Immunopharmacology · Module 3 of 5

Biologic Immunosuppressants

TNF inhibitors, interleukin antagonists, and B-cell therapies

Five TNF inhibitors span three structural classes: infliximab (chimeric IgG1, most immunogenic), adalimumab and golimumab (fully human IgG1), certolizumab (PEGylated Fab, no Fc → no placental transfer, preferred in pregnancy), and etanercept (TNFR2-Fc fusion binding TNF-alpha and lymphotoxin-alpha); etanercept is uniquely ineffective in IBD and granulomatous diseases because it binds soluble but not membrane-bound TNF and cannot induce the reverse signaling needed for granuloma dissolution.
All TNF inhibitors require mandatory pre-treatment TB screening (TST or IGRA — IGRA preferred in BCG-vaccinated patients) and hepatitis B serology; active TB, hepatitis B, moderate-to-severe heart failure (NYHA III/IV), active demyelinating disease, and active malignancy are absolute contraindications; never combine two biologic agents (additive immunosuppression → unacceptable infection risk).
Tocilizumab and sarilumab block the IL-6Rα chain so completely that CRP falls to near zero — it can no longer be used as an infection biomarker; use procalcitonin and clinical assessment instead; tocilizumab is also the primary treatment for cytokine release syndrome complicating CAR-T cell therapy.
IL-17A inhibitors (secukinumab, ixekizumab, bimekizumab) carry a class-specific contraindication in active IBD and cause mucocutaneous candidiasis in 3–4% (IL-17A is required for mucosal antifungal defense); selective IL-23 p19 inhibitors (guselkumab, risankizumab) do not carry the IBD risk and are preferred when psoriasis and IBD coexist.
Rituximab (anti-CD20) depletes B cells but spares plasma cells (CD20-negative) — the critical limitation in autoantibody-driven diseases; its most serious complication is PML from JC virus reactivation; belimumab (anti-BLyS/BAFF) is approved for autoantibody-positive SLE; dupilumab (anti-IL-4Rα) produces no significant immunosuppression, making its safety profile uniquely favorable among this drug class.

ADA = anti-drug antibody · BAFF = B-cell activating factor · BCG = Bacille Calmette-Guérin · BLyS = B lymphocyte stimulator · CRP = C-reactive protein · CRS = cytokine release syndrome · IBD = inflammatory bowel disease · IFNAR1 = type I interferon receptor subunit 1 · IGRA = interferon-gamma release assay · IL = interleukin · PML = progressive multifocal leukoencephalopathy · RA = rheumatoid arthritis · SLE = systemic lupus erythematosus · TNF = tumor necrosis factor · TST = tuberculin skin test · TSLP = thymic stromal lymphopoietin

TNF Inhibitors — Five Agents, Three Structural Classes

Feature	Infliximab	Adalimumab	Golimumab	Certolizumab	Etanercept
Structure	Chimeric IgG1 mAb (~25% murine)	Fully human IgG1 mAb	Fully human IgG1 mAb	PEGylated Fab — no Fc region	TNFR2-Fc fusion protein
Fc region	Yes	Yes	Yes	No → no placental transfer; preferred in pregnancy	Yes
Targets	TNF-alpha (membrane + soluble)	TNF-alpha	TNF-alpha	TNF-alpha	TNF-alpha + lymphotoxin-alpha (TNF-beta)
IBD approved	Yes (Crohn's + UC)	Yes (Crohn's + UC)	Yes (Crohn's + UC)	Crohn's only	No — ineffective in IBD and granulomatous disease
Route / freq	IV q8wk; t½ ~9.5 days	SC q2wk; t½ ~14 days	SC monthly; t½ ~14 days	SC q2–4wk; t½ ~14 days	SC weekly; t½ ~4 days

Interleukin Axis Targeted Biologics

IL-6 Receptor

Tocilizumab / Sarilumab

Block IL-6Rα chain → suppress JAK1/2-STAT3 signaling
RA, giant cell arteritis, systemic JIA
Tocilizumab: CRS treatment (CAR-T therapy complication) — reverses fever and hemodynamic instability within 24 hours
CRP suppressed to near zero — cannot use for infection monitoring; use procalcitonin instead

