Table 3.
Clinically used blocking immunomodulatory biologics
| Biologic | Type | Mechanism of action | Indications | Immune-related safety warnings |
|---|---|---|---|---|
| Abatacept | Fusion protein (CTLA4–Fc–IgG1) | Binds to CD80 and/or CD86 to prevent interaction with CD28 and so inhibits selective T cell co-stimulation | Rheumatoid arthritis, JIA | • No boxed or product label warnings issued |
| Adalimumab | Human mAb | Binds to TNF and blocks its interaction with its receptors | Rheumatoid arthritis, JIA, psoriatic arthritis, ankylosing spondylitis, Crohn's disease |
• Boxed warnings for serious infections (tuberculosis and invasive fungal infections) and malignancies (lymphoma and leukaemia) • HSTCL reported in postmarketing studies • Immunogenicity reported178 |
| Alefacept | Fusion protein (soluble LFA3–Fc–IgG1) | Binds to CD2 and inhibits the interaction between CD2 and LFA3 during lymphocyte activation | Chronic plaque psoriasis |
• No boxed or product label warnings issued • Infection and malignancy reported in postmarketing studies |
| Anakinra | Recombinant human IL-1RA derived from Escherichia coli | Binds to IL-1 competitively and prevents the interaction between IL-1 and IL-1R1 | Rheumatoid arthritis |
• No boxed warnings issued • Warning for hypersensitivity to E. coli products on label |
| Basiliximab | Chimeric mouse–human mAb | Binds to IL-2Rα and prevents the interaction between IL-2 and IL-2R | Renal transplant rejection |
• Warnings for hypersensitivity and anaphylaxis20 on product label • Immunogenicity reported20 |
| Belatacept | Fusion protein (CTLA4–Fc–IgG1) | Binds to CD80 and/or CD86 to prevent the interaction with CD28 and so inhibits selective T cell co-stimulation | Renal transplant rejection |
• Boxed warnings for PTLD, malignancy and infection (EBV) • Additional monitoring required by the MHRA |
| Belimumab | Human mAb | BAFF-specific inhibitor | Systemic lupus erythematosus |
• No boxed or product label warnings issued • Hypersensitivity and anaphylaxis reported in postmarketing studies • Additional monitoring required by the MHRA |
| Canakinumab | Human mAb | Binds to IL-1β to prevent the interaction with IL-1R | Cryopyrin-associated periodic syndromes, FCAS, MWS |
• Warning for risk of infection on product label • Additional monitoring required by the MHRA |
| Certolizumab pegol | Pegylated Fab′ humanized mAb | Binds to TNF and blocks its interaction with TNFR | Crohn's disease, rheumatoid arthritis |
• Boxed warnings for serious infections (tuberculosis, invasive fungal infection, Legionella spp. and Listeria monocytogenes) and malignancy • Severe skin reactions reported in postmarketing studies • Additional monitoring required by the MHRA |
| Daclizumab (withdrawn from the market owing to non-safety reasons) | Humanized mAb | Binds to IL-2Rα and prevents the interaction between IL-2 and IL-2R | Renal transplant rejection | • No boxed or product label warnings issued |
| Denosumab | Human mAb | Prevents RANKL binding to receptors; inhibits osteoclast formation, function and survival | Osteoporosis |
• No boxed or product-label warnings issued • Hypersensitivity reported in postmarketing studies • Additional monitoring required by the MHRA |
| Eculizumab | Humanized mAb | Binds to complement protein C5 and inhibits its cleavage to C5a and C5b, and prevents formation of the terminal complement complex C5b–9 | Paroxysmal nocturnal haemoglobinuria, atypical haemolytic-uremic syndrome |
• Boxed warnings for serious infections (meningococcal) • Additional monitoring required by the MHRA |
| Efalizumab (withdrawn from the market owing to safety reasons) | Humanized mAb | Binds to CD11a: the alpha subunit of LFA1 | Psoriasis | • Boxed warnings for serious infections (PML) |
| Etanercept | Fusion protein (TNFR2–IgG1) | Binds to TNF and blocks its interaction with TNFR | Rheumatoid arthritis, JIA, ankylosing spondylitis, psoriasis | • Boxed warnings for serious infections (tuberculosis, invasive fungal infections, Legionella spp. and L. monocytogenes) and malignancy |
| Golimumab | Human mAb | Binds to TNF and blocks its interaction with TNFR | Rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis |
• Boxed warnings for serious infections and malignancy • Additional warnings for cytopaenia and hypersensitivity |
| Infliximab | Chimeric mouse–human mAb | Binds to TNF and blocks its interaction with TNFR | Crohn's disease, paediatric Crohn's disease, ulcerative colitis, paediatric ulcerative colitis, rheumatoid arthritis, ankylosing spondylitis |
• Boxed warnings for serious infections and malignancy • PML reported179 • HSTCL reported in postmarketing studies • Immunogenicity reported156 |
| Ipilimumab | Human mAb | Binds to CTLA4 to block the interaction of CTLA4 with its ligands (CD80 and CD86) | Melanoma (unresectable and/or metastatic) |
• Boxed warnings for immune-mediated adverse reactions • Additional monitoring required by the MHRA |
| Natalizumab | Humanized mAb | Binds to α4 subunit of α4β1 and α4β7 integrins, and inhibits α4 integrin-mediated adhesion of leukocytes (except in neutrophils) to their counter-receptors | Relapsing–remitting multiple sclerosis, Crohn's disease |
• Boxed warnings for serious infections (PML) • Immunogenicity reported180 • Additional monitoring required by the MHRA |
| Omalizumab | Humanized mAb IgG1κ | Binds to IgE and thus prevents IgE-mediated activation of mast cells and basophils | Asthma |
• Boxed warnings for anaphylaxis • Parasitic (helminth) infections reported181 • Additional monitoring required by the MHRA |
| Rilonacept | Fusion protein (IL-1R–Fc–IgG1) | Binds to IL-1β and neutralizes its activity by blocking its interaction with IL-1R | Cryopyrin-associated periodic syndromes | • No boxed or product label warnings issued |
| Tocilizumab | Humanized mAb | Binds to soluble and membrane-bound IL-6R and prevents IL-6 from binding to IL-6R | Rheumatoid arthritis, systemic JIA |
• Boxed warnings for serious infections (latent tuberculosis infection and opportunistic infections) • Risk of anaphylaxis reported in postmarketing studies • Immunogenicity reported182 • Additional monitoring required by the MHRA |
| Ustekinumab | Human mAb | Blocks the function of IL-12 and IL-23 by binding to the p40 subunit of these cytokines | Psoriasis |
• No boxed or product label warnings issued • Allergy and/or hypersensitivity reported in postmarketing studies |
| BAFF, B cell-activating factor; CTLA4, cytotoxic T lymphocyte antigen 4; EBV, Epstein–Barr virus; FCAS, familial cold autoinflammatory syndrome; HSTCL, hepatosplenic T cell lymphoma; IgG1, immunoglobulin G1; IL-1, interleukin-1; IL-1R1, IL-1 receptor 1; IL-1RA, IL-1R antagonist; JIA, juvenile idiopathic arthritis; LFA, lymphocyte function-associated antigen; mAb, monoclonal antibody; MHRA, Medicines and Healthcare products Regulatory Agency (UK); MWS, Muckle–Wells syndrome; PML, progressive multifocal leukoencephalopathy; PTLD, post-transplant lymphoproliferative disease; RANKL, receptor activator of NF-κB ligand; TNF, tumour necrosis factor; TNFR, TNF receptor. | ||||