Alternative pathway C3 convertase (C3bBb)

The alternative pathway C3 convertase, denoted as C3bBb, is a critical enzymatic complex of the innate immune system responsible for the rapid amplification of the complement cascade. It is formed on biological surfaces when C3b, a cleavage product of C3, associates with Factor B, which is then activated by the serine protease Factor D. This complex acts as a C3-cleaving enzyme, generating more C3b and thus creating a potent positive feedback loop that enhances opsonization, inflammation, and the formation of the membrane attack complex (Merle et al., 2015, Frontiers in Immunology). Dysregulation of this convertase is a central driver in the pathogenesis of several complement-mediated diseases, including paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), and C3 glomerulopathy (C3G). Therapeutic targeting of the convertase, through the inhibition of Factor B, Factor D, or C3, has emerged as a highly effective strategy to control intravascular hemolysis and tissue damage in these conditions (Risitano et al., 2020, Frontiers in Immunology). By specifically blocking the alternative pathway amplification loop, these drugs provide a more targeted approach than broad terminal complement inhibition.

Other names

C3bBb complexAlternative pathway C3-cleaving enzymeC3bBbPAP C3 convertase

Drugs targeting the alternative pathway C3 convertase function by either inhibiting the enzymatic activity of its components (Factor B or Factor D) or by binding to the substrate (C3) to prevent its cleavage. For instance, Factor B inhibitors like iptacopan prevent the formation of the active C3bBb complex, while Factor D inhibitors like danicopan block the rate-limiting step of convertase assembly (Ricklin et al., 2018, Nature Reviews Drug Discovery). These actions effectively shut down the alternative pathway's amplification loop, preventing downstream complement-mediated tissue damage.