IL-33 Monoclonal Antibody Indications in Respiratory Diseases
IL-33 monoclonal antibodies are primarily indicated for moderate-to-severe allergic asthma, particularly in patients with type 2 inflammation, and show promise for chronic rhinosinusitis with nasal polyps (CRSwNP), especially in those with comorbid asthma. 1
Mechanism of Action and Pathophysiological Basis
- IL-33 functions as a key upstream alarmin that mediates type 2 inflammation in airways by binding to a heterodimeric cell-surface receptor (IL-1 receptor accessory protein and ST2) on immune cells 1, 2
- This activation triggers inflammatory pathways in multiple cells including TH2 cells, ILC2s, basophils, eosinophils, mast cells, and dendritic cells 1, 3
- Direct exposure of airway epithelium to pathogens (particularly S. aureus) increases IL-33 expression, consecutively elevating IL-5 and IL-13 in respiratory tissues 2
Primary Clinical Indications
Moderate-to-Severe Allergic Asthma
- Clinical trials demonstrate that IL-33 blockade (itepekimab) leads to lower incidence of asthma exacerbations and improved lung function in moderate-to-severe asthma 4
- Particularly effective in patients with elevated blood eosinophil counts, as IL-33 levels are significantly higher in eosinophilic asthma phenotypes (1001.10 ± 199.11 pg/mL vs 337.49 ± 72.68 pg/mL in non-eosinophilic asthma) 5
- Anti-IL-33 therapy reduces serum IgE, eosinophil counts, and proinflammatory cytokines (IL-4, IL-5, IL-13) in experimental models 6
Chronic Rhinosinusitis with Nasal Polyps (CRSwNP)
- Particularly promising for patients with CRSwNP who have comorbid type 2 diseases such as asthma 2
- ILC2s are found in higher numbers in CRSwNP patients with comorbid asthma, making them ideal candidates for IL-33 pathway targeting 2
- Direct exposure of nasal polyp epithelium to pathogens increases IL-33 expression, suggesting a mechanistic basis for targeting this pathway 2
Patient Selection Considerations
- Most appropriate for patients with confirmed type 2 inflammation profiles 1
- Particularly effective in allergic asthma patients, as IL-33 levels are significantly higher compared to non-allergic asthmatics (844.61 ± 152.08 pg/mL vs 369.56 ± 77.94 pg/mL) 5
- May be considered for treatment-dependent allergic bronchopulmonary aspergillosis (ABPA), though other biologics like omalizumab currently have more clinical evidence 2
- Not recommended for patients with predominant neutrophilic airway inflammation, as IL-33 primarily drives type 2/eosinophilic responses 2
Emerging Applications
- Potential application in atopic dermatitis, as IL-33 is implicated in skin barrier dysfunction and Th2 immune activation 2
- Novel bispecific antibodies targeting IL-33 alongside other cytokines (e.g., anti-TSLP/IL-13) may offer enhanced efficacy compared to single-target approaches 2
- May have preventive potential in allergic rhinitis patients at risk for developing asthma, though more research is needed 2
Monitoring and Response Assessment
- Clinical response should be assessed after 8-12 weeks using symptom scores, lung function, and biomarkers 2
- Reduction in blood eosinophil count can serve as a biomarker of response to IL-33 pathway inhibition 4
- Therapeutic drug monitoring is recommended when using biological agents targeting cytokine pathways 2
Pitfalls and Considerations
- Patient phenotyping is crucial for optimal response, as approximately 50% of asthma patients have TH2-low asthma and may not respond optimally 1
- The regulation of IL-33 is dependent on the balance of proteases and anti-proteases in respiratory tissues, which may influence treatment response 2
- Consider combination approaches with other biologics in patients with mixed inflammatory patterns 2