Complement C5 Pathway

The complement system comprises over 30 proteins forming a proteolytic cascade of innate immunity, activated via three convergent pathways: the classical pathway (antibody-antigen complexes), the lectin pathway (pattern recognition by MBL/ficolins), and the alternative pathway (spontaneous C3 hydrolysis amplified on non-host surfaces). All three pathways converge on C3, generating C3b for opsonisation and C3a as an anaphylatoxin. Downstream, C5 convertase cleaves C5 to generate C5a (potent anaphylatoxin and chemotactic factor) and C5b, which seeds the membrane attack complex (MAC, C5b-9). Physiologically, host cells are protected from autologous complement attack by surface-expressed regulatory proteins including CD55 (DAF) and CD59.

In paroxysmal nocturnal haemoglobinuria (PNH), a somatic mutation in the PIGA gene leads to deficiency of GPI-anchored proteins including CD55 and CD59 on haematopoietic cells, rendering them exquisitely sensitive to alternative pathway-driven complement attack and MAC-mediated intravascular haemolysis. Chronic haemolysis leads to haemoglobin release with nitric oxide scavenging, causing smooth muscle dystonias, thrombosis (the leading cause of mortality in PNH), and renal impairment. Atypical haemolytic uraemic syndrome (aHUS) results from dysregulation of the alternative complement pathway due to mutations or autoantibodies against complement regulatory proteins, driving thrombotic microangiopathy.

Eculizumab, a humanised anti-C5 monoclonal antibody, was the first approved complement inhibitor and transformed PNH and aHUS management by blocking C5 cleavage and preventing MAC formation. Ravulizumab, an engineered derivative with extended half-life via modified FcRn recycling and optimised C5 binding, enables 8-weekly IV dosing (versus 2-weekly for eculizumab) with equivalent efficacy. Both agents require meningococcal vaccination due to the critical role of MAC in Neisseria meningitidis clearance. Proximal complement inhibition (pegcetacoplan, targeting C3) addresses C3-fragment-mediated extravascular haemolysis that can persist with C5 inhibition alone, representing a clinically important distinction in patients with persistent anaemia despite C5 blockade.