Depleting autoantibodies for the treatment of autoimmunity

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PROJECT SUMMARY/ABSTRACT 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 in adults 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 and even death. In 2009, the M-type phospholipase A2 receptor (PLA2R) that is present on podocytes was identified as the target of autoantibodies in about 70-80% of MN patients. Such autoantibodies are used as a diagnostic marker for MN, and patients with high PLA2R-specific antibody levels typically have a poor prognosis. Although there are currently several therapies for MN, they can result in general immunosuppression and other severe side effects. For example, cycles of high dose steroids and alkylating 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 are also associated with increased risk of infection combined with a significant relapse rate. As a result of the limitations of existing therapies for MN, there is an unmet need for the development of improved, selective therapeutic approaches. This application seeks to address the need for new therapies for MN by generating engineered, antibody-based reagents that specifically and rapidly deplete PLA2R-specific antibodies that are associated with disease. Importantly, these depleting agents do not affect the levels of other antibodies that have a protective role against infection etc. This first-in-class, novel technology 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 this potentially devastating disease, but would also lay the foundations for analogous Seldeg-based strategies to be taken in many other clinical settings where pathogenic antibodies lead to disease.