Structural highlights
Publication Abstract from PubMedAbstract MEDI546 is an antagonist human monoclonal antibody that targets interferon alpha receptor 1 (IFNAR1). MEDI546 has been developed to treat autoimmune diseases and is currently in clinical trials. To decipher the molecular basis of its mechanism of action, we engaged in multiple epitope mapping approaches to determine how it interacts with IFNAR1 and antagonizes the receptor. We identified the epitope of MEDI546 using enzymatic fragmentation, phage-peptide library panning and mutagenesis approaches. Our studies revealed that MEDI546 recognizes the SD3 subdomain of IFNAR1 with the critical residue R279. Further, we solved the crystal structure of MEDI546 Fab to a resolution of 2.3 A. Guided by our epitope mapping studies, we then used in silico protein docking of the MEDI546 Fab crystal structure to IFNAR1 and characterized the corresponding mode of binding. We find that MEDI546 sterically inhibits the binding of IFN ligands to IFNAR1, thus blocking the formation of the ternary IFN/IFNAR1/IFNAR2 signaling complex. This report provides the molecular basis for the mechanism of action of MEDI546 and may provide insights towards designing antibody therapies against IFNAR1. Molecular basis for the antagonistic activity of an anti- interferon alpha receptor 1 antibody.,Peng L, Oganesyan V, Wu H, Dall'Acqua WF, Damschroder MM MAbs. 2015 Jan 21:0. PMID:25606664[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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