Chapter 40 · Module 5
Complement, IVIG, and Emerging Targets
Complement inhibitors, intravenous immunoglobulin, co-stimulation blockade, and plasma cell-directed therapy
ADCC = antibody-dependent cellular cytotoxicity  ·  aHUS = atypical hemolytic uremic syndrome  ·  ANCA = anti-neutrophil cytoplasmic antibody  ·  AQP4 = aquaporin-4  ·  BTK = Bruton tyrosine kinase  ·  CIDP = chronic inflammatory demyelinating polyneuropathy  ·  CLL = chronic lymphocytic leukemia  ·  CTLA-4 = cytotoxic T-lymphocyte-associated protein 4  ·  DAF = decay-accelerating factor  ·  EBV = Epstein-Barr virus  ·  FcRn = neonatal Fc receptor  ·  GBS = Guillain-Barre syndrome  ·  gMG = generalized myasthenia gravis  ·  GPI = glycosylphosphatidylinositol  ·  ITP = immune thrombocytopenia  ·  IVIG = intravenous immunoglobulin  ·  MAC = membrane attack complex  ·  NMOSD = neuromyelitis optica spectrum disorder  ·  PNH = paroxysmal nocturnal hemoglobinuria  ·  RA = rheumatoid arthritis  ·  SLE = systemic lupus erythematosus
Complement Cascade and Drug Intervention Points
3 Pathways
Classical Lectin Alternative
→
C3 Convertase
C3 → C3a + C3b
▼ Pegcetacoplan (C3)
▼ Iptacopan (factor B)
→
C5 Convertase
C5 → C5a + C5b
▼ Eculizumab / Ravulizumab
→
C5a
Neutrophil activation inflammation
▼ Avacopan (C5aR1)
→
MAC (C5b-9)
Cell lysis
Anti-C5 mAb
Eculizumab
  • Blocks C5 cleavage → no C5a, no MAC
  • PNH, aHUS, gMG, NMOSD
  • IV every 2 weeks
  • MenACWY + MenB vaccine mandatory
Anti-C5 mAb (long-acting)
Ravulizumab
  • Same mechanism as eculizumab
  • Same indications, same vaccine mandate
  • IV every 8 weeks — key advantage
C3 inhibitor
Pegcetacoplan
  • Binds C3 and C3b — blocks all 3 pathways
  • PNH inadequately controlled on anti-C5
  • Prevents extravascular hemolysis
  • SC twice weekly
Factor B inhibitor (oral)
Iptacopan
  • Blocks alternative pathway only
  • PNH monotherapy (oral, once daily)
  • Superior to anti-C5 for extravascular hemolysis
  • Meningococcal vaccination required
Intravenous Immunoglobulin (IVIG) — Mechanisms and Uses
High-dose immunomodulatory (1-2 g/kg)
IVIG Mechanisms
  • FcRn saturation → accelerated autoantibody catabolism
  • Fc-gamma receptor blockade on macrophages → prevents platelet destruction (ITP)
  • Anti-idiotypic antibodies neutralize autoantibodies
  • Modulates complement and cytokine production
Clinical applications
IVIG Indications
  • Replacement: primary immunodeficiency (CVID, XLA), hypogammaglobulinemia
  • Immunomodulation: GBS, CIDP, ITP, Kawasaki disease
  • Dermatomyositis, pemphigus, myasthenia gravis crisis
  • IgA deficiency: risk of anaphylaxis — use IgA-depleted preparation
Co-stimulation Blockade and Plasma Cell-Directed Therapy
CTLA-4-Ig (RA / transplant)
Abatacept / Belatacept
  • CTLA-4-Ig binds CD80/CD86 on APC — blocks CD28 co-stimulation
  • T cells become anergic without co-stimulatory signal
  • Abatacept: RA, PsA, JIA, prevention of aGVHD
  • Belatacept: kidney transplant (CNI alternative)
  • Belatacept: EBV-seronegative recipients at PTLD risk
Anti-CD38 mAb (plasma cells)
Daratumumab
  • CD38 expressed on plasma cells (and myeloma cells)
  • Depletes long-lived plasma cells rituximab cannot reach
  • Approved: multiple myeloma, light chain amyloidosis
  • Investigational: refractory autoimmune disease
  • Positive DAT: interferes with blood compatibility testing
Proteasome inhibitor
Bortezomib
  • Blocks 26S proteasome → unfolded protein response
  • Plasma cells most vulnerable — high Ig synthesis rate
  • Approved: multiple myeloma, mantle cell lymphoma
  • Off-label: AMR, lupus nephritis
  • Dose-limiting toxicity: peripheral neuropathy (30-40%)
Co-stimulation Blockade Direction — Critical Distinction

Abatacept/belatacept ACTIVATE the CTLA-4 checkpoint → suppress T-cell responses (immunosuppression). Oncology checkpoint inhibitors (ipilimumab, pembrolizumab) BLOCK CTLA-4/PD-1 → release T-cell inhibition (immunostimulation). Immune-related adverse events from checkpoint inhibitors are autoimmune in nature and may be treated with abatacept.