Interleukin inhibitors

1. Introduction

• Interleukin inhibitors are targeted immunomodulatory agents designed to block the activity of specific interleukins (ILs) involved in inflammation and immune regulation.

• They include monoclonal antibodies and receptor antagonists that either:

  • Bind directly to the interleukin and neutralize it.

  • Block the interleukin receptor to prevent downstream signaling.

• Developed to treat autoimmune, inflammatory, and autoinflammatory disorders, as well as certain complications like cytokine release syndrome (CRS).

• Offer high specificity, reducing broad immunosuppression compared to older systemic agents.

---

2. Mechanism of Action

• Interleukin inhibitors target specific cytokine pathways by:

  • Ligand neutralization – binding to the interleukin molecule itself (e.g., canakinumab targeting IL-1β).

  • Receptor blockade – binding to interleukin receptors (e.g., tocilizumab targeting IL-6 receptor).

  • Shared subunit inhibition – targeting a protein subunit common to multiple interleukins (e.g., ustekinumab blocking IL-12/IL-23 p40 subunit).

• Blocking interleukin signaling prevents activation of pro-inflammatory genes mediated through pathways like JAK/STAT, MAPK, and NF-κB.

---

3. Major Classes and Examples

A. IL-1 Inhibitors

• Anakinra – recombinant IL-1 receptor antagonist.

• Canakinumab – monoclonal antibody against IL-1β.

• Rilonacept – soluble decoy receptor that traps IL-1α and IL-1β.

B. IL-2 Pathway Inhibitors

• Basiliximab – monoclonal antibody targeting IL-2 receptor α-chain (CD25) for transplant rejection prophylaxis.

C. IL-4/IL-13 Inhibitors

• Dupilumab – monoclonal antibody blocking IL-4Rα, inhibiting both IL-4 and IL-13 signaling.

D. IL-5 Inhibitors

• Mepolizumab, Reslizumab – monoclonal antibodies against IL-5.

• Benralizumab – binds IL-5 receptor α.

E. IL-6 Inhibitors

• Tocilizumab, Sarilumab – monoclonal antibodies against IL-6 receptor.

• Used for rheumatoid arthritis, CRS, giant cell arteritis.

F. IL-12/IL-23 Inhibitors

• Ustekinumab – targets p40 subunit common to IL-12 and IL-23.

• Guselkumab, Tildrakizumab, Risankizumab – target IL-23 p19 subunit.

G. IL-17 Inhibitors

• Secukinumab, Ixekizumab – monoclonal antibodies against IL-17A.

• Brodalumab – targets IL-17 receptor A.

H. IL-23 Inhibitors (Selective)

• Target only IL-23 p19 subunit (as above) without affecting IL-12.

I. IL-31 Inhibitors

• Nemolizumab – investigational, for pruritus in atopic dermatitis.

---

4. Indications

• Autoimmune diseases: rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus.

• Chronic inflammatory diseases: psoriasis, ankylosing spondylitis, inflammatory bowel disease.

• Autoinflammatory syndromes: cryopyrin-associated periodic syndromes (CAPS), Still’s disease.

• Severe asthma with eosinophilic phenotype (IL-5 pathway).

• Cytokine release syndrome from CAR-T cell therapy (IL-6 inhibitors).

---

5. Contraindications

• Known hypersensitivity to drug or excipients.

• Active, severe infections (e.g., tuberculosis, sepsis).

• Caution in chronic infections or latent TB without prior treatment.

• Live vaccines should be avoided during therapy.

---

6. Adverse Effects

A. Common

• Injection site reactions.

• Headache, arthralgia, fatigue.

• Upper respiratory tract infections.

B. Serious

• Opportunistic infections (e.g., TB, fungal infections).

• Reactivation of hepatitis B virus.

• Neutropenia, thrombocytopenia.

• Hypersensitivity reactions, anaphylaxis.

• Rare malignancy risk with long-term immunosuppression.

---

7. Drug Interactions

• Immunosuppressants – increased risk of infections when combined.

• Live vaccines – contraindicated during treatment.

• CYP450 substrates – IL-6 inhibitors can normalize CYP450 enzyme activity, altering plasma levels of drugs such as warfarin, cyclosporine, and statins.

---

8. Monitoring

• CBC with differential at baseline and periodically.

• Liver function tests (especially for IL-6 inhibitors).

• TB and hepatitis screening before initiation.

• Infection surveillance during therapy.

• Lipid profile (for IL-6 inhibitors).

---

9. Advantages

• Targeted mechanism, minimizing systemic immunosuppression.

• Effective in patients unresponsive to conventional DMARDs or steroids.

• Well-defined safety monitoring protocols.

---

10. Limitations

• High cost and limited accessibility in some regions.

• Injectable or infusion routes may affect patient compliance.

• Long-term safety data still evolving for newer agents.