An unexpected N-terminal loop in PD-1 dominates binding by nivolumab

Area of Science:

• Immunology
• Structural Biology
• Cancer Research

Background:

• Cancer immunotherapy utilizes immune checkpoint inhibitors like nivolumab, a PD-1 targeting antibody.
• Understanding nivolumab's binding mechanism to PD-1 is crucial for optimizing cancer treatments.
• Previous studies speculated PD-1 glycosylation's role in nivolumab recognition.

Purpose of the Study:

• To elucidate the binding mechanism of nivolumab to PD-1.
• To investigate the role of PD-1 N-glycosylation in nivolumab interaction.
• To compare the binding site of nivolumab with that of pembrolizumab.

Main Methods:

• Determined the complex structure of nivolumab with PD-1.
• Performed structural and functional analyses.
• Evaluated the impact of PD-1 N-glycosylation on nivolumab binding.

Main Results:

• Identified an N-terminal loop outside the IgV domain of PD-1 crucial for nivolumab binding.
• Demonstrated that PD-1 N-glycosylation does not influence nivolumab binding.
• Revealed that nivolumab binds to a distinct site on PD-1 compared to pembrolizumab.

Conclusions:

• Nivolumab binding to PD-1 is mediated by an N-terminal loop, independent of N-glycosylation.
• The distinct binding site of nivolumab offers new avenues for designing PD-1-targeting immunotherapies.
• Structural insights advance the development of next-generation cancer checkpoint inhibitors.