Therapeutic Monoclonal Antibodies & Immunomodulatory Biologics
Know the target and you can predict the use and the toxicity
Naming and structure
Why structure matters. A therapeutic antibody binds its target through the variable region, while its IgG Fc region supplies a long half-life (via FcRn recycling) and effector functions such as antibody-dependent cellular cytotoxicity and complement activation. Mouse-derived sequence is foreign to the patient, so the more of it a drug contains, the more anti-drug antibodies, loss of response and infusion reactions it provokes. Low-dose methotrexate given with infliximab suppresses these anti-drug antibodies.
- -ximab (chimeric): mouse variable regions on human constant regions (infliximab, rituximab).
- -zumab (humanized): only the mouse CDR loops remain (tocilizumab, natalizumab, ocrelizumab).
- -umab (fully human): least immunogenic (adalimumab, secukinumab, denosumab).
- -cept (fusion protein): a soluble receptor or ligand-binding domain fused to an IgG1 Fc, acting as a decoy (etanercept, abatacept, rilonacept).
Cytokine blockers
TNF-α inhibitors. Five agents block TNF-α: infliximab (chimeric, intravenous), adalimumab and golimumab (human), certolizumab pegol (a PEGylated Fab' fragment without Fc) and etanercept (a TNF receptor-Fc fusion). All treat rheumatoid arthritis, psoriasis, psoriatic arthritis and ankylosing spondylitis, but only the monoclonal antibodies work in Crohn disease and ulcerative colitis; etanercept fails in IBD. Because certolizumab lacks an Fc region, it barely crosses the placenta, which makes it useful in pregnancy.
TNF and granulomas. TNF-α sustains macrophage activation and holds granulomas together. Blockade can reactivate latent tuberculosis, often as extrapulmonary, disseminated or miliary disease, and increases histoplasmosis and other granulomatous infections. Hepatitis B can also reactivate.
- Screen for latent TBInterferon-γ release assay or tuberculin skin test; treat latent infection before starting
- Screen for hepatitis BHBsAg and anti-HBc
- Exclude contraindicationsDemyelinating disease (MS, optic neuritis), decompensated NYHA III–IV heart failure, active serious infection
- MonitorInfection, drug-induced lupus, paradoxical psoriasis
IL-6 receptor blockade. Tocilizumab treats rheumatoid arthritis, giant cell arteritis and the cytokine release syndrome that follows CAR-T cell therapy. Hepatic CRP synthesis depends on IL-6, so infections can present without fever or a CRP rise. Intestinal perforation, usually from diverticulitis, is a known hazard.
IL-1 blockade. Anakinra (a recombinant IL-1 receptor antagonist given by daily injection), canakinumab (a monoclonal anti-IL-1β) and rilonacept (an IL-1 trap fusion protein) treat inflammasome-driven disease: CAPS, colchicine-resistant familial Mediterranean fever, Still disease and gout flares. Bacterial infections increase.
IL-17A and IL-12/23. Secukinumab and ixekizumab block IL-17A and are highly effective for psoriasis, psoriatic arthritis and ankylosing spondylitis. IL-17 defends mucosal surfaces, so these drugs increase mucocutaneous candidiasis and can trigger or worsen inflammatory bowel disease. IL-12 (p35 + p40) drives Th1 cells and IL-23 (p19 + p40) sustains Th17 cells. Ustekinumab blocks the shared p40 subunit and treats psoriasis, psoriatic arthritis, Crohn disease and ulcerative colitis; guselkumab and risankizumab block the IL-23-specific p19 subunit.
Type 2 (allergic) biologics. Dupilumab blocks IL-4Rα, a component of both the IL-4 and IL-13 receptors, and treats atopic dermatitis, asthma and eosinophilic esophagitis; conjunctivitis is a common side effect. Mepolizumab neutralizes IL-5 and depletes eosinophils (severe eosinophilic asthma, EGPA, hypereosinophilic syndrome). Omalizumab binds free IgE, preventing it from arming mast cells (allergic asthma, chronic urticaria).
