Complement Inhibitors
Pharmacology of complement-targeting therapies including C5 inhibitors, C3 inhibitors, and factor-targeted agents for PNH, aHUS, and other diseases.
## The Complement System
The complement system comprises over 30 plasma and membrane-bound proteins that form three activation pathways (classical, lectin, alternative), all converging at C3 and proceeding through C5 to form the membrane attack complex (MAC, C5b-9). Complement mediates opsonization, inflammation (C3a, C5a anaphylatoxins), and direct cell lysis.
Dysregulated complement activation drives pathology in paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), C3 glomerulopathy, and autoimmune conditions.
## C5 Inhibitors
**Eculizumab** was the first complement inhibitor, a humanized monoclonal antibody that binds C5 and prevents its cleavage into C5a (anaphylatoxin) and C5b (MAC initiator). Approved indications include PNH, aHUS, generalized myasthenia gravis (anti-AChR antibody-positive), and neuromyelitis optica spectrum disorder (anti-AQP4 antibody-positive).
**Ravulizumab** is a engineered eculizumab variant with 4-fold longer half-life (~50 days vs ~11 days), allowing dosing every 8 weeks instead of every 2 weeks. It achieves this through pH-dependent FcRn recycling -- the antibody releases C5 in acidic endosomes, freeing it to re-enter circulation and bind more C5.
Both agents leave C3-mediated opsonization intact, meaning PNH patients may still experience extravascular hemolysis.
## C3 Inhibitors
**Pegcetacoplan** is a PEGylated C3-targeted peptide that blocks cleavage of C3 into C3a and C3b. By inhibiting upstream of C5, it prevents both intravascular hemolysis (MAC) and extravascular hemolysis (C3b opsonization). It is approved for PNH in patients with inadequate response to C5 inhibitors.
**Iptacopan** is a first-in-class oral Factor B inhibitor that selectively blocks the alternative pathway. Approved for PNH, it offers the convenience of oral dosing while controlling both intravascular and extravascular hemolysis.
## Factor-Targeted Agents
**Sutimlimab** inhibits C1s in the classical pathway and is approved for cold agglutinin disease, where classical pathway activation drives IgM-mediated red blood cell destruction. **Danicopan** is an oral Factor D inhibitor used as add-on therapy to C5 inhibitors in PNH.
## Infection Risk and Vaccination
Complement inhibition dramatically increases susceptibility to encapsulated bacteria, particularly **Neisseria meningitidis**. Meningococcal vaccination (MenACWY and MenB) is mandatory at least 2 weeks before initiating complement therapy. Many centers also prescribe prophylactic antibiotics (penicillin or ciprofloxacin) for the treatment duration. Patients must carry emergency cards and seek immediate care for fever.
## Key Takeaways
- C5 inhibitors prevent MAC formation but leave C3-mediated extravascular hemolysis intact
- C3 and alternative pathway inhibitors offer broader complement blockade
- Mandatory meningococcal vaccination before initiating any complement inhibitor
- Engineered antibodies (ravulizumab) extend dosing intervals through pH-dependent recycling