Drugs That Act Against Interleukin-8 (IL-8)
Several drugs specifically target interleukin-8 (IL-8) or its receptors, with reparixin being the most well-studied IL-8 receptor antagonist showing significant mortality reduction in high-risk patients. 1
IL-8 Receptor Antagonists
Reparixin
- Mechanism of action: Non-competitive allosteric inhibitor of CXCL8 (IL-8) receptors CXCR1 and CXCR2 2
- Clinical evidence:
- Meta-analysis of randomized trials showed significantly lower all-cause mortality in high-risk patients (2.3% vs 6.5% in control group) 1
- Blocks multiple IL-8-mediated activities including:
- Neutrophil adhesion to fibrinogen
- CD11b up-regulation
- Secondary and tertiary granule release
- Pro-inflammatory cytokine production 2
- Does not affect neutrophil phagocytosis, preserving important immune functions 2
Repertaxin
- Similar to reparixin, blocks CXCR1/R2 by locking these receptors in an inactive conformation
- Inhibits T lymphocyte and natural killer (NK) cell migration induced by IL-8 2
Monoclonal Antibodies Against IL-8
Fully Human Anti-IL-8 Monoclonal Antibodies
- Examples: K4.3 and K2.2 antibodies
- Mechanism: Directly bind to IL-8 with high affinity (Kd ≈ 2.1-2.5×10⁻¹⁰ M)
- Effects:
- Block IL-8 binding to neutrophils
- Inhibit neutrophil activation
- Prevent up-regulation of CD11b/CD18 adhesion receptors
- Reduce neutrophil chemotaxis
- Demonstrated inhibition of IL-8-induced skin inflammation in animal models 3
Anti-Cytokine Therapies Used in Inflammatory Conditions
Several biologic disease-modifying anti-rheumatic drugs (bDMARDs) that target other cytokines can indirectly affect IL-8 pathways as part of broader anti-inflammatory effects:
- Anti-IL-6 receptor therapies: Tocilizumab, sarilumab 4
- TNF-α inhibitors: Infliximab, adalimumab, etanercept, certolizumab, golimumab 4
- JAK inhibitors: Ruxolitinib, tofacitinib, baricitinib - these affect multiple cytokine pathways including those involving IL-8 4
Clinical Applications
IL-8 inhibitors have potential applications in:
- Inflammatory disease states: Where IL-8-mediated neutrophil recruitment plays a key role 3
- Critical care settings: Meta-analysis shows survival benefit in patients at high risk for in-hospital mortality 1
- Immune-related adverse events: May help manage inflammatory complications of immunotherapy 4
Important Considerations
- Specificity: Reparixin and other IL-8 receptor antagonists provide more targeted anti-inflammatory effects compared to broad-spectrum agents like corticosteroids 4
- Preservation of immune function: Unlike some immunosuppressants, IL-8 inhibitors like reparixin don't increase infection risk in clinical studies 1
- Pharmacokinetics: Human anti-IL-8 monoclonal antibodies have favorable half-life profiles (α-phase: 9.4h, β-phase: 10.9 days) 3
IL-8 pathway inhibition represents a promising targeted approach to managing inflammatory conditions while potentially preserving critical immune functions.