Immunopharmacology · Module 5 of 5

Complement, IVIG, and Emerging Targets

Complement inhibitors, intravenous immunoglobulin, co-stimulation blockade, and plasma cell-directed therapy

Eculizumab and ravulizumab block C5 cleavage, preventing C5a and MAC formation while preserving upstream C3b opsonization; ravulizumab’s engineered FcRn affinity extends its half-life to allow q8-week dosing vs. q2-week for eculizumab; both are approved for PNH, aHUS, generalized myasthenia gravis, and NMOSD with anti-AQP4 antibodies; MenACWY + MenB vaccination at least 2 weeks before first dose is mandatory for all complement inhibitors except avacopan (which does not block MAC).
Approximately 30% of PNH patients on anti-C5 therapy experience residual extravascular hemolysis from C3b-opsonized erythrocytes removed by spleen/liver; pegcetacoplan (C3 inhibitor, SC twice weekly) blocks all three pathways upstream, preventing both intravascular and extravascular hemolysis; iptacopan (oral factor B inhibitor, once daily) selectively blocks the alternative pathway amplification loop and demonstrated superiority over anti-C5 for extravascular hemolysis.
High-dose IVIG (1–2 g/kg) acts through four converging mechanisms: FcRn saturation (accelerates autoantibody catabolism by 10–14 days), Fc-gamma receptor blockade on macrophages (key mechanism in ITP — blocks platelet destruction), anti-idiotypic antibody neutralization of autoantibodies, and complement/cytokine modulation; patients with IgA deficiency who have anti-IgA antibodies risk anaphylaxis from standard preparations — use IgA-depleted IVIG.
Abatacept (CTLA-4-Ig) and belatacept (higher-affinity variant) block CD80/CD86 on antigen-presenting cells, preventing CD28 co-stimulation and inducing T-cell anergy; abatacept is approved for RA, PsA, JIA, and acute GVHD prevention; belatacept is a CNI alternative in kidney transplant with better long-term renal function but higher acute rejection risk and is absolutely contraindicated in EBV-seronegative recipients (PTLD risk).
Long-lived plasma cells lack CD20 and are immune to rituximab; daratumumab (anti-CD38) depletes them via ADCC, CDC, and direct apoptosis — approved for myeloma/amyloidosis; CD38 on erythrocytes causes pan-reactive positive direct antiglobulin test requiring specialized pre-transfusion testing; bortezomib (proteasome inhibitor) exploits plasma cell vulnerability to high Ig synthesis load (triggers unfolded protein response); dose-limiting toxicity is peripheral neuropathy (30–40%).

aHUS = atypical hemolytic uremic syndrome · ANCA = anti-neutrophil cytoplasmic antibody · AQP4 = aquaporin-4 · CIDP = chronic inflammatory demyelinating polyneuropathy · CTLA-4 = cytotoxic T-lymphocyte-associated protein 4 · EBV = Epstein-Barr virus · FcRn = neonatal Fc receptor · GBS = Guillain-Barré 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 · SLE = systemic lupus erythematosus

Complement Cascade and Drug Intervention Points

3 Pathways

Classical / Lectin / Alternative

→

C3 Convertase

C3 → C3a + C3b

▼ Pegcetacoplan (C3/C3b)
▼ Iptacopan (factor B — alt. pathway)

→

C5 Convertase

C5 → C5a + C5b

▼ Eculizumab / Ravulizumab

→

C5a

Neutrophil chemotaxis & activation

▼ Avacopan (C5aR1 antagonist)
no MAC block → no MenB required

→

MAC (C5b-9)

Osmotic cell lysis

Anti-C5 mAb

Eculizumab

Blocks C5 cleavage → no C5a, no MAC
Preserves C3b-mediated opsonization (upstream intact)
PNH, aHUS, gMG, NMOSD (anti-AQP4)
IV every 2 weeks after loading
MenACWY + MenB mandatory ≥2 wk before first dose; antibiotic prophylaxis throughout

Anti-C5 mAb — Long-Acting

Ravulizumab

Same mechanism and indications as eculizumab
4 amino acid substitutions → increased FcRn affinity → ~4× longer half-life
IV every 8 weeks — key dosing advantage
Same meningococcal vaccination mandate as eculizumab

C3 Inhibitor

Pegcetacoplan

PEGylated cyclic peptide binding C3 and C3b — blocks all 3 pathways upstream of C5
Prevents both intravascular hemolysis (MAC) and extravascular hemolysis (C3b opsonization)
PNH inadequately controlled on anti-C5 therapy
SC twice weekly

Factor B Inhibitor (Oral)

Iptacopan

Blocks factor B → inhibits alternative pathway C3 convertase (C3bBb) only
Spares classical and lectin pathways — broader innate immune preservation
PNH oral monotherapy; superior to anti-C5 for extravascular hemolysis
Meningococcal vaccination required (alternative pathway contributes to terminal complement)

C5a Receptor Antagonist (Oral)

Avacopan

Oral small-molecule antagonist of C5aR1 (CD88)
Blocks C5a-driven neutrophil activation in the renal glomerulus without affecting MAC formation
ANCA-associated vasculitis (GPA, MPA) — corticosteroid-sparing strategy
Does not block MAC → meningococcal vaccination NOT mandatory

Mandatory Safety — All C5/C3 Inhibitors

Meningococcal Disease Rule

Terminal complement is primary defense against Neisseria meningitidis — blockade allows fulminant, potentially fatal disease within hours
MenACWY conjugate + MenB (Bexsero or Trumenba) ≥2 weeks before first dose of any MAC-blocking complement inhibitor
If urgent start required: begin penicillin V prophylaxis immediately, continue until ≥2 wk post-vaccination
Educate: sudden headache, fever, neck stiffness, petechial rash → emergency immediately

