BPCO-AND ANTI–IL-33: THE REVOLUTION OF 'UPSTREAM' Biologics

For decades, the therapy for chronic obstructive pulmonary disease (COPD) has remained essentially anchored to a symptomatic approach based on:

bronchodilators

inhaled corticosteroids

oxygen therapy

pulmonary rehabilitation

These treatments have improved symptoms and quality of life, but have had a limited impact on the biological progression of the disease.

In recent years, however, research is opening a new phase in pulmonology: that of targeted biologics. Among the most promising targets is interleukin-33 (IL-33), a molecule that could redefine the treatment of COPD.

COPD: a disease much more complex than expected

Traditionally, COPD has been considered a disease caused mainly by cigarette smoking and characterized by:

chronic airway obstruction

persistent inflammation

progressive decline in lung function

Today we know that the reality is much more complex.

BPCO is indeed a disease: biologically heterogeneous, immunologically variable, characterized by different phenotypes and endotypes. This explains why seemingly similar patients may have: different frequency of exacerbations, different response to therapies, very variable clinical progression. IL-33: a key molecule in inflammation. IL-33 belongs to the family of "alarmins," molecules released by epithelial cells in response to damage or stress. In the lung, IL-33 is released when the airways are exposed to: smoke, pollution, infections, oxidative damage. Once released, it activates an inflammatory cascade involving: neutrophils, macrophages, innate lymphoid cells, mucus production pathways.

This contributes to: chronic inflammation mucus hypersecretion structural damage of the airways COPD exacerbations Why IL-33 is an “upstream” target Most traditional biological therapies act “downstream” of the inflammatory cascade, blocking mediators that are already activated. IL-33, on the other hand, is located much more “upstream.” For this reason, it is defined as an “upstream” target. Blocking IL-33 potentially means: reducing the activation of multiple inflammatory pathways interfering early with the immune cascade acting on different disease phenotypes This approach could be particularly important in COPD, where inflammation is often: neutrophilic mixed poorly responsive to steroids Tozorakimab: the first anti–IL-33 drug in COPD The most advanced drug in this area is tozorakimab, a monoclonal antibody developed to neutralize IL-33.

An interesting feature of the drug is its ability to block both the reduced and the oxidized form of the molecule, enhancing its potential biological effect. The phase 3 OBERON and TITANIA trials have recently shown very promising results. In patients with symptomatic COPD treated with tozorakimab, the following were observed: a significant reduction in moderate-severe exacerbations improvement in some respiratory parameters a good safety profile The efficacy was observed in: active smokers former smokers patients with different levels of eosinophils This is particularly important because it suggests activity beyond the classic T2-high model already known in asthma. A new era of biologics in COPD? For years, COPD has been considered a 'difficult' disease for biologics.

Unlike asthma, in fact: biomarkers are less defined inflammation is more heterogeneous the role of neutrophils is predominant Anti–IL-33 could change this scenario. For the first time, the possibility emerges of treating specific biological mechanisms of COPD and not just the symptoms or bronchial obstruction. Clinical implications If these results are confirmed in the long term, the implications could be significant. 1. Reduction of exacerbations Exacerbations represent one of the main drivers of: disease progression hospitalizations mortality 2. Personalized medicine COPD could be treated according to: biological endotypes specific biomarkers individual inflammatory profiles 3. New therapeutic combinations Biologics could be combined with: bronchodilators inhaled corticosteroids advanced anti-inflammatory strategies The challenges still open Despite the enthusiasm, several questions remain: which patients respond best? which biomarkers should be used? how sustainable will the cost be? what will be the long-term effect? Moreover, COPD remains a multifactorial disease in which environment, microbiome, pollution, and immunity interact in a complex way. IL-33 represents one of the most interesting targets that have emerged in recent years in respiratory research. The concept of blocking inflammation “upstream” could allow intervention earlier and more effectively on the mechanisms of the disease. For COPD, historically poor in truly transformative pharmacological innovations, this could represent the beginning of a new therapeutic era. COPD is entering the era of biological medicine.

Targeting IL-33 does not simply represent a new drug, but a new way of interpreting the disease: no longer a single uniform entity but a constellation of treatable biological endotypes. Modern pulmonology is shifting from symptomatic medicine to: molecular, personalized, predictive medicine. And 'upstream' biologics could be one of the pillars of this transformation.