Novel therapy for Goodpasture syndrome

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Novel therapy for Goodpasture syndrome Abstract Goodpasture syndrome (GS) is a rare autoimmune pulmonary disorder evolving from glomerular basement membrane (GBM) disease. GBM disease and GS are rapidly progressing, leading to renal failure and death if not treated. Current treatments are immunosuppressive and ineffective, and carry a high risk of adverse effects. Autoantibodies to the noncollagenous-1 (NC1) domain of the α3 chain of type IV collagen (α3(IV)NC1), a component of the basement membrane of glomeruli and alveoli, trigger an immune response leading to antibody deposition on the basement, with subsequent inflammation and necrosis. Both antibody- mediated cytotoxicity (ADCC) and complement-mediated cytotoxicity (CDC) are involved. Blocking antibodies lacking effector functions have proven effective therapies in other autoimmune disorders of similar etiology (e.g., neuromyelitis optica). During this Phase I project, we will engineer a high affinity anti-type IV collagen human monoclonal antibody to eliminate all residual effector functions for linkage to a robust complement inhibitor. The resulting dual function fusion protein will inhibit GBM-binding by pathogenic antibodies as well as locally target complement activation. The outcome of this work will be a novel, mechanism-based therapy for Goodpasture syndrome.