To highlight the molecular, cellular, and in vivo non-clinical properties of nipocalimab supporting its clinical development.

Nipocalimab is a clinically validated monoclonal antibody that exclusively blocks binding of Immunoglobulin G (IgG) to the neonatal fragment crystallizable (Fc) receptor (FcRn) resulting in decreased levels of circulating IgG, including IgG autoantibodies. Nipocalimab is the only anti-FcRn currently being studied across the 3 segments of autoantibody diseases: maternal fetal, rare autoantibody, and prevalent rheumatology. Here we focus on the key non-clinical properties and clinical outcomes in generalized myasthenia gravis (gMG).

Nipocalimab binding epitopes on FcRn were determined using x-ray crystallography. Cell based assays, in vivo mouse and cynomolgus monkey studies, and human clinical data to demonstrate binding to FcRn, IgG lowering, and pharmacokinetic- pharmacodynamic- receptor occupancy relationships.

Nipocalimab is a fully human IgG1 monoclonal antibody engineered to bind with high affinity and specificity to the IgG binding site on FcRn at both endosomal and extracellular pH. A 2.41 Å isotropic resolution structure indicates a unique binding conformation and explains it’s high affinity and specificity of binding to the IgG binding site in FcRn. The selectivity and functional activity were observed in biomolecular and cell-based assays. Nipocalimab demonstrates a consistent dose-dependent pharmacokinetic-pharmacodynamic-receptor occupancy relationship in nonclinical and clinical studies leading to rapid decreases in IgG including IgG autoantibodies correlating to clinical response in gMG.

These data demonstrate that nipocalimab is a high affinity, immuno-selective FcRn blocker that demonstrates a consistent concentration dependent receptor occupancy that results in rapid, deep, and sustained lowering of IgG, including IgG autoantibodies to a favorable clinical outcome in gMG.