Molecular basis for antagonistic activity of anifrolumab, an anti-interferon–α receptor 1 antibody

摘要: Anifrolumab (anifrolumab) is an antagonist human monoclonal antibody that targets interferon α receptor 1 (IFNAR1). has been developed to treat autoimmune diseases and currently in clinical trials. To decipher the molecular basis of its mechanism action, we engaged multiple epitope mapping approaches determine how it interacts with IFNAR1 antagonizes receptor. We identified anifrolumab using enzymatic fragmentation, phage-peptide library panning mutagenesis approaches. Our studies revealed recognizes SD3 subdomain critical residue R(279). Further, solved crystal structure Fab a resolution 2.3 A. Guided by our studies, then used silico protein docking characterized corresponding mode binding. find sterically inhibits binding IFN ligands IFNAR1, thus blocking formation ternary IFN/IFNAR1/IFNAR2 signaling complex. This report provides for action may provide insights toward designing therapies against IFNAR1.