PROJECT SUMMARY/ABSTRACT The overall goal of this project is to develop a novel therapeutic for the treatment of autoimmune atypical hemolytic uremic syndrome (aHUS). Autoimmune aHUS is a rare, life-threatening disease that affects both children and adults. It is caused by autoantibodies that recognize the negative regulator of the alternative complement pathway, factor H (FH). FH-specific antibodies both block FH activity and result in FH depletion. The dysregulated complement activation that ensues results in microangiopathic hemolytic anemia, thrombocytopenia and acute kidney damage that can culminate in renal failure. Although there are currently several therapies for autoimmune aHUS, all of these lead to general immunosuppression and other severe side effects. For example, plasma exchange results in adverse consequences in a high percentage of patients. The more recently developed use of antibodies such as eculizumab that are specific for complement component C5 has beneficlal therapeutic effects. However, C5 blockade also substantially increases the risk of infection by pathogens that include meningococci and pneumococci. In addition, the underlying cause of disease, namely the levels of FH-specific antibodies are not affected by complement blockade. The risk of recurrence following discontinuation of C5-targeted therapy is therefore high, and such recurrence is usually severe and rapid. As a result of the limitations of existing therapies for autoimmune aHUS, there is a need for the development of therapeutics that target the pathogenic antibodies. This application seeks to address this need by generating engineered, antibody-based reagents that specifically and rapidly deplete FH-specific antibodies, whilst not affecting the levels of antibodies that have a protective role against infection etc. This first-in-class, novel technology is called Seldeg technology (for selective degradation). The Specific aims of the study are: 1. To design and express Seldegs to target FH-specific antibodies. 2. To analyze the stability and binding activity of the Seldegs. This approach could not only be transformative for the management of this potentially devastating disease, but would also lay the foundations for analogous approaches to be taken in many other clinical settings where pathogenic antibodies lead to disease.