The overall goal of this project is to develop a novel therapeutic for the treatment of primary(idiopathic) membranous nephropathy (MN). MN is a leading cause of nephrotic syndrome inadults and has a variable clinical course. About one third of patients enter spontaneous remission,whereas the remainder have persistent proteinuria that can lead to end stage renal disease andeven death. In 2009, the M-type phospholipase A2 receptor (PLA2R) that is present on podocyteswas identified as the target of autoantibodies in about 70-80% of MN patients. Suchautoantibodies are used as a diagnostic marker for MN, and patients with high PLA2R-specificantibody levels typically have a poor prognosis. Although there are currently several therapies for MN, they can result in generalimmunosuppression and other severe side effects. For example, cycles of high dose steroids andalkylating agents can lead to cancer, osteoporosis and diabetes, and relapses occur in up to 30%patients within five years following treatment. B cell-depleting antibodies such as rituximab arealso associated with increased risk of infection combined with a significant relapse rate. As aresult of the limitations of existing therapies for MN, there is an unmet need for the developmentof improved, selective therapeutic approaches. This application seeks to address the need for new therapies for MN by generatingengineered, antibody-based reagents that specifically and rapidly deplete PLA2R-specificantibodies that are associated with disease. Importantly, these depleting agents do not affect thelevels of other antibodies that have a protective role against infection etc. This first-in-class, noveltechnology has been named Seldeg technology (for selective degradation). The Specific aims of the study are: 1. To design and express Seldegs to target PLA2R-specific antibodies. 2. To analyze the stability and binding activity of the Seldegs. The proposed approach could not only be transformative for the management of thispotentially devastating disease, but would also lay the foundations for analogous Seldeg-basedstrategies to be taken in many other clinical settings where pathogenic antibodies lead to disease.
Public Health Relevance Statement: PROJECT NARRATIVE
Treatments that are currently available for antibody-mediated autoimmune diseases such as
membranous nephropathy are generally immunosuppressive, are associated with adverse events
and/or have limited efficacy. To address this issue, in this application we propose to develop a
novel treatment that selectively removes the autoreactive antibodies which are involved in the
disease process, without affecting the levels of other antibodies that are important for protection
against infectious agents such as bacteria and viruses. This approach has the potential to be a
game-changer for the clinical management of membranous nephropathy.
Project Terms: <21+ years old><7S Gamma Globulin> | 