| Target | Drugs | Main uses | Key hazards |
|---|---|---|---|
| TNF-α | Infliximab, adalimumab, golimumab, certolizumab, etanercept | RA, psoriasis, PsA, AS; IBD (not etanercept) | TB and HBV reactivation; worsens MS and decompensated HF |
| IL-6 receptor | Tocilizumab | RA, giant cell arteritis, CAR-T cytokine release syndrome | Masked CRP and fever; GI perforation |
| IL-1 | Anakinra, canakinumab, rilonacept | CAPS, FMF, Still disease, gout flares | Bacterial infection |
| IL-17A | Secukinumab, ixekizumab | Psoriasis, PsA, AS | Candida; new or worse IBD |
| IL-12/23 p40; IL-23 p19 | Ustekinumab; guselkumab, risankizumab | Psoriasis, PsA, Crohn disease, UC | Generally mild infection risk |
| IL-4Rα | Dupilumab | Atopic dermatitis, asthma, eosinophilic esophagitis | Conjunctivitis |
| IL-5 | Mepolizumab | Eosinophilic asthma, EGPA, HES | Few |
| IgE | Omalizumab | Allergic asthma, chronic urticaria | Rare anaphylaxis |
Cell, adhesion and costimulation targets
Anti-CD20. Rituximab (chimeric) and ocrelizumab (humanized, used in multiple sclerosis) kill CD20+ B cells through ADCC, complement and apoptosis. Rituximab treats B-cell lymphomas, CLL, rheumatoid arthritis, ANCA vasculitis, pemphigus vulgaris and ITP. Plasma cells lack CD20, so preexisting antibody levels largely persist, but responses to new vaccines are poor for months.
Before anti-CD20 therapy, check HBsAg and anti-HBc: hepatitis B can reactivate even in HBsAg-negative, anti-HBc-positive patients. PML is a rare but feared complication.
Anti-CD52. Alemtuzumab depletes T cells, B cells, NK cells and monocytes for months. Used in relapsing MS (and CLL), it causes infusion reactions, opportunistic infections and delayed secondary autoimmunity: autoimmune thyroid disease (often Graves) in roughly a third of MS patients, with ITP and anti-GBM disease less often.
Integrin blockers. Natalizumab binds the α4 integrin subunit (α4β1, also called VLA-4, and α4β7), blocking leukocyte adhesion to VCAM-1 on brain endothelium and MAdCAM-1 in the gut; it treats MS and Crohn disease. Without CNS immune surveillance, JC polyomavirus can infect oligodendrocytes and cause progressive multifocal leukoencephalopathy, with risk rising with anti-JCV antibody positivity, more than 2 years of therapy and prior immunosuppressants. Vedolizumab targets α4β7 only, blocking homing to gut MAdCAM-1 while sparing brain trafficking, so it treats ulcerative colitis and Crohn disease without meaningful PML risk.
BAFF and costimulation. BAFF (BLyS) is a B-cell survival factor overproduced in lupus; belimumab neutralizes it and is approved for SLE and lupus nephritis. Abatacept (CTLA-4-Ig) binds B7 (CD80/CD86) on antigen-presenting cells so CD28 cannot deliver signal 2, leaving T cells anergic; it treats rheumatoid arthritis, juvenile idiopathic arthritis and psoriatic arthritis. Belatacept, a higher-affinity relative, prevents kidney transplant rejection.
Complement and bone targets
Eculizumab. This anti-C5 antibody prevents generation of C5a and the membrane attack complex (C5b-9). It controls paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, generalized myasthenia gravis and neuromyelitis optica spectrum disorder.
Denosumab. RANKL on osteoblasts activates RANK on osteoclast precursors; osteoprotegerin is the natural decoy that blocks it. Denosumab is a human anti-RANKL antibody that mimics osteoprotegerin. It is given subcutaneously every 6 months for osteoporosis and more often for bone metastases. Risks include hypocalcemia (especially in CKD), osteonecrosis of the jaw and atypical femoral fractures. By contrast, romosozumab builds bone by inhibiting sclerostin.
Stopping denosumab without a follow-on bisphosphonate causes rebound bone loss and multiple vertebral fractures.
Recombinant cytokines
| Agent | Uses | Notable toxicity |
|---|---|---|
| Aldesleukin (IL-2) | Metastatic melanoma, renal cell carcinoma | Capillary leak syndrome (hypotension, edema) |
| IFN-α | Chronic hepatitis B, some malignancies | Flu-like illness, depression, cytopenias, thyroiditis |
| IFN-β | Relapsing multiple sclerosis | Flu-like illness, injection-site reactions |
| IFN-γ | Chronic granulomatous disease (fewer serious infections) | Flu-like illness |
Intravenous immunoglobulin
What it is. IVIG is IgG pooled from thousands of donors. At replacement doses (about 400–600 mg/kg every 3–4 weeks) it supplies missing antibody in X-linked agammaglobulinemia and common variable immunodeficiency. At high doses (1–2 g/kg) it modulates immunity in Kawasaki disease (with aspirin, to prevent coronary aneurysms), immune thrombocytopenia and Guillain-Barré syndrome. Mechanisms include saturating Fc receptors on splenic macrophages, saturating FcRn so pathogenic IgG is cleared faster, and supplying anti-idiotype antibodies.
Selective IgA deficiency (often with recurrent sinopulmonary infections or celiac disease) can come with anti-IgA antibodies that react with trace IgA in IVIG or blood products and cause anaphylaxis; use IgA-depleted products.
Other IVIG hazards. Aseptic meningitis, thrombosis, acute kidney injury and hemolysis from donor anti-A/anti-B antibodies.