Abstract: TH-PO0417
Selective Clearance of Phospholipase A2 Receptor (PLA2R) Autoantibodies for the Treatment of Experimental Membranous Nephropathy
Session Information
- Glomerular Diseases: Autoimmune Diseases
October 22, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology
Authors
- Seifert, Larissa, Universitatsklinikum Hamburg-Eppendorf, Hamburg, HH, Germany
- Schweitzer, Lawrence, Merida Biosciences, Cambridge, Massachusetts, United States
- Dehde, Silke, Universitatsklinikum Hamburg-Eppendorf, Hamburg, HH, Germany
- Jacobowitz, Joseph R., Merida Biosciences, Cambridge, Massachusetts, United States
- Suryaprakash, Deepika, Merida Biosciences, Cambridge, Massachusetts, United States
- Patterson, Troy D., Merida Biosciences, Cambridge, Massachusetts, United States
- Wu, Tsai-yi, Chang Gung University, Taoyuan, Taoyuan City, Taiwan
- Capili, Allan D., Merida Biosciences, Cambridge, Massachusetts, United States
- Ku, Cheng-Lung, Chang Gung University, Taoyuan, Taoyuan City, Taiwan
- Zahner, Gunther, Universitatsklinikum Hamburg-Eppendorf, Hamburg, HH, Germany
- Gutierrez, Dario A., Merida Biosciences, Cambridge, Massachusetts, United States
- Tomas, Nicola M., Universitatsklinikum Hamburg-Eppendorf, Hamburg, HH, Germany
Background
Anti-PLA2R autoantibodies are key drivers of membranous nephropathy (MN). Current treatments are unspecific, toxic and often associated with incomplete and delayed remission. The clear causal role of anti-PLA2R antibodies, however, enables more specific, less toxic strategies. The aim of this study was the generation and evaluation of PLA2R-specific antigen-Fc fusion proteins (AgFcs) with optimized Fc domains to selectively clear anti-PLA2R autoantibodies in MN.
Methods
AgFcs involving the CysR- and CysR/CTLD1-epitope regions of PLA2R and optimized human and murine Fc domains were designed, expressed, and evaluated in vitro and in vivo (see also related abstract: Schweitzer et al.). AgFcs were tested in in vitro neutralization assays using serum from patients with PLA2R-associated MN. AgFcs were further applied in in vivo models, involving (i) passive transfer of patient-derived anti-PLA2R IgG to human PLA2R-expressing mice as well as (ii) active immunization of human/mouse chimeric PLA2R-expressing mice.
Results
CysR- and CysR/CTLD1-specific AgFcs effectively neutralized patient serum reactivity with PLA2R. In passive transfer experiments, AgFc treatment rapidly reduced anti-PLA2R domain titers, proteinuria, glomerular human IgG deposition, and podocyte foot process effacement. In active immunization models, AgFc treatment after development of substantial proteinuria reduced anti-PLA2R domain titers, proteinuria, glomerular mouse IgG and complement deposition, and podocyte foot process effacement. Treatment also improved nephrotic syndrome-associated serum parameters such as serum albumin, cholesterol and triglycerids.
Conclusion
PLA2R-specific antigen-Fc fusion proteins selectively neutralize and deplete pathogenic anti-PLA2R autoantibodies, resulting in marked improvement of serological, histological, and functional disease parameters in complementary passive and active models of membranous nephropathy. These findings establish AgFc-mediated autoantibody clearance as a highly specific, mechanism-based therapeutic strategy with the potential to transform treatment of PLA2R-associated MN while avoiding the toxicity of broad immunosuppression.
Funding
- Commercial Support – Merida Biosciences, Boston, USA