IL-12 / IL-23 p40

Ustekinumab

Blocks shared p40 subunit → suppresses both IL-12 and IL-23
Psoriasis, PsA, Crohn's disease, UC
SC q12wk maintenance — least frequent dosing of any approved biologic in these indications
Biosimilar available

IL-23 p19 Selective

Guselkumab / Risankizumab

Block IL-23 p19 only — preserve IL-12-dependent Th1 immunity
Psoriasis, PsA; risankizumab also approved for Crohn's and UC
No IBD risk — preferred over IL-17 inhibitors when psoriasis + IBD coexist

IL-17A Inhibitors

Secukinumab / Ixekizumab / Bimekizumab

Secukinumab / ixekizumab: block IL-17A; bimekizumab: blocks IL-17A + IL-17F
Psoriasis, PsA, ankylosing spondylitis; highest efficacy in plaque psoriasis (PASI 90: 60–90%)
Contraindicated in active IBD — IL-17A inhibitors worsened Crohn's disease in trials
Mucocutaneous candidiasis 3–4% — IL-17A required for antifungal mucosal immunity; manage topically

Type 2 Inflammation

Dupilumab / Anti-IL-5 / Tezepelumab / Omalizumab

Dupilumab (anti-IL-4Rα): blocks IL-4 + IL-13 simultaneously; AD, asthma, CRSwNP, EoE, prurigo nodularis; no significant immunosuppression
Mepolizumab / reslizumab (anti-IL-5), benralizumab (anti-IL-5Rα): severe eosinophilic asthma; reduce exacerbations ~50% when eosinophils >300/µL
Tezepelumab (anti-TSLP): effective in both eosinophilic and non-eosinophilic severe asthma (upstream alarmin block)
Omalizumab (anti-IgE): allergic asthma, chronic spontaneous urticaria, CRSwNP

B-Cell and Plasma Cell Targeted Biologics

Anti-CD20

Rituximab

Chimeric anti-CD20 mAb; depletes pre-B through memory B cells via CDC, ADCC, and apoptosis
Plasma cells (CD20-negative) are spared — limitation in autoantibody-driven diseases
RA (post-TNF failure), GPA, MPA, pemphigus vulgaris
PML risk: JC virus reactivation in profoundly immunosuppressed; monitor JC virus antibody titers
HBV reactivation: mandatory serology screening before treatment

Anti-BLyS / Anti-BAFF

Belimumab

Blocks BLyS (BAFF) → reduces B-cell survival; BLyS elevated in SLE and correlates with anti-dsDNA titers
Active, autoantibody-positive SLE; also approved for lupus nephritis
IV or SC administration

Anti-IFNAR1

Anifrolumab

Blocks type I interferon receptor (IFNAR1) → suppresses entire type I IFN response
Moderate-to-severe SLE; most effective in patients with positive IFN gene signature (60–80% of SLE patients)
Herpes zoster reactivation: slightly increased rate (impaired IFN antiviral defense)

Universal Pre-Treatment Screening — All Biologic Immunosuppressants

Tuberculosis: TST or IGRA (IGRA preferred in BCG-vaccinated patients — BCG causes false-positive TST, not IGRA); confirmed latent TB requires at least 4 weeks of isoniazid prophylaxis before biologic initiation. Hepatitis B: HBsAg, anti-HBs, total anti-HBc; surface antigen-positive → antiviral prophylaxis (entecavir or tenofovir) before and throughout therapy; core antibody-positive/surface antigen-negative → monitor HBV DNA every 3 months. CBC and metabolic panel at baseline. Complete all live vaccines at least 2–4 weeks before starting (live vaccines contraindicated once biologic is initiated). Shingrix (inactivated — safe during biologic therapy) is strongly recommended before initiation. Never combine two biologic immunosuppressants. Immunogenicity: concurrent methotrexate or azathioprine substantially reduces anti-drug antibody formation against infliximab and adalimumab.

Suggested References

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