Telitacicept targets Gd-IgA1 and autoantibody-producing B cells in IgA nephropathy

Abstract IgA nephropathy (IgAN) is the most common primary glomerulonephritis and a leading cause of end-stage renal disease (ESRD) for young adults. The key pathogenesis of IgAN involves overproduction of galactose-deficient IgA1 (Gd-IgA1) and anti-Gd-IgA1 antibodies, resulting in formation of circulating immune complexes that deposit in the glomerular mesangium. Consequently, emerging therapeutic strategies for IgAN aim to target and reduce aberrant Gd-IgA1 and its associated immune complexes. This disease-modifying approach confers benefits across multiple stages of IgAN progression, particular in the early phase to halt irreversible renal damage. B-cell activating factor (BAFF) and proliferation-inducing ligand (APRIL) are critical cytokines that promote the differentiation, development, and activation of B cells and plasma cells. Telitacicept, a novel recombinant fusion protein that dual-targets BAFF and APRIL, exhibits considerable therapeutic potential by inhibiting the production of Gd-IgA1 and its autoantibodies. Stage A results of the phase 3 clinical trial demonstrated that patients in the telitacicept group achieved a 55% reduction in 24-hour urinary protein-to-creatinine ratio (UPCR) and stable eGFR at week 39 versus the placebo group, with favorable tolerability and safety. This review summarizes current progresses in targeting Gd-IgA1-producing cells for the treatment of IgAN, with a focus on therapeutic strategies including BAFF/APRIL inhibitors. Furthermore, it delineates the major challenges and future research directions aimed at optimizing these interventions.