Abstract: SA-PO727
Assessing the Therapeutic Potential of a Myeloperoxidase Inhibitor in a Preclinical Rat Model of MPO-ANCA Autoimmune Vasculitis
Session Information
- Glomerular Diseases: Therapeutic Strategies
October 26, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology
Authors
- Veenit, Vandana, AstraZeneca R&D Cambridge, Cambridge, United Kingdom
- Prendecki, Maria, Imperial College London, London, United Kingdom
- McAdoo, Stephen Paul, Imperial College London, London, United Kingdom
- Seth, Asha, AstraZeneca R&D Cambridge, Cambridge, United Kingdom
- Hale, Lorna J., AstraZeneca R&D Cambridge, Cambridge, United Kingdom
- Rosengren, Birgitta E., AstraZeneca R&D Cambridge, Cambridge, United Kingdom
- Laerkegaard Hansen, Pernille B., AstraZeneca R&D Cambridge, Cambridge, United Kingdom
- Collén, Anna, AstraZeneca R&D Cambridge, Cambridge, United Kingdom
- Williams, Julie, AstraZeneca R&D Cambridge, Cambridge, United Kingdom
Background
Antineutrophil cytoplasmic antibody (ANCA)- associated vasculitis (AAV) is a rare systemic autoimmune disease characterised by the inflammation of blood vessels and involves multiple organ systems. ANCA binds to proteins on the neutrophil surface, particularly myeloperoxidase (MPO) which is a major disease driver of AAV.
Methods
We evaluated a tool MPO inhibitor- AZM198 on human AAV relevant readouts using a well characterised preclinical rat model of AAV which involves immunising adult male WKY rats with human MPO followed by an intravenous administration of 1:100 dilution of nephrotoxic serum (NTS) on day 14. We first assessed AZM198 in a prevention setting by dosing AZM198 at 125 mg/kg peroral from day 7 until day 27. We then conducted an intervention study where one group received AZM198 from day 16 until day 35 (early intervention) and another group received AZM198 from day 25 until day 35 (late intervention). Animals were sacrificed one day after the last treatment (AZM-198 or vehicle).
Results
In prevention and early intervention groups, but not in the late intervention group, AZM198 treated rats showed reductions in human AAV pertinent readouts -haematuria, proteinuria, kidney/lung injury and inflammatory cell infiltration compared to vehicles. There was no change in MPO antibody titre or MPO mass in response to AZM198 treatment. However, there was a significant reduction seen for the MPO activity/mass ratio both in plasma and kidney in AZM198 treated animals in prevention and early intervention groups but not in the late intervention group. Interestingly, we also saw a significant correlation between kidney MPO activity and proteinuria in both studies which corroborates the role of MPO activity in driving AAV pathogenesis.
Conclusion
Our preclinical data confirms a key role of MPO activity in AAV aetiology and suggests strongly that inhibition of MPO activity might offer protection in AAV patients.