Targeting IL-33 in COPD: Who Benefits and What Remains Unknown

Interleukin-33 (IL-33)-targeted therapy could extend biologic treatment to most patients with COPD, as opposed to the eosinophil-defined minority eligible for current agents, according to Francesca Polverino, MD, PhD, Lester and Sue Smith Professor of Medicine at Baylor College of Medicine.¹

Polverino discussed the potential reach of IL-33 blockade and the unresolved questions surrounding its biology in an interview with the editorial team at HCPLive at the time of the GOLD 2026 COPD International Conference held in Philadelphia.¹

Which Patients with COPD Could Benefit From Targeting IL-33?

Available COPD biologics have been limited to patients with elevated blood eosinophil counts, Polverino said. Some clinicians use a threshold of 150 cells/µL, but the most compelling data support counts above 300 cells/µL.²

Polverino estimated these type 2-high patients represent roughly 20% of the COPD population. By contrast, IL-33 is enriched in the blood and lungs of most patients with COPD, and its pathway extends beyond type 2 inflammation. Under current eosinophil-based criteria, most patients with COPD remain without a biologic option.

Because of this broader expression, a drug targeting the IL-33 pathway could reach the majority of patients, she explained. Polverino pointed to a recently reported successful trial of IL-33-targeted therapy, which enrolled patients regardless of blood eosinophil count, as evidence clinicians may soon be able to treat patients with COPD independent of eosinophilia.³ She characterized this ability to treat across the eosinophil spectrum as the central advance offered by the IL-33 pathway.

What Questions About IL-33 Biology Still Need Answers?

In vitro and ex vivo studies using primary bronchial epithelial cells have convincingly shown IL-33 exists in reduced and oxidized forms with distinct, complementary roles, according to Polverino. The oxidized form contributes most to mucus plugging, while the reduced form drives inflammation and inflammatory cell recruitment.⁴

Polverino said more research is needed to confirm whether different drugs target these 2 forms differentially. Because the reduced form can rapidly convert to the oxidized form, current evidence cannot yet show whether a given agent preferentially targets one form over the other.

She called for studies demonstrating both forms can be effectively targeted, which she views as a key step before IL-33-directed therapy becomes a routine part of COPD care.

Editor’s Note: This summary was edited for grammar and clarity using artificial intelligence tools. Polverino had no relevant financial disclosures to note.

References

1. Polverino F. The duality of IL-33 in COPD: inflammation and mucus dysfunction. Presented at: GOLD 2026 COPD International Conference; November [X], 2026; Philadelphia, PA.

2. Bhatt SP, Rabe KF, Martinez FJ, et al. Dupilumab for COPD with blood eosinophil evidence of type 2 inflammation. N Engl J Med. 2024;390(24):2274-2283. doi:10.1056/NEJMoa2401304.

3. Sciurba FC, Watz H, Bourdin A, et al. Tozorakimab to prevent COPD exacerbations. N Engl J Med. Published online September 8, 2026. doi:10.1056/NEJMoa2606998.

4. England E, Rees DG, Scott IC, et al. Tozorakimab (MEDI3506): an anti-IL-33 antibody that inhibits IL-33 signalling via ST2 and RAGE/EGFR to reduce inflammation and epithelial dysfunction. Sci Rep. 2023;13(1):9825. doi:10.1038/s41598-023-36642-y.