Structural basis for the activity and specificity of the immune checkpoint inhibitor lirilumab

Area of Science:

• Immunology
• Structural Biology
• Cancer Research

Background:

• Immune checkpoint inhibitors (ICIs) targeting cytotoxic T-cells have shown clinical success in cancer treatment.
• Natural killer (NK) cells possess potent anticancer activities, but NK cell-specific checkpoint inhibitors are lacking FDA approval.
• Lirilumab, an NK cell checkpoint inhibitor targeting killer immunoglobulin-like receptors (KIRs), has yet to demonstrate conclusive clinical efficacy.

Purpose of the Study:

• To elucidate the crystal structure of lirilumab in complex with KIR2DL3.
• To identify the precise epitope of lirilumab and the molecular mechanisms of KIR checkpoint blockade.
• To investigate the impact of human KIR variations on lirilumab binding and clinical efficacy.

Main Methods:

• X-ray crystallography to determine the structure of lirilumab bound to KIR2DL3.
• Epitope mapping to pinpoint the binding site of lirilumab.
• Binding studies to assess the influence of KIR amino acid variations on lirilumab interaction.

Main Results:

• The crystal structure reveals the precise epitope of lirilumab on KIR2DL3.
• Key amino acids within the epitope exhibit population-level variation.
• These variations significantly impact lirilumab binding affinity.

Conclusions:

• Structural insights into lirilumab-KIR interaction provide a basis for understanding checkpoint blockade mechanisms.
• Patient-specific KIR variations may influence lirilumab's clinical efficacy in cancer immunotherapy.
• Generalizable principles for developing novel NK cell-targeting immune checkpoint inhibitors are established.