Q&A: Why IL-33 Matters for Mucus Plugs, Inflammation in COPD

Interleukin-33 (IL-33) has become a leading biologic target in COPD, with activity extending beyond airway inflammation to epithelial and mucus dysfunction. Preclinical work has shown reduced IL-33 signals through the ST2 receptor to drive inflammatory responses, while oxidized IL-33 signals through a RAGE/EGFR complex to impair epithelial repair.¹ Tozorakimab, an anti-IL-33 monoclonal antibody, was engineered to inhibit both pathways.¹

Clinical research followed. In the replicate phase 3 OBERON and TITANIA trials, published in The New England Journal of Medicine, add-on tozorakimab reduced annualized moderate to severe exacerbations among former smokers by 29% and 34%, respectively, as opposed to those on placebo.²

Mucus plugging adds a structural dimension to the IL-33 story. In an analysis of 4363 participants with COPD from the COPDGene cohort, published in JAMA, airway-occluding mucus plugs in 1 to 2 and 3 or more lung segments were associated with adjusted hazard ratios for all-cause mortality of 1.15 and 1.24, respectively, compared with no plugs.³ These findings position mucus plugs as both a prognostic marker and a potential treatment target as IL-33-directed therapies advance.

Francesca Polverino, MD, PhD, Lester and Sue Smith Professor of Medicine at Baylor College of Medicine, where she leads a COPD translational research group, examined these mechanisms in her session, “The Duality of IL-33 in COPD: Inflammation and Mucus Dysfunction.” In the following interview, Polverino spoke with HCPLive at the GOLD 2026 COPD International Conference in Philadelphia about how the 2 forms of IL-33 shape inflammation and mucus plug formation, and what this means for emerging IL-33-targeted therapies:

HCPLive: What is the duality of IL-33 in COPD, and how does it drive both inflammation and mucus dysfunction?

Francesca Polverino, MD, PhD: IL-33 is a very interesting molecule. It’s called an alarmin. Alarmins are cytokines produced by the bronchial epithelium in response to a danger signal, like an alarm. In particular, you can have viral infection. You can even have cigarette smoke. Anything that triggers the epithelium, the epithelium responds to this danger signal with the production of these alarmins. IL-33 is one of these alarmins, and it is a potent mediator of inflammation and structural changes in the COPD lung.

Why do we say it has a dual role? Because there are 2 forms of IL-33. One is oxidized, and one is reduced. We know the oxidized form is the one that causes hyperproduction of mucus, mucus dysfunction, and even changes in the mucus composition, in particular MUC5AC and MUC5B. The other form, the reduced form, serves more as a chemoattractant for inflammatory cells, in particular T cells, eosinophils, and so forth. So the oxidized form, which is targeted by one of the newest biologics, acts more on mucus production and the chronic bronchitis phenotype. The other one, the reduced form, is more of a chemoattractant for inflammatory cells.

HCPLive: Where does IL-33 fit into mucus plug formation, and why does it matter clinically?

Francesca Polverino, MD, PhD: It does matter a lot, because it has been shown multiple times, over multiple years, that mucus plugging is a really big deal for patients with COPD. The number and extent of areas infiltrated by mucus plugs is directly associated with mortality and hospitalization in patients with COPD. So the more plugs patients have, the worse they are going to do.

The problem with plugging is that not all patients with CT scan evidence of mucus plugging actually have symptoms of plugging, like chronic bronchitis, productive cough, and phlegm. On the other hand, not all patients with symptoms of chronic bronchitis have CT scan evidence of mucus plugging. But regardless, we have multiple studies showing mucus plugging is a sensitive measurement of inflammation in COPD and of response to treatment in COPD. There was a beautiful trial with hyperpolarized MRI showing one of the previous biologics effectively reduced the number of mucus plugs, and this was associated with improvement of symptoms and a decrease in exacerbations.

So it is important, because the oxidized form of IL-33 directly acts on mucus formation and the composition of the mucus. We expect these drugs directly targeting IL-33 will also directly affect the formation and the composition of mucus plugs.

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

References

1. 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.

2. 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.

3. Diaz AA, Orejas JL, Grumley S, et al. Airway-occluding mucus plugs and mortality in patients with chronic obstructive pulmonary disease. JAMA. 2023;329(21):1832-1839. doi:10.1001/jama.2023.2065.