Efficacy of MOD06051: A Novel Cathepsin C Inhibitor in MPO-ANCA Vasculitis Preclinical Model

MPO-ANCA-associated vasculitis (MPO-AAV) is a systemic disease characterized by the presence of MPO-ANCA in the serum, which leads to renal and pulmonary complications. The pathogenesis of this condition is linked to the formation of neutrophil extracellular traps (NETs) and the role of neutrophil elastase (NE). Cathepsin C (CatC) is a crucial enzyme in activating several neutrophil serine proteases (NSPs), including NE.

The current standard treatment for MPO-AAV involves glucocorticoids and immunosuppressive drugs, which can induce remission but also present challenges such as severe side effects, treatment resistance, and relapse. Hence, there is a need for novel therapeutic approaches.

This study aimed to evaluate the efficacy of MOD06051, a newly developed CatC inhibitor, in an MPO-AAV rat model. In vitro experiments measured the inhibitory activity of MOD06051 on CatC and NE using recombinant enzymes and fluorescent substrates. The compound was found to inhibit CatC with high specificity and potency, without affecting other cathepsins or NE at higher concentrations.

In vivo studies involved the use of Wistar Kyoto rats immunized with human MPO. Rats were treated with MOD06051 at varying doses, and the effects were assessed through serological and histological evaluations. The treatment resulted in a significant reduction in the percentage of affected glomeruli, NET-forming neutrophils, and glomerular neutrophil counts in a dose-dependent manner. Additionally, MOD06051 significantly decreased hematuria, urinary NGAL levels, tubular erythrocyte cast counts, and pulmonary hemorrhage.

The findings indicate that MOD06051 effectively inhibits CatC activity, leading to the suppression of serine proteases activation in human neutrophils and the reduction of NET formation in the MPO-AAV rat model. This resulted in an improvement in tissue damage caused by MPO-ANCA, including renal and pulmonary complications. The study suggests that MOD06051 has potential as a promising therapeutic agent for MPO-AAV patients.