Biologics for Asthma: Targeting Type 2 Inflammation in Severe Cases

Currently, most biologics used to treat asthma are approved for individuals with uncontrolled moderate-to-severe asthma and elevated biomarkers of type 2 (T2) inflammation, driven by T2 cytokines like IL-4, IL-13, and IL-5, according to a study published in Cytokine.

Researchers used methods to assess gene changes and chemokine release in human eosinophils and endothelial cells, stimulating them with IL-4, IL-13, or IL-5. They also studied mice exposed to house dust mite extract, to explore outcomes of treatment with anti-IL-4Rα (dupilumab), anti-IL-5, or control antibodies to determine if there were any changes in lung histological and inflammatory endpoints.

While many biologics targeting T2 inflammation have been approved and shown to reduce asthma exacerbations, study results revealed inconsistent improvements in FEV1, and FeNO did not improve despite decreased exacerbations and notable decreases in eosinophils when using humanized IL-5 antagonist monoclonal antibodies, mepolizumab, and reslizumab.

The mechanisms of these drugs play a role in shaping these distinctions. According to researchers, "clinical studies with the IL-4Rα blocking antibody, dupilumab, demonstrated that inhibiting signaling of the T2 cytokines, IL-4 and IL-13, results in decreased exacerbations and consistent improvements in FEV1 and in FeNO without decreasing circulating eosinophils." However, "studies with the humanized IL-5Rα specific monoclonal antibody, benralizumab, which effectively depletes eosinophils, results in decreased exacerbations and an improved FEV1 profile, but only decreases FeNO in subjects with higher levels of FeNO (greater than 75 ppb)."

Reducing exacerbations has become a key measure of treatment efficacy in asthma. However, the similarities in treatment efficacy among various biologics have led to overlapping patient populations and indications in clinical guidelines. Researchers emphasize that clinical observations are crucial to understanding the mechanistic differences among these therapies.

For the mouse model, dupilumab normalized a significant proportion of genes associated with T2 inflammation, mucus production, airway remodeling, and bronchoconstriction. Anti-IL-5 had a minor effect, mainly impacting genes associated with eosinophilia. These findings suggest that IL-5 blockade has specific effects on genes related to eosinophil function, while IL-4Rα blockade affects a broader range of T2 inflammation-related genes.

In vitro studies support the observation that IL-4 and IL-13 stimulation of human eosinophils affects gene expression related to migration, while the effects of IL-5 are limited to differentiation genes. These findings provide insight into the mechanisms driving different pathological outcomes in asthma.

Multiple factors of T2 inflammation are required to protect lung function and modify the disease. "Eosinophils are not the sole contributor to asthma pathophysiology or lung function decline and emphasizes the need to block additional mediators to modify lung inflammation and impact lung function," said researchers.

Reference

Scott G, Asrat S, Allinne J, et al. IL-4 and IL-13, not eosinophils, drive type 2 airway inflammation, remodeling and lung function decline. Cytokine. 2023;162:156091. doi:10.1016/j.cyto.2022.156091