OP0090 PRECLINICAL STUDIES OF A NOVEL CATHEPSIN C INHIBITOR IN MPO-ANCA-ASSOCIATED VASCULITIS MODEL

Background MPO-ANCA-associated vasculitis (MPO-AAV) is a systemic small vessel with the production of MPO-ANCA in serum. This disease develops necrotizing and crescent glomerulonephritis (NCGN) peritubular capillaritis-mediated interstitial damages kidneys, pulmonary hemorrhage due to capillaritis lungs. Recent studies have revealed that neutrophil extracellular traps (NETs) induced by are critically involved its pathogenesis, 1 elastase (NE) plays an essential role formation NETs. 2 Cathepsin C (CatC) functions as key enzyme activation process several serine proteases (NSPs) such NE, proteinase 3 cathepthin G converting inactive forms NSPs active digesting dipeptides at N-terminus enzymes. Objectives Although glucocorticoids immunosuppressive drugs used standard cares can lead remission MPO-AAV patients, there remaining unmet medical needs severe side effects, resistance treatment relapse. Therefore, development new therapeutic strategies awaited. The aim this study demonstrate efficacy MOD06051, novel CatC inhibitor, against MPO-AAV, using rat model established previously. 4 Methods In vitro studies: Cathpsins NE inhibitory activity was measured recombinant enzymes fluorescent substrates. Cellular granulocytes differentiated from primary human bone marrow-derived hematopietic stem cells under presence or absence MOD06051 determined vivo 4-week-old Wistar Kyoto (WKY) rats were immunized MPO according Little’s protocol. divided into three groups (n=8 each group), vehicle (0.5% methylcellulose) (0.3 mg/kg bid) orally administered every day for 42 days. All euthanized end serological histological evaluations. Results inhibited enzymatic IC50 value 1.5 nM, no other cathepsins nor inhibition observed 10 μM. suppressed 18 nM. all same level. percentage affected glomeruli including those NCGN, NET-forming neutrophils peripheral blood glomeruli, glomerular counts significantly dose-dependent manner. Furthermore, hematuria score, urinary NGAL (Neutrophil Gelatinase-Associated Lipocalin), tubular erythrocyte cast counts, foci decreased treated group similar trends 0.3 group. Conclusion showed sepcific activity. compound NET rats, resulting amelioration MPO-ANCA-induced tissue destruction, NCGN disorder alveolar septal capillaries appears be promising agent patients. References [1]Nakazawa D, et al. Nat Rev Rheumatol 15: 91-101, 2019. [2]Papayannopoulos V, J Cell Biol 191: 677-691, 2010. [3]Korkmaz B, Pharmacol Ther 190: 202-236, 2018. [4]Little MA, Am Pathol 174: 1212-1220, 2009. Disclosure Interests Akihiro Ishizu Grant/research support from: Modulus Discovery, Inc., Mai Taniguchi: None declared, Suishin Arai: Yuka Nishibata Sakiko Masuda Utano Tomaru: Takafumi Shimizu Shareholder of: Employee William Sinko Tadashi Nagakura Yoh Terada Inc.