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Cited by 545Asthma and respiratory diseasesIL-33, ST2, and ILC PathwaysDermatology and Skin Diseases

Dual blockade of IL‐4 and IL‐13 with dupilumab, an IL‐4Rα antibody, is required to broadly inhibit type 2 inflammation

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Le Floc’h, Audrey, Allinne, Jeanne, Nagashima, Kirsten, Scott, George, Birchard, Dylan, Asrat, Seblewongel, Bai, Yu, Lim, Wei Keat +11 more·2020·Allergy
DOI 10.1111/all.14151PMC PMC7317958
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Abstract

Background: Dupilumab, a fully human monoclonal antibody that binds IL‐4Rα and inhibits signaling of both IL‐4 and IL‐13, has shown efficacy across multiple diseases with underlying type 2 signatures and is approved for treatment of asthma, atopic dermatitis, and chronic sinusitis with nasal polyposis. We sought to provide a comprehensive analysis of the redundant and distinct roles of IL‐4 and IL‐13 in type 2 inflammation and report dupilumab mechanisms of action. Methods: Using primary cell assays and a mouse model of house dust mite–induced asthma, we compared IL‐4 vs IL‐13 vs IL‐4Rα blockers. Results: Intranasal administration of either IL‐4 or IL‐13 confers an asthma‐like phenotype in mice by inducing immune cell lung infiltration, including eosinophils, increasing cytokine/chemokine expression and mucus production, thus demonstrating redundant functions of these cytokines. We further teased out their respective contributions using human in vitro culture systems. Then, in a mouse asthma model by comparing in head‐to‐head studies, either IL‐4 or IL‐13 inhibition to dual IL‐4/IL‐13 inhibition, we demonstrate that blockade of both IL‐4 and IL‐13 is required to broadly block type 2 inflammation, which translates to protection from allergen‐induced lung function impairment. Notably, only dual IL‐4/IL‐13 blockade prevented eosinophil infiltration into lung tissue without affecting circulating eosinophils, demonstrating that tissue, but not circulating eosinophils, contributes to disease pathology. Conclusions: Overall, these data support IL‐4 and IL‐13 as key drivers of type 2 inflammation and help provide insight into the therapeutic mechanism of dupilumab, a dual IL‐4/IL‐13 blocker, in multiple type 2 diseases.

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Authors
Le Floc’h, A., Allinne, J., Nagashima, K., Scott, G., Birchard, D., Asrat, S., Bai, Y., Lim, W. K., Martin, J., Huang, T., Potocky, T. B., Kim, J. H., Rafique, A., Papadopoulos, N. J., Stahl, N., Yancopoulos, G. D., Murphy, A. J., Sleeman, M. A., & Orengo, J. M.
Affiliations
  • Regeneron Pharmaceuticals Tarrytown NY USA
  • Regeneron (United States) (US)
Corresponding author
Orengo, Jamie M.
ORCID
Venue
Allergy
Publisher
Wiley
Published
2020-01-03
Volume
75
Issue
5
Pages
1188-1204
ISSN
  • 0105-4538 (ISSN-L)
  • 1398-9995
DOI
10.1111/all.14151
PMC
PMC7317958
OpenAlex
W2996174934
Cited by
545
References
4
Citations by year
2026: 110 · 2025: 126 · 2024: 106 · 2023: 67 · 2022: 74 · 2021: 41 · 2020: 20 · 2019: 1
FWCI
23.32
Type
journal article
Language
en
Open access
Licence
Locations
  • Allergy (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Funders
  • Sanofi
  • Regeneron Pharmaceuticals
Topics
  • Health Sciences › Medicine › Physiology › Asthma and respiratory diseases
  • Life Sciences › Immunology and Microbiology › Immunology › IL-33, ST2, and ILC Pathways
  • Health Sciences › Medicine › Dermatology › Dermatology and Skin Diseases
Keywords
dupilumab, IL-4, IL-13, IL-4 receptor alpha, type 2 inflammation, asthma, eosinophil infiltration, house dust mite-induced asthma, mucus production, cytokine redundancy, allergic airway inflammation, atopic dermatitis
MeSH terms
Animals, Inflammation, Interleukin-4, Interleukin-13, Mice, Antibodies, Monoclonal, Humanized

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