PROJECT SUMMARY/ABSTRACT The overall goal of this project is to develop a novel therapeutic for the treatment of pemphigus. Pemphigus involves blistering of the skin or mucosal surfaces and can lead to difficulty in swallowing, very painful lesions, and a ~2-3 fold increased risk of mortality. About 90-95% of pemphigus cases can be accounted for by pemphigus vulgaris (PV) or pemphigus foliaceus (PF). Autoantibodies of the IgG class that are specific for desmogleins 1 and 3 (Dsg1 and Dsg3) disrupt the desmosomal-mediated adhesion of keratinocytes and are the causative agents of disease. PV can present as a mucosal-dominant form involving Dsg3-specific autoantibodies, or a form with both Dsg1- and Dsg3-specific autoantibodies that affects skin and mucosal surfaces. PF is a skin-dominant disease, involving only Dsg1-specific autoantibodies. Current treatments for pemphigus, such as the combination of corticosteroids and the B cell- depleting antibody, rituximab, have associated adverse effects such as osteoporosis and hypertension. In addition, the onset of action of rituximab takes several months since this therapeutic agent targets B cells, rather than the autoantibodies themselves. The combination of rituximab with tapered corticosteroids is also accompanied by a significant relapse rate (25-60%) and increased infection risk due to the immunosuppressive effects of B cell depletion. Other therapeutic approaches for pemphigus include the use of intravenous gammaglobulin, plasmapheresis or immunoadsorption, and can lead to undesirable side effects. Consequently, there is an unmet need to develop therapies for pemphigus that have rapid onset and high specificity for the autoantibodies. This application seeks to address the need for new and improved therapies for pemphigus by generating engineered, antibody-based reagents that specifically and rapidly deplete Dsg-specific antibodies. Importantly, these depleting agents are highly selective and do not affect the levels of other antibodies that have a protective role against infection. 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 Dsg-specific antibodies. 2. To analyze the stability and binding activity of the Seldegs. The proposed approach could be transformative for the management of pemphigus, and also has relevance to the use of Seldeg-based strategies for multiple other clinical settings where pathogenic antibodies cause disease.