Intravenous Immunoglobulin (IVIG)

High-Dose Immunomodulation (1–2 g/kg)

IVIG Mechanisms

FcRn saturation → accelerates catabolism of endogenous IgG (including autoantibodies) — reduces pathogenic IgG half-life by 10–14 days
Fc-gamma receptor blockade on macrophages → prevents phagocytosis of antibody-coated cells; primary mechanism in ITP (rapid platelet count rise)
Anti-idiotypic antibodies → directly neutralize pathogenic autoantibodies
Modulates complement activation and cytokine production

Clinical Applications

IVIG Indications and Safety

Replacement (400–600 mg/kg/month): CVID, XLA, hypogammaglobulinemia (post-CLL, post-HCT)
Immunomodulation (1–2 g/kg): GBS, CIDP, ITP, Kawasaki disease, dermatomyositis, pemphigus, myasthenia gravis crisis
Thromboembolic risk: DVT, PE, MI, stroke — higher in elderly/CV risk; hydrate and slow infusion rate
IgA deficiency with anti-IgA antibodies: anaphylaxis risk from standard IVIG — 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 with ~500–2,500× higher affinity than CD28 → blocks co-stimulatory signal → T-cell anergy
Abatacept: RA (especially seropositive), PsA, JIA, acute GVHD prevention after HCT
Belatacept: kidney transplant as CNI alternative — superior long-term renal function; higher early acute rejection rate
Belatacept: EBV-seronegative recipients — absolute contraindication (post-transplant lymphoproliferative disorder)

Anti-CD38 (Plasma Cells)

Daratumumab

Fully human IgG1 anti-CD38 mAb; depletes CD38-expressing cells via ADCC, CDC, phagocytosis, and direct apoptosis
CD38 highly expressed on plasma cells (malignant and long-lived non-malignant) — reaches cells rituximab cannot (CD20-negative)
Approved: multiple myeloma, light chain amyloidosis; investigational in refractory autoimmune disease (gMG, SLE, pemphigus)
CD38 on erythrocytes → pan-reactive positive direct antiglobulin test — specialized pre-transfusion testing required

Proteasome Inhibitor

Bortezomib

Reversible 26S proteasome inhibitor; plasma cells uniquely vulnerable: extreme Ig synthesis rate generates misfolded protein burden that requires proteasome clearance
Proteasome block → terminal unfolded protein response → plasma cell apoptosis
Approved: multiple myeloma, mantle cell lymphoma
Off-label: antibody-mediated transplant rejection, lupus nephritis, NMOSD
Dose-limiting toxicity: peripheral sensory neuropathy (30–40%)

Co-stimulation Blockade vs. Checkpoint Inhibition — Opposite Pharmacological Directions

Abatacept and belatacept activate the CTLA-4 inhibitory checkpoint by competitively occupying CD80/CD86 — suppressing autoreactive T-cell responses (immunosuppression). Oncology checkpoint inhibitors (ipilimumab blocks CTLA-4; pembrolizumab/nivolumab block PD-1) remove inhibitory constraints on anti-tumor T cells — the pharmacologically opposite direction (immunostimulation). Immune-related adverse events from checkpoint inhibitor cancer therapy are autoimmune in nature — inflammatory arthritis, colitis, thyroiditis, pneumonitis — and can be treated with corticosteroids; abatacept is emerging as a treatment specifically for checkpoint inhibitor-induced inflammatory arthritis, directly illustrating this pharmacological reciprocity.

Chapter Complete — Immunopharmacology (IMUN) · Pharmacological Core

Immunopharmacology maps drug classes to immune system architecture: innate cells (TNF inhibitors, IL-1 antagonists, IL-6 inhibitors, G-CSF/GM-CSF); adaptive T cells (calcineurin inhibitors, mTOR inhibitors, JAK inhibitors, abatacept/belatacept); B cells and plasma cells (rituximab anti-CD20, belimumab anti-BLyS, daratumumab anti-CD38, bortezomib proteasome inhibitor). The Fc-region rule governs placental transfer and ADCC: certolizumab (no Fc → preferred in pregnancy) differs fundamentally from the four Fc-containing TNF inhibitors. Etanercept is ineffective in IBD and granulomatous disease because it preferentially binds soluble TNF and does not induce reverse signaling through membrane-bound TNF. JAK inhibitors carry a class-wide black box (ORAL Surveillance) and require prior TNF inhibitor failure in rheumatic indications; deucravacitinib (TYK2 allosteric) does not. All complement inhibitors that block MAC require mandatory meningococcal vaccination; avacopan (C5aR1 antagonist) does not. IVIG’s primary mechanism in ITP is Fc-gamma receptor blockade on splenic macrophages, not autoantibody neutralization. Abatacept activates CTLA-4 (immunosuppression); pembrolizumab and ipilimumab block it (immunostimulation) — mechanistically opposite interventions at the same checkpoint.

CRP monitoring caveat (IL-6 receptor inhibitors): tocilizumab and sarilumab suppress CRP to near zero — use procalcitonin for infection detection. Safety rules unique to this chapter: TPMT genotyping before azathioprine; allopurinol/febuxostat absolutely contraindicated with azathioprine (fatal pancytopenia); MMF is an absolute teratogen; belatacept is absolutely contraindicated in EBV-seronegative transplant recipients; meningococcal vaccination (MenACWY + MenB) is mandatory before eculizumab, ravulizumab, pegcetacoplan, and iptacopan; IgA-depleted IVIG in patients with IgA deficiency and anti-IgA antibodies; daratumumab causes pan-reactive positive direct antiglobulin test requiring specialized cross-matching.

Suggested References

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Brunton L, Knollmann B, Hilal-Dandan R, eds.	Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 14th ed.	McGraw-Hill; 2023
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