Atacicept: dual BAFF/APRIL inhibition and clinical evidence in IgA nephropathy

Immunoglobulin A nephropathy (IgAN) is a B-cell–mediated autoimmune kidney disease characterized by production of galactose-deficient immunoglobulin A1 (Gd-IgA1) and anti-Gd-IgA1 autoantibodies that form circulating immune complexes that deposit within the glomerular mesangium. These immune complexes initiate inflammatory and complement-mediated injury that leads to progressive nephron loss and chronic kidney disease. Despite advances in supportive care and the recent introduction of targeted therapies, many patients remain at risk of long-term kidney function decline, highlighting the need for disease-modifying therapies. Two cytokines in the tumor necrosing factor family are key signaling proteins driving B cell and plasma cell activity: B-cell activating factor (BAFF) and A proliferation-inducing ligand (APRIL). Therefore, dual inhibition of BAFF/APRIL represents a logical and mechanistically targeted therapeutic approach to reduce production of immune complexes. Atacicept is a rationally designed native human transmembrane activator and calcium-modulator and cyclophilin-ligand interactor (TACI)-Fc fusion protein, which represents a soluble receptor for BAFF and APRIL, and which has demonstrated reductions in proteinuria, serum Gd-IgA1, and hematuria with stabilization of estimated glomerular filtration rate in patients with IgAN. This review examines the scientific rationale and emerging clinical evidence supporting atacicept as a disease-modifying treatment in IgAN that addresses the B-cell–mediated drivers of disease.