The complement cascade is activated through three pathways converging at C3 (complement component 3) cleavage, generating opsonins, anaphylatoxins, and the membrane attack complex that lyses target cells. When host regulatory proteins are genetically absent or overwhelmed, complement drives severe hematological, renal, and neurological disease. Pharmacological complement inhibition has become a transformative strategy for several rare but life-threatening conditions.
The classical pathway is triggered by C1q binding to antibody-antigen complexes on cell surfaces, sequentially activating C4 (complement component 4) and C2 (complement component 2) to form the classical pathway C3 convertase (C4b2a). The lectin pathway is activated by mannose-binding lectin or ficolins recognizing carbohydrate patterns on microbial surfaces, activating MBL-associated serine proteases to form the same C4b2a convertase. The alternative pathway operates as a continuous low-level surveillance mechanism through spontaneous C3 hydrolysis (tick-over), amplified on pathogen or damaged cell surfaces lacking host regulatory proteins — primarily CD55 (decay-accelerating factor, which accelerates convertase decay), CD59 (protectin, which blocks membrane attack complex assembly), and factor H (which promotes C3b cleavage by factor I). All three pathways converge on C3 convertases that cleave C3 into C3a (an anaphylatoxin promoting mast cell degranulation and vascular permeability) and C3b (an opsonin that deposits on target surfaces). C5 (complement component 5) convertases then cleave C5 into C5a (the most potent complement-derived inflammatory mediator, driving neutrophil chemotaxis and activation) and C5b, which nucleates the membrane attack complex (C5b-9) causing osmotic lysis.
Paroxysmal nocturnal hemoglobinuria (PNH) is caused by somatic mutations in the PIGA gene (phosphatidylinositol glycan biosynthesis class A) in hematopoietic stem cells, impairing GPI (glycosylphosphatidylinositol) anchor biosynthesis and depleting CD55 and CD59 from erythrocyte and platelet surfaces. Without these regulators, PNH erythrocytes undergo spontaneous complement-mediated intravascular hemolysis, and platelets are activated, causing the thrombotic complications that are the leading cause of mortality in PNH. Atypical hemolytic uremic syndrome (aHUS) results from mutations or autoantibodies affecting alternative pathway regulatory proteins (factor H, factor I, or CD46 known as membrane cofactor protein), producing uncontrolled alternative pathway activation in the renal microvasculature causing thrombotic microangiopathy with hemolytic anemia, thrombocytopenia, and acute kidney injury. In neurology, neuromyelitis optica spectrum disorder (NMOSD) with anti-aquaporin-4 (anti-AQP4) antibodies activates complement at astrocyte foot processes causing astrocyte destruction, and generalized myasthenia gravis (gMG) with anti-acetylcholine receptor antibodies activates terminal complement at the neuromuscular junction.
Eculizumab is a humanized monoclonal antibody that binds C5 with high affinity, preventing its cleavage into C5a and C5b by the C5 convertase. This blocks both C5a-mediated inflammation and membrane attack complex formation while preserving upstream C3b-mediated opsonization, which is important for ongoing host defense. Eculizumab is approved for PNH, aHUS, gMG, and NMOSD with anti-AQP4 antibodies. In PNH it dramatically reduces intravascular hemolysis, transfusion requirements, and thrombotic events. It is administered intravenously every two weeks after a loading phase.
Ravulizumab is an engineered successor to eculizumab with four amino acid substitutions that extend its plasma half-life approximately four-fold through increased affinity for the neonatal Fc receptor, allowing maintenance dosing every eight weeks rather than every two weeks. It has the same mechanism, the same approved indications, and the same safety requirements as eculizumab. The clinical decision between the two agents is primarily based on dosing convenience.
Because the terminal complement complex is the primary defense mechanism against encapsulated bacteria — particularly Neisseria meningitidis (meningococcus) — all complement inhibitors carry a mandatory meningococcal vaccination requirement. Both the meningococcal ACWY conjugate vaccine and the meningococcal type B vaccine (Bexsero or Trumenba) must be administered at least two weeks before the first dose. Prophylactic antibiotics (penicillin V or amoxicillin) are recommended throughout therapy. Patients must be educated about the symptoms of meningococcal disease — sudden severe headache, fever, stiff neck, petechial rash — and the need for immediate emergency evaluation, because complement inhibitor-related meningococcal disease can be fulminant and fatal within hours.
Approximately 30% of PNH patients treated with anti-C5 therapy experience residual hemolysis through extravascular mechanisms: C5 inhibition does not prevent C3b deposition on PNH erythrocytes, and C3b-opsonized erythrocytes are removed by splenic and hepatic macrophages. Pegcetacoplan is a pegylated cyclic peptide that binds C3 and C3b directly, blocking all three complement pathways upstream of C5 and preventing both intravascular hemolysis (through downstream MAC blockade) and extravascular hemolysis (through prevention of C3b opsonization). It is approved for PNH in adults inadequately controlled on eculizumab or ravulizumab and is administered subcutaneously twice weekly.
Iptacopan is an oral factor B inhibitor; factor B is the serine protease that associates with C3b to form the alternative pathway C3 convertase (C3bBb). By selectively inhibiting factor B, iptacopan blocks only the alternative pathway amplification loop while leaving the classical and lectin pathways intact, preserving a broader component of innate immune defense than upstream pan-complement inhibitors. Iptacopan is approved as oral monotherapy for PNH and demonstrated superiority over anti-C5 therapy in reducing extravascular hemolysis and improving hemoglobin levels in clinical trials. Avacopan is an oral small-molecule antagonist of the C5a receptor 1 (C5aR1, also called CD88), approved for anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis — specifically granulomatosis with polyangiitis and microscopic polyangiitis — where it serves as a corticosteroid-sparing strategy by blocking C5a-driven neutrophil activation in the renal glomerulus without requiring meningococcal vaccination because MAC formation is unaffected.
Terminal complement is the primary defense against Neisseria meningitidis. All complement inhibitors — eculizumab, ravulizumab, pegcetacoplan, iptacopan — increase the risk of fulminant meningococcal disease. Required before first dose: meningococcal ACWY conjugate vaccine AND meningococcal type B vaccine at least two weeks before initiation. If urgent treatment is needed, start prophylactic antibiotics (penicillin V 250 milligrams twice daily) immediately and continue until at least two weeks after vaccination. Continue antibiotic prophylaxis throughout therapy. Educate patients: sudden headache, fever, neck stiffness, or petechial rash requires immediate emergency evaluation — meningococcal disease in complement-inhibited patients can be fatal within hours. Note: avacopan (C5a receptor 1 antagonist) does not block MAC formation and does not require meningococcal vaccination.
