The IL-33 and IL-4Rα blocking antibodies itepekimab and dupilumab modulate both distinct and common inflammatory mediators in asthma

Biologics targeting interleukin-4 receptor subunit α (IL-4Rα) and interleukin-33 (IL-33) have demonstrated clinical efficacy in asthma, highlighting the importance of IL-4, IL-13, and IL-33 in respiratory diseases. Despite this, few studies have linked preclinical models to human diseases or evaluated disease biology in clinical trials. To address these gaps, we evaluated transcriptional, cellular, and pathophysiological processes driven by IL-4/IL-13 and IL-33 using human innate cells in vitro, a mouse model of airway inflammation, and a bronchial allergen challenge (BAC) in house dust mite (HDM)-sensitized individuals with mild asthma. Our findings in mice revealed that the prophylactic blockade of IL-4/IL-13, but not IL-33, prevented the initiation of HDM-induced type 2 inflammation, whereas blocking IL-4Rα or IL-33 during peak inflammation ameliorated airway inflammation and remodeling. Each pathway had unique and overlapping effects on airway inflammation and remodeling, with combination blockade showing no additional benefit. Initiating either monotherapy during severe, mixed inflammation resulted in partial efficacy, whereas a combination of these two treatments led to a substantial reduction in airway inflammation and remodeling in sensitized mice. Some of these mechanistic observations translated to a human BAC model, where blocking IL-4Rα or IL-33 alone suppressed gene expression in sputum and circulating biomarkers. As observed in mice, combination treatment in individuals with allergic asthma did not provide additional benefit compared to monotherapy. Overall, these results provide insight into the differences in targeting IL-4Rα or IL-33 pathways in asthma independently or in combination.

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Publication Details

Journal
Science Translational Medicine
Published
2025-10-29
DOI
https://doi.org/10.1126/scitranslmed.adu3759
Citations
4
Primary Topic
IL-33, ST2, and ILC Pathways
Type
article
Field-Weighted Citation Impact
3.19
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article

The IL-33 and IL-4Rα blocking antibodies itepekimab and dupilumab modulate both distinct and common inflammatory mediators in asthma

Matthew F. Wipperman, Caroline Sandén, Andrea T. Hooper, George D. Kalliolias et al.
4 citations
Science Translational Medicine
IL-33, ST2, and ILC Pathways
3.19
article

The IL-33 and IL-4Rα blocking antibodies itepekimab and dupilumab modulate both distinct and common inflammatory mediators in asthma

Matthew F. Wipperman, Caroline Sandén, Andrea T. Hooper, George D. Kalliolias, Julie Horowitz, Seblewongel Asrat, Jamie Marie Orengo, Sara Hamon, Jeanne Allinne, Hélène Goulaouic, Jennifer Maloney, Dylan Birchard, Li‐Hong Ben, Jennifer D. Hamilton, Erica Chio, B. Buonagurio, Matthew A. Sleeman, Jonas S. Erjefält, George Scott, Dave Singh, Sivan Harel, Audrey Le Floc’h, Kaitlyn Gayvert, Gary Herman, Wei Keat Lim, Subhashini Srivatsan, Andrew Murphy, Marcella Ruddy, Kirsten Nagashima
article en
4 citations

Abstract

Biologics targeting interleukin-4 receptor subunit α (IL-4Rα) and interleukin-33 (IL-33) have demonstrated clinical efficacy in asthma, highlighting the importance of IL-4, IL-13, and IL-33 in respiratory diseases. Despite this, few studies have linked preclinical models to human diseases or evaluated disease biology in clinical trials. To address these gaps, we evaluated transcriptional, cellular, and pathophysiological processes driven by IL-4/IL-13 and IL-33 using human innate cells in vitro, a mouse model of airway inflammation, and a bronchial allergen challenge (BAC) in house dust mite (HDM)-sensitized individuals with mild asthma. Our findings in mice revealed that the prophylactic blockade of IL-4/IL-13, but not IL-33, prevented the initiation of HDM-induced type 2 inflammation, whereas blocking IL-4Rα or IL-33 during peak inflammation ameliorated airway inflammation and remodeling. Each pathway had unique and overlapping effects on airway inflammation and remodeling, with combination blockade showing no additional benefit. Initiating either monotherapy during severe, mixed inflammation resulted in partial efficacy, whereas a combination of these two treatments led to a substantial reduction in airway inflammation and remodeling in sensitized mice. Some of these mechanistic observations translated to a human BAC model, where blocking IL-4Rα or IL-33 alone suppressed gene expression in sputum and circulating biomarkers. As observed in mice, combination treatment in individuals with allergic asthma did not provide additional benefit compared to monotherapy. Overall, these results provide insight into the differences in targeting IL-4Rα or IL-33 pathways in asthma independently or in combination.

Science Translational MedicineVol. 17(822)
Regeneron (United States) (US), Lund University (SE), Sanofi (France) (FR), Medicon Village (SE), Medicines Evaluation Unit (GB)
Openalex Percentile: Top 7%
IL-33, ST2, and ILC Pathways
3.19
DOISourceOpenAlex
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