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 cleaves ultra large aggregates of von Willebrand factor (VWF). Such aggregates of VWF 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 30-50% iTTP patients. Further, the treatments can have adverse effects such as abnormal bleeding (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. This application seeks to address the need for new and improved therapies for iTTP by generating engineered, antibody-based reagents that specifically and rapidly deplete ADAMTS13-specific antibodies. Importantly, these depleting agents are highly selective and do not have general immunosuppressive effects. 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 ADAMTS13-specific antibodies. 2. To analyze the stability and binding activity of the Seldegs. 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.
Public Health Relevance Statement: PROJECT NARRATIVE Current treatments for immune-mediated thrombotic thrombocytopenic purpura (iTTP), that is caused by autoantibodies specific for a protein called ADAMTS13, are generally immunosuppressive and/or are associated with adverse side effects. 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 transformative for the management of iTTP.
Project Terms: Corticoids; Corticosteroids; Adrenal Cortex Hormones; Affect; Hemolytic Anemia; Antibodies; immunogen; Antigens; arteriole; Autoantibodies; autoimmune antibody; autoreactive antibody; self reactive antibody; Autoimmune Diseases; autoimmune condition; autoimmune disorder; autoimmunity disease; B-Lymphocytes; B blood cells; B cell; B cells; B-Cells; B-cell; Bacteria; Biological Assay; Assay; Bioassay; Biologic Assays; Blood coagulation; Blood Clotting; Blood Platelets; Marrow platelet; Platelets; Thrombocytes; Blood capillaries; capillary; Disadvantaged; Disease; Disorder; Engineering; Goals; Hemorrhage; Bleeding; blood loss; Immune Tolerance; Immunologic Tolerance; immune system tolerance; immune unresponsiveness; immunological paralysis; Immunosuppression; Immunosuppression Effect; Immunosuppressive Effect; immune suppression; immune suppressive activity; immune suppressive function; immunosuppressive activity; immunosuppressive function; immunosuppressive response; Immunosuppressive Agents; Immunosuppressants; Immunosuppressive drug; Immunosuppressive treatment; immune suppressive agent; immune suppressor; immunosuppressive substance; immunosuppressor; Immunotherapy; Immune mediated therapy; Immunologically Directed Therapy; immune therapeutic approach; immune therapeutic interventions; immune therapeutic regimens; immune therapeutic strategy; immune therapy; immune-based therapies; immune-based treatments; immuno therapy; Infection; Ischemia; Kidney; Kidney Urinary System; renal; Kupffer Cells; Stellate Sinusoidal Macrophage; liver macrophage; Laboratories; Lead; Pb element; heavy metal Pb; heavy metal lead; Liver; hepatic body system; hepatic organ system; Lysosomes; Metalloproteases; Metallopeptidases; Metalloproteinases; mortality; Mutation; Genetic Alteration; Genetic Change; Genetic defect; genome mutation; Names; name; named; naming; Patients; Peptide Hydrolases; Esteroproteases; Peptidases; Protease Gene; Proteases; Proteinases; Proteolytic Enzymes; Plasma; Blood Plasma; Plasma Serum; Reticuloendothelial System, Serum, Plasma; Plasma Exchange; Platelet aggregation; Proteins; Thrombotic Thrombocytopenic Purpura; Moschkowitz Disease; Thrombotic Thrombopenic Purpura; Reagent; Cell Surface Receptors; Research; Research Design; Study Type; study design; Specificity; Technology; Texas; Thrombocytopenia; Thrombopenia; Thrombosis; thrombotic disease; thrombotic disorder; Translating; Universities; Virus; von Willebrand Factor; Ristocetin Cofactor; Ristocetin-Willebrand Factor; von Willebrand Protein; Work; aggregation factor; cell aggregation factor; oligodendrocyte-myelin glycoprotein; MOG glycoprotein; myelin oligodendrocyte glycoprotein; Thrombospondins; Generations; Mediating; Thrombus; Chimera Protein; Fusion Protein; Chimeric Proteins; Disintegrins; Organ; improved; Acute; Clinical; Phase; Neurological; Neurologic; Endothelial Cells; Funding; antibody based therapies; antibody treatment; antibody-based therapeutics; antibody-based treatment; Antibody Therapy; Therapeutic; Infectious Agent; infectious organism; Inflammatory; Deposition; Deposit; Life; rituximab; C2B8 Monoclonal Antibody; MabThera; Rituxan; Immune; Immunes; Clinic; Reaction; gastrointestinal; Infusion procedures; Infusion; infusions; novel; member; new technology; novel technologies; Modality; Excision; Abscission; Extirpation; Removal; Surgical Removal; resection; Gene Proteins; Protein Gene Products; Sampling; Property; Adverse event; Adverse Experience; Adverse effects; Pathogenicity; Molecular Interaction; Binding; ward; ADAMTS; Address; Dose; Applications Grants; Grant Proposals; in vivo; Process; Cardiac; designing; design; new approaches; novel approaches; novel strategy; novel strategies; site targeted delivery; targeted delivery; new drug treatments; new drugs; new pharmacological therapeutic; new therapeutics; new therapy; next generation therapeutics; novel drug treatments; novel drugs; novel pharmaco-therapeutic; novel pharmacological therapeutic; novel therapy; novel therapeutics; murine model; mouse model; develop therapy; intervention development; treatment development; therapy development; commercialization; nanobody; sdAb; single domain antibodies; nanobodies; targeted drug therapy; targeted drug treatments; targeted therapeutic; targeted therapeutic agents; targeted therapy; targeted treatment; Antibody Response; relapse patients; side effect; infection risk; thrombotic; pathogenic autoantibodies
