Figure 1.

Discovery and development of the complement inhibitor eculizumab for the treatment of paroxysmal nocturnal hemoglobinuria. Schematic diagram of the complement cascade. The 3 primary routes for activation of complement are the lectin pathway (LP), the classical pathway (CP), and the alternative pathway (AP). The LP and CP are activated when specific triggers are recognized by host pattern-recognition receptors. The AP is constitutively active. Initial activation through the LP or CP generates a shared C3 convertase (C4b·C2a). In the AP, C3b pairs with factor B (FB) to form the AP proconvertase (C3b·B), which is processed by factor D (FD) to form the AP C3 convertase (C3b·Bb·P). Both types of C3 convertases cleave C3 to generate C3a and C3b. C3a is a weak anaphylatoxin, a substance that promotes an inflammatory response. Nascent C3b binds covalently to cell surface proteins, forming the nidus of the C3 convertase. C3b that binds to the surface of a healthy host cell is quickly inactivated; C3b that attaches to the surface of a pathogen or altered host cell triggers a rapid amplification loop to generate more C3b, resulting in opsonization. C3b also complexes with the C3 convertases to form the C5 convertases (C4b·C2a·C3b and C3b·Bb·C3b·P). In the terminal complement cascade, C5 convertases cleave C5 into C5a (a strong anaphylatoxin) and C5b. C5b combines with C6-9 to form the membrane attack complex (MAC), also referred to as the terminal complement complex. Regulatory factors act at various stages of the cascade to control complement activation via their decay accelerating activity and/or cofactor activity. MASPs, mannose-binding lectin-associated serine proteases; MBL, mannose-binding lectin; PAMPs, pathogen-associated molecular patterns.