Abstract: SA-PO609
APL-2 Prevents Both C3 and C5 Convertase Formation and Activity: A Potential Therapeutic for Renal Diseases
Session Information
- Glomerular Diseases: Immunology, Inflammation - II
November 09, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1202 Glomerular Diseases: Immunology and Inflammation
Authors
- Simon-Tillaux, Noémie, Hôpital Européen Georges Pompidou, Paris, France
- Chauvet, Sophie, Hôpital Européen Georges Pompidou, Paris, France
- El mehdi, Delphine, Apelllis Pharmaceuticals, Crestwood, Kentucky, United States
- Deschatelets, Pascal, Apelllis Pharmaceuticals, Crestwood, Kentucky, United States
- Fremeaux-Bacchi, Veronique, Hôpital Européen Georges Pompidou, Paris, France
Background
C3 glomerulopathy (C3G) is a group of renal diseases characterized by isolated glomerular deposits of C3 fragments as a result of an uncontrolled activation of the complement alternative pathways (AP). The excessive activation of C3 and C5 convertases leading to C3b production and formation of the membrane attack complex is associated with renal function impairment. About 50% of the patients progress to end stage renal disease within 10 years of the diagnosis. The disease is caused either by genetic abnormalities in complement regulatory proteins or by the presence of autoantibodies, C3 or C5 nephritic factors (NeFs), that bind and stabilize the convertases. APL-2 is a small, synthetic, cyclic peptide that binds and inhibits C3 and C3b. The objective of this study was to better understand the impact of APL-2 on the formation of the AP C3 and the C5 convertases and on the activity of pre-formed convertases. We also evaluated the ability of APL-2 toinhibit NeFs-mediated overactivation of both convertases.
Methods
This study was performed in in vitromodel of hemolysis using C3b-recovered sheep erythrocytes and purified complement proteins. IgG positive for C3NeF (n=14) and C3/C5NeF (n=9) were isolated from patients with C3G and added with or without APL-2 (25 µg/ml).
Results
APL-2 prevents the formation of AP C3 and C5 convertases and inhibits the activity of both pre-formed convertases. APL-2 also decreased the prolonged convertase activity mediated by C3NeF and C5NeF. In 6/14 C3NeF and 7/9 C5NeF the stabilizing effect of the autoantibodies became undetectable demonstrating that APL-2 is still effective to inhibit the convertase hyperactivity in the presence of NeFs.
Conclusion
APL-2 is a C3 inhibitor that also interrupts the formation and inhibits the activity of pre-formed AP C3 and C5 convertases, therefore blocking the activation of both C3 and C5. The effect of APL-2 on the convertases occurs also in the presence of NeFs. This data supports potential therapeutic effects of APL-2 in patients with C3G as well as for other renal diseases associated with overactivation of complement.
Funding
- Commercial Support – Apellis Pharmaceuticals