Nipocalimab a High Affinity, Immunoselective Clinical FcRn Blocker with Unique Properties: Observations from Non-clinical and Clinical Studies
Nilufer Seth1, Rui Xu1, Steven Tyler2, William Avery3, Traymon Beavers1, Viraj Prage1, Sam Sihapong1, Julia Brown1, Sayak Bhattacharya1, Sindhu Ramchandren1, Kristin Heerlein1, Hong Sun1, Katie Abouzahr1, Leona Ling1
1J&J, 2AVROBIO Inc, 3Kisbee Therapeutics
Objective:
To highlight the molecular, cellular, and in vivo non-clinical properties of nipocalimab supporting its clinical development.
Background:
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).
Design/Methods:
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.
Results:
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.
Conclusions:
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.