RO5461111, a highly specific and orally active Cathepsin S antagonist, exhibits potent inhibitory effects with IC50 values of 0.4 nM (human Cathepsin S) and 0.5 nM (murine Cathepsin S), respectively. It effectively suppresses the activation of antigen-specific T cells and B cells, and can ameliorate pulmonary inflammation and lupus nephritis.