Chapter 40 · Module 1
Immunopharmacology Foundations
Immune cells, cytokines, JAK-STAT signaling, and complement at a glance
ADCC = antibody-dependent cellular cytotoxicity  ·  AS = ankylosing spondylitis  ·  BAFF = B-cell activating factor  ·  CAPS = cryopyrin-associated periodic syndromes  ·  G-CSF = granulocyte colony-stimulating factor  ·  GM-CSF = granulocyte-macrophage colony-stimulating factor  ·  IBD = inflammatory bowel disease  ·  IL = interleukin  ·  JAK = Janus kinase  ·  MACE = major adverse cardiovascular events  ·  NK = natural killer  ·  PsA = psoriatic arthritis  ·  RA = rheumatoid arthritis  ·  TNF = tumor necrosis factor  ·  UC = ulcerative colitis  ·  VTE = venous thromboembolism
Immune Cell Drug Targets
Macrophage / Monocyte
Innate Effectors
  • TNF inhibitors
  • IL-1 antagonists
  • IL-6 inhibitors
  • Corticosteroids
T Cells
Adaptive Effectors
  • Calcineurin inhibitors
  • mTOR inhibitors
  • JAK inhibitors
  • Abatacept / belatacept
B Cells / Plasma Cells
Humoral Arm
  • Rituximab (anti-CD20)
  • Belimumab (anti-BAFF)
  • IVIG
  • Daratumumab (anti-CD38)
Eosinophils / Mast Cells
Type 2 Effectors
  • Dupilumab (IL-4Rα)
  • Mepolizumab (IL-5)
  • Benralizumab (IL-5Rα)
  • Omalizumab (IgE)
Cytokine Axis → Drug
TNF-α Axis
Five Inhibitors
  • Infliximab — chimeric mAb
  • Adalimumab — fully human mAb
  • Etanercept — TNFR2 fusion
  • Certolizumab — Fab, no Fc → safe in pregnancy
  • Golimumab — fully human mAb
IL-23 / IL-17 Axis
Psoriasis / SpA
  • Ustekinumab — anti-p40 (IL-12 & IL-23)
  • Guselkumab / risankizumab — anti-p19 (IL-23)
  • Secukinumab / ixekizumab — anti-IL-17A
  • IL-17 inhibitors: avoid in active IBD
IL-1 Axis
Inflammasome Output
  • Anakinra — IL-1Ra (blocks IL-1α + IL-1β)
  • Canakinumab — anti-IL-1β mAb
  • Rilonacept — IL-1 trap
  • Gout, CAPS, pericarditis
JAK-STAT Signaling Pathway
Cytokine
Binds receptor
→
JAK
Trans-phosphorylation
→
STAT
Phosphorylated, dimerizes
→
Nucleus
Gene transcription
█
JAK Inhibitor
ATP-competitive block
JAK1 + JAK3
Tofacitinib
  • Blocks γ-c chain cytokines (IL-2, 4, 7, 15, 21)
  • RA, PsA, UC, AS
JAK1 + JAK2
Baricitinib / Upadacitinib
  • Broader cytokine suppression incl. IFN pathways
  • RA, AD, alopecia areata, IBD (upadacitinib)
Class-Wide Warning
Black Box Risks
  • Serious infections / TB reactivation
  • MACE, VTE, malignancy
  • Use after TNF inhibitor failure
  • Shingrix before starting
Complement Cascade and Drug Targets
Classical / Lectin / Alternative
3 Activation Pathways
→
C3 Convertase
C3 → C3a + C3b
→
C5 Convertase
C5 → C5a + C5b
→
MAC (C5b-9)
Cell lysis
Anti-C5 Agents
Eculizumab / Ravulizumab
  • Block C5 cleavage → no C5a, no MAC
  • Preserve C3b opsonization
  • PNH, aHUS, gMG, NMOSD
  • Ravulizumab: q8wk vs. eculizumab q2wk
Mandatory Safety Rule
Meningococcal Vaccination
  • MenACWY + MenB ≥2 wk before first dose
  • Antibiotic prophylaxis throughout therapy
  • Applies to all complement inhibitors
  • Rapid fatal meningococcal disease possible