Sibeprenlimab

Sibeprenlimab is a humanized immunoglobulin G2 (IgG2) monoclonal antibody designed to treat IgA nephropathy (IgAN) by neutralizing the cytokine known as A Proliferation-Inducing Ligand (APRIL). In patients with IgAN, elevated levels of APRIL drive the "four-hit" pathogenic process by promoting B-cell dysregulation, class switching to IgA, and the survival of plasma cells that produce aberrant antibodies. Specifically, APRIL is a key factor in the overproduction of galactose-deficient IgA1 (Gd-IgA1), the autoantigen responsible for the formation of nephritogenic immune complexes that deposit in the glomeruli and cause kidney injury.

At the molecular level, sibeprenlimab binds to APRIL with high affinity (dissociation constant [KD] of 0.95 pM). This binding effectively sequesters the cytokine and blocks it from interacting with its receptors on B cells and plasma cells: the B-cell maturation antigen (BCMA) and the transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI). By inhibiting the APRIL-BCMA and APRIL-TACI signaling pathways, sibeprenlimab disrupts the survival signals sent to antibody-secreting cells. This disruption directly halts the production of the pathogenic Gd-IgA1, thereby reducing the burden of circulating immune complexes and preventing further renal deposition and damage.