrelizumab primarily uses its heavy chain for PD-1 binding, while the light chain blocks PD-L1 interaction.
• N-glycosylation at N58 enhances camrelizumab binding and PD-L1 inhibition, with reduced efficiency in glycosylation-deficient PD-1.

Conclusions:

• N-glycosylation significantly influences the binding and functional activity of PD-1-specific MAbs like camrelizumab.
• Understanding PD-1 glycosylation is critical for optimizing immune checkpoint therapies.
• Structural insights reveal how glycosylation modulates MAb efficacy in cancer treatment.