The IL-33 and IL-4Rα blocking antibodies itepekimab and dupilumab modulate both distinct and common inflammatory mediators in asthma
(2025) In Science Translational Medicine 17(822).- 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... (More)
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.
(Less)
- author
- organization
- publishing date
- 2025-10-29
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Science Translational Medicine
- volume
- 17
- issue
- 822
- article number
- eadu3759
- publisher
- American Association for the Advancement of Science (AAAS)
- external identifiers
-
- pmid:41160665
- scopus:105020480730
- ISSN
- 1946-6234
- DOI
- 10.1126/scitranslmed.adu3759
- language
- English
- LU publication?
- yes
- additional info
- Publisher Copyright: Copyright © 2025 The Authors, some rights reserved.
- id
- f9165c7b-ba72-4882-b63b-25c082aa9950
- date added to LUP
- 2025-12-17 10:50:15
- date last changed
- 2025-12-17 10:51:34
@article{f9165c7b-ba72-4882-b63b-25c082aa9950,
abstract = {{<p>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.</p>}},
author = {{Asrat, Seblewongel and Lim, Wei Keat and Srivatsan, Subhashini and Harel, Sivan and Gayvert, Kaitlyn and Birchard, Dylan and Wipperman, Matthew F. and Singh, Dave and Hooper, Andrea T. and Scott, George and Horowitz, Julie E. and Erjefält, Jonas S. and Sanden, Caroline and Nagashima, Kirsten and Buonagurio, Brianna and Ben, Li Hong and Chio, Erica and Le Floc’h, Audrey and Allinne, Jeanne and Maloney, Jennifer and Kalliolias, George D. and Ruddy, Marcella and Hamon, Sara C. and Herman, Gary A. and Murphy, Andrew J. and Goulaouic, Helene and Sleeman, Matthew A. and Hamilton, Jennifer D. and Orengo, Jamie M.}},
issn = {{1946-6234}},
language = {{eng}},
month = {{10}},
number = {{822}},
publisher = {{American Association for the Advancement of Science (AAAS)}},
series = {{Science Translational Medicine}},
title = {{The IL-33 and IL-4Rα blocking antibodies itepekimab and dupilumab modulate both distinct and common inflammatory mediators in asthma}},
url = {{http://dx.doi.org/10.1126/scitranslmed.adu3759}},
doi = {{10.1126/scitranslmed.adu3759}},
volume = {{17}},
year = {{2025}},
}