Alternative pathway C3 and C5 convertase complexes (AP C3/C5 convertases)

The alternative pathway (AP) C3 and C5 convertase complexes are multi-protein enzyme assemblies essential for the amplification and effector phases of the complement system, a key component of innate immunity (Ricklin et al., 2010, Nature Immunology). The AP C3 convertase, denoted as C3bBb, is formed when complement Factor B binds to C3b and is subsequently cleaved by Factor D; this complex catalyzes the cleavage of C3 into C3a and C3b, creating a powerful positive feedback loop (StatPearls, 2023, Complement System). Upon the binding of an additional C3b molecule, the complex shifts its substrate specificity to become the AP C5 convertase (C3bBbC3b), which cleaves C5 into the anaphylatoxin C5a and the fragment C5b, the latter of which initiates the assembly of the membrane attack complex (MAC) (Janeway's Immunobiology, 2001). Dysregulation or overactivation of these convertases is a primary driver in the pathogenesis of several rare diseases, including paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), and C3 glomerulopathy (C3G) (Nester et al., 2015, Molecular Immunology). Therapeutic strategies involve inhibiting the formation or activity of these complexes by targeting their constituents, such as Factor B (e.g., iptacopan) or Factor D (e.g., danicopan), thereby preventing the downstream inflammatory and hemolytic consequences of complement overactivation (FDA, 2023, Fabhalta Prescribing Information).

Other names

C3bBbC3bBbC3bAlternative pathway convertasesAP C3 convertaseAP C5 convertaseC3bBb3b

Inhibition of the formation, stabilization, or enzymatic activity of the C3 and C5 convertase complexes to prevent the cleavage of C3 and C5, thereby reducing opsonization, inflammation, and terminal membrane attack complex formation.