Abstract: SA-OR026
Cathepsin C as a Treatment Target in ANCA Vasculitis
Session Information
- ANCA It Is
November 09, 2019 | Location: 207, Walter E. Washington Convention Center
Abstract Time: 05:30 PM - 05:42 PM
Category: Glomerular Diseases
- 1202 Glomerular Diseases: Immunology and Inflammation
Authors
- Kettritz, Ralph, Medical Faculty of the Charité, Experimental and Clinical Research Center (ECRC), 13125 Berlin, Germany
- Jerke, Uwe, Medical Faculty of the Charité, Experimental and Clinical Research Center (ECRC), 13125 Berlin, Germany
- Eulenberg-Gustavus, Claudia, Experimental and Clinical Research Center (ECRC) Campus Buch, Berlin, Germany
- Rousselle, Anthony, Medical Faculty of the Charité, Experimental and Clinical Research Center (ECRC), 13125 Berlin, Germany
- Kreideweiss, Stefan, Boehringer Ingelheim Pharma, Biberach, Germany
- Grundl, Marc Alexander, Boehringer-Ingelheim Pharma GmbH&Co, Biberach, Germany
- Nicklin, Paul, Boehringer Ingelheim, Biberach an der Riss, Germany
- Eickholz, Peter, Johann Wolfgang Goethe-University Frankfurt, Frankfurt, Germany
- Nickles, Katrin, Poliklinik für Parodontologie, ZZMK Carolinum, Goethe University Grankfurt, Frankfurt an Main, Germany
- Schreiber, Adrian, Medical Faculty of the Charité, Experimental and Clinical Research Center (ECRC), 13125 Berlin, Germany
- Korkmaz, Brice, INSERM U-1100, Tours, France
Background
Neutrophil serine proteases (NSPs) of neutrophils and monocytes contribute to ANCA-associated vasculitis (AAV). Cathepsin C (CatC) proteolytically activates pro-NSPs in the bone marrow (BM) producing mature neutrophil elastase (HNE), cathepsin G (CatG), and PR3 - a major ANCA antigen. We showed previously that CatC gene-deficient mice were protected from AAV, implicating CatC as a treatment target.
Methods
We characterized NSPs and NSP-mediated functions in healthy individuals and Papillon-Lefèvre syndrome (PLS) patients with CatC loss-of-function mutations and developed a highly specific CatC inhibitor to reduce NSPs in a human neutrophil stem cell model and in mice.
Results
NSP proteins and proteolytical activity were abrogated in neutrophils and monocytes from PLS patients. PLS cells gave a negative PR3-ANCA, showed reduced membrane-PR3 (mPR3) on viable and apoptotic neutrophils, and supernatants (SN) from activated PLS neutrophils caused less endothelial cell (EC) damage. We developed the pharmacological CatC-inhibitor BI01169740 that strongly reduced NSP proteins (by 80% for PR3, 94% for HNE, and 99% for CatG) and the corresponding proteolytic activity (by 98% for PR3, 88% for HNE, and 79% for CatG) in differentiated neutrophils without affecting cell differentiation. mPR3 on viable and apoptotic differentiated neutrophils was diminished, viable cells showed less respiratory burst to PR3-ANCA, and SN caused less EC damage. Finally, 12-day treatment of Bl6 mice with increasing CatC inhibitor BI01169740 doses (0.05, 0.5, and 5 mg/kg/qd) lead to increasing compound plasma exposure (15±1, 164±26, and 1195±57 nM) and BM (478±52, 512±25, and 1680±190 nM), respectively. The highest dose strongly reduced NSP proteins and activity in BM cells, and reduced HNE activity in neutrophils from bronchoalveolar lavage fluid.
Conclusion
CatC gene-deficiency down-regulates NSPs and NSP-dependent neutrophil functions with relevance to ANCA. CatC inhibition with the novel BI01169740 compound recapitulates these effects in a stem cell model in vitro and effectively reduces NSP proteins and proteolytical activity in mice. These findings provide us with the opportunity to explore pharmacological CatC inhibition as a treatment strategy in AAV disease models and ultimately in AAV patients.
Funding
- Commercial Support – Boehringer Ingelheim