Novel approaches for the treatment of autoimmune disease

PROJECT SUMMARY/ABSTRACT The overall goal of this project is to develop a novel therapeutic for the treatment of immune- mediated thrombotic thrombocytopenic purpura (iTTP). iTTP is an acute, life-threatening disease that without treatment, leads to a >90% mortality rate. It is caused by deficiency of a disintegrin and metalloprotease thrombospondin type 1 motif, member 13 (ADAMTS13), which is a protease that regulates the levels of ultra-large aggregates of von Willebrand factor (VWF). Such VWF aggregates bind to platelets, resulting in blood clots. Consequently, ADAMTS13 deficiency leads to microthrombus formation in arterioles and capillaries, and iTTP is characterized by hemolytic anemia, thrombocytopenia and organ damage, with possible severe cardiac, renal, neurological and gastrointestinal effects. For iTTP, ADAMTS13 deficiency is caused by autoantibodies specific for this protease. Current treatments are therefore directed towards reducing the levels of these antibodies by plasma exchange and the use of general immunosuppressants (corticosteroids, rituximab). In addition, a bivalent nanobody (caplacizumab) that inhibits VWF-platelet interactions has recently been approved to treat iTTP. Despite treatment, however, relapses occur in about 30-50% iTTP patients. Further, the treatments can have adverse effects such as severe bleeding events that can be fatal (caplacizumab) and/or increased risk of infection due to general immunosuppression. Rituximab also has a slow onset of action and is used in combination with plasma exchange. Consequently, there is a need to develop therapies for iTTP that have rapid effects and high specificity for the causal agent of disease, namely the autoantibodies. The goal of the Phase I project was to generate proof-of-concept by designing a Seldeg to target ADAMTS13-specific antibodies, and show the suitability of the Seldeg for clinical development using in vitro assays. In this Phase II application, we propose to progress the Seldeg along the development path, using a combination of in vitro analyses to further characterize the Seldeg and studies in animal models. The Specific aims are: 1. To carry out drug development and testing of the ADAMTS13-Seldeg using in vitro analyses. 2. To analyze the in vivo behavior of the ADAMTS13-Seldeg and targeted autoantibodies. The proposed approach could be transformative for the management of iTTP, and also has relevance to the use of Seldeg-based strategies for multiple other clinical settings where pathogenic antibodies cause disease.