Systemic lupus erythematosus(SLE)is a chronic,heterogeneous autoimmune disease short of effective therapeutic agents.A multitude of studies of SLE in the last decade have accentuated a central role of the interferon alpha(IFN-α)pathway in SLE pathogenesis.We report here a candidate therapeutic neutralizing antibody,AIA22,with a different binding epitope and discrepant neutralizing profile from the anti-multiple IFN-α subtype antibodies currently in clinical trials.AIA22 specifically interacts with multiple IFN-α subtypes,binds to the type Ⅰ IFN receptor 2(IFNAR2)recognition region of IFN-α(considered a novel antigen epitope),and effectively neutralizes the activity of almost all of the IFN-α subtypes(with the exception of IFN-α7)both in vitro and in vivo.Concurrently,structural modeling and computational design yielded a mutational antibody of AIA22,AlAmut,which exhibited substantially improved neutralizing activity to multiple IFN-α subtypes.