Cathepsin C inhibition reduces neutrophil serine protease activity and improves activated neutrophil-mediated disorders

Abstract Cathepsin C (CatC) is an enzyme which regulates the maturation of neutrophil serine proteases (NSPs) essential for neutrophil activation. Activated neutrophils are key players in the innate immune system, and are also implicated in the etiology of various inflammatory diseases. This study aims to demonstrate a therapeutic potential for CatC inhibitors against disorders in which activated neutrophil-derived neutrophil extracellular traps (NETs) play a significant role. We developed a novel CatC inhibitor, MOD06051, which dose-dependently suppressed the cellular activity of NSPs, including neutrophil elastase (NE), in vitro. Next, neutrophils derived from MOD06051-administered rats were evaluated for NE activity and NET-forming ability, with results significantly lower than controls. Furthermore, MOD06051 dose-dependently ameliorated vasculitis and significantly decreased NETs when administered to a rat model of myeloperoxidase (MPO)-antineutrophil cytoplasmic antibody-associated vasculitis (AAV). These findings suggest that CatC inhibition is a promising strategy to reduce neutrophil activation and improve activated neutrophil-mediated diseases such as MPO-AAV.