Current Efficacy of IL-33 Inhibitors in Respiratory Diseases
IL-33 inhibitors show promising results in reducing asthma exacerbations and improving symptoms, with tezepelumab demonstrating up to 71% reduction in exacerbation rates in patients with allergic and eosinophilic asthma phenotypes. 1
Mechanism of Action of IL-33 in Respiratory Disease
- IL-33 functions as a key upstream mediator of type 2 inflammation within the airways, binding to a heterodimeric cell-surface receptor consisting of IL-1 receptor accessory protein and ST2 on immune cells 2
- This alarmin activates multiple inflammatory cells including TH2 cells, ILC2s, basophils, eosinophils, mast cells, and dendritic cells, triggering intracellular signaling pathways that support allergic airway inflammation 2
- Direct exposure of airway epithelium to pathogens like S. aureus increases the expression of IL-33 and TSLP, consecutively elevating IL-5 and IL-13 in respiratory tissues 2
- In chronic rhinosinusitis with nasal polyps (CRSwNP), ILC2s are increased compared to controls and spontaneously release type 2 cytokines including IL-5 and IL-13 2
Current Evidence for IL-33 Inhibitors
Tezepelumab (Anti-TSLP)
- Tezepelumab, while primarily targeting TSLP rather than IL-33 directly, affects the same inflammatory pathway and has shown significant clinical benefits 1
- In a pooled analysis of phase 2b PATHWAY and phase 3 NAVIGATOR studies, tezepelumab reduced annualized asthma exacerbation rates by:
- Tezepelumab decreases airway epithelial IL-33 expression and protein levels in bronchoalveolar lavage fluid after 12 weeks of treatment 3
- Tezepelumab reduces IL-33 gene and protein levels in bronchial epithelial cells challenged with viral mimics, suggesting a protective effect against virus-induced exacerbations 3
Direct IL-33 Receptor Inhibition
- GSK3772847, a human monoclonal antibody directed against the IL-33 receptor (IL-33R), showed an 18% reduction in loss of asthma control compared to placebo in patients with moderate-to-severe uncontrolled asthma 4
- In preclinical models, blocking IL-33 activity with a soluble ST2 receptor significantly decreased eosinophil numbers and reduced airway inflammation 2
Clinical Applications and Patient Selection
- IL-33 pathway inhibition appears most effective in patients with type 2 inflammation, particularly those with comorbid type 2 diseases 2, 5
- Patients with CRSwNP who have comorbid asthma show higher numbers of ILC2s and may particularly benefit from IL-33 pathway targeting 2
- The regulation of IL-33 is dependent on the balance of proteases and anti-proteases in respiratory tissues, which may influence treatment response 2
Future Directions and Emerging Approaches
- Specific antibodies to IL-33 or its receptor are being developed for therapeutic intervention in CRSwNP and other respiratory diseases 2
- Novel bispecific antibodies that concurrently inhibit multiple cytokine pathways (e.g., anti-TSLP/IL-13) may offer enhanced efficacy compared to single-target approaches 2
- The SOURCE trial is evaluating tezepelumab's potential to reduce oral corticosteroid dependence in severe asthma, which could significantly improve quality of life by reducing steroid-related adverse effects 6
Pitfalls and Considerations
- Patient phenotyping is crucial for optimal response to IL-33 pathway inhibitors, as approximately 50% of asthma patients have TH2-low asthma and may not respond optimally to these therapies 5
- Most current clinical evidence focuses on asthma, with limited data on efficacy in other respiratory conditions like COPD or non-type 2 inflammatory diseases 7
- The most frequent treatment-related adverse events with IL-33 receptor inhibition include cardiac disorders and musculoskeletal/connective tissue disorders, though these appear relatively rare 4