A novel inhibitor of the classical pathway of the complement system Abstract The classical pathway of the complement system is implicated in the pathogenesis of a number of human autoimmune diseases, including systemic lupus erythematosus, rheumatoid arthritis, alloantibody-mediated transplant rejection and autoimmune hemolytic anemia. Despite a large body of literature documenting the role of the complement system in these disorders, a specific inhibitor of the classical pathway has yet to be developed. Cold agglutinin disease (CAD) is a type of autoimmune hemolytic anemia (AIHA). It is an orphan disease that accounts for ~15% of AIHA cases. The pathophysiology of CAD is driven by the classical pathway of the complement system. The current treatment options for CAD are broadly immunosuppressive and are associated with a number of off-target effects. We have identified a human autoantibody that inhibits the classical pathway at the step of C4 activation. Activated C4 is the first of two subunits that compose the classical pathway C3 convertase, which is the central enzyme of the classical pathway of complement. In a number of autoimmune diseases, dysregulation of the classical pathway can lead to uncontrolled inflammation through the production of potent anaphylotoxins and other inflammatory mediators. We propose that an anti-C4- MAb will be effective at inhibiting activation of the classical pathway in certain autoimmune diseases. In particular, we propose that this therapeutic MAb could be used to treat cold agglutinin disease and potentially other complement mediated disorders. In this Phase I SBIR, we will characterize the C4 inhibitory MAb and test it in proof-of-principle in vitro assays to demonstrate feasibility of this therapeutic strategy.
Public Health Relevance Statement: Project Narrative AnthroBio has identified a human antibody that inhibits complement activation via the classical pathway. We hypothesize that this antibody can be developed into an effective treatment for certain autoimmune inflammatory diseases mediated by the classical pathway of complement.
Project Terms: Advanced Development; American; Anemia; Antibodies; Autoantibodies; Autoimmune Diseases; Autoimmune hemolytic anemia; Autoimmune Process; B-Lymphocytes; Binding; Biological Assay; Classical Complement Pathway; cold agglutinins; Cold Hemagglutinin Disease; cold temperature; Complement; Complement 3 Convertase; Complement 3b; Complement 4b; Complement Activation; complement C4d; Complement component C4a; Complement Inactivators; complement system; Cytolysis; Data; Deposition; Disease; Disease model; Dissociation; drug development; Drug Kinetics; effective therapy; Enzyme-Linked Immunosorbent Assay; Enzymes; Erythrocytes; experimental study; Feasibility Studies; Flare; Flow Cytometry; Functional disorder; Goals; Graft Rejection; Hemolysis; Human; Immunoglobulin M; Immunosuppressive Agents; In Vitro; in vitro Assay; Incidence; Inflammation; Inflammation Mediators; Inflammatory; inhibiting antibody; inhibitor/antagonist; Isoantibodies; Lead; Literature; Liver; Mediating; Modeling; Monoclonal Antibodies; Monoclonal Antibody CD20; novel; Pathogenesis; Pathway interactions; Patients; Phagocytosis; Pharmacodynamics; Phase; prevent; Production; Program Development; Proteins; Rare Diseases; Rheumatoid Arthritis; rituximab; Role; Serum; Small Business Innovation Research Grant; Species Specificity; Specificity; success; Surface Plasmon Resonance; Systemic Lupus Erythematosus; Testing; Therapeutic; Therapeutic Monoclonal Antibodies; Toxic effect; Western Blotting
