Abstract: TH-PO052

Alkylating Histone Deacetylase Inhibitor Treatment in Animal Models of MPO-ANCA Vasculitis

Session Information

Category: Glomerular

  • 1001 Glomerular: Basic/Experimental Immunology and Inflammation

Authors

  • Dooley, Dearbhaile, Trinity College Dublin, Dublin, Ireland
  • O'Brien, Eóin, Trinity College Dublin, Dublin, Ireland
  • Fazekas, Barbara, Trinity College Dublin, Dublin, Ireland
  • Pusey, Charles D., Imperial College London, London, United Kingdom
  • Tam, Frederick W.K., Imperial College Kidney and Transplant Institute, London, United Kingdom
  • Hickey, Fionnuala B., Trinity College Dublin, Dublin, Ireland
  • Mehrling, Thomas, EDO GmbH, Basel, Switzerland
  • Heeringa, Peter, University Medical Center Groningen, Groningen, Netherlands
  • Little, Mark Alan, Trinity College Dublin, Dublin, Ireland
Background

Anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) is a systemic inflammatory, autoimmune condition that affects the microvasculature. The lungs and kidneys are most frequently affected, leading to lung haemorrhage and glomerulonephritis (GN). When left untreated, AAV has a mortality rate of around 80% in year one and a 25% five-year mortality rate with current conventional treatments consisting of cyclophosphamide and steroids. However, these therapies do not prevent disease relapse and patients often require long-term treatment which is associated with severe morbidity. Recently, histone deacetylase inhibitors (HDACi) were shown to have beneficial effects in inflammatory rodent models and have been found to act synergistically with a diverse range of pharmacological agents including cyclophosphamide.

Methods

EDO-S101, a small molecule compound developed by Mundipharma EDO GmbH, is an alkylating HDACi fusion molecule which combines the strong DNA damaging effect of bendamustine, with a fully functional pan-HDACi, vorinostat. In this study, we investigated the effects of EDO-S101 in 2 well established rodent models of AAV. These consisted of a passive mouse model of anti-myeloperoxidase (MPO) IgG-induced GN and an active rat model of MPO-ANCA microscopic polyangitis: experimental autoimmune vasculitis (EAV).

Results

Our data indicate that although pre-treatment with EDO-S101 reduced circulating leukocyte populations, it did not affect development of anti-MPO IgG-induced GN in mice. On the other hand, EDO-S101 in EAV significantly reduced the degree of lung haemorrhage, severe GN and almost completely abolished crescent formation. EDO-S101 treatment in EAV also significantly depleted B and T cells compared with vehicle-treated controls, suggesting a selective effect on the adaptive immune response.

Conclusion

Taken together, we have demonstrated that EDO-S101 is a promising novel therapy for treatment of AAV that operates primarily through its effects on the adaptive immune response to the autoantigen MPO.

Funding

  • Commercial Support