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Anti-alarmins in asthma: targeting the airway epithelium with next-generation biologics

Celeste M. Porsbjerg, Asger Sverrild, Clare M. Lloyd, Andrew N. Menzies-Gow, Elisabeth H. Bel
European Respiratory Journal 2020; DOI: 10.1183/13993003.00260-2020
Celeste M. Porsbjerg
1Department of Respiratory Medicine, Bispebjerg Hospital, Copenhagen, Denmark
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  • For correspondence: Celeste.Porsbjerg@regionh.dkax
Asger Sverrild
1Department of Respiratory Medicine, Bispebjerg Hospital, Copenhagen, Denmark
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Clare M. Lloyd
2National Heart and Lung Institute, Imperial College London, London, UK
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Andrew N. Menzies-Gow
3Royal Brompton Hospital, London, UK
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Elisabeth H. Bel
4Department of Respiratory Medicine, Amsterdam University Medical Centre, University of Amsterdam, Amsterdam, Netherlands
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Abstract

Monoclonal antibody therapies have significantly improved treatment outcomes for patients with severe asthma; however, a significant disease burden remains. Available biologic treatments, including anti-immunoglobulin (Ig) E, anti-interleukin (IL)-5, anti-IL-5Rα and anti-IL-4Rα, reduce exacerbation rates in study populations by approximately 50% only. Furthermore, there are currently no effective treatments for patients with severe, type 2 (T2)-low asthma. Existing biologics target immunologic pathways that are downstream in the T2 inflammatory cascade, which may explain why exacerbations are only partly abrogated. For example, T2 airway inflammation results from several inflammatory signals in addition to IL-5. Clinically, this can be observed in how fractional exhaled nitric oxide (FeNO), which is driven by IL-13, may remain unchanged during anti-IL-5 treatment despite reduction in eosinophils, and how eosinophils may remain unchanged during anti-IL-4Rα treatment despite reduction in FeNO. The broad inflammatory response involving cytokines including IL-4, IL-5 and IL-13 that ultimately results in the classic features of exacerbations (eosinophilic inflammation, mucus production and bronchospasm) is initiated by release of “alarmins” thymic stromal lymphopoietin (TSLP), IL-33 and IL-25 from the airway epithelium in response to triggers. The central, upstream role of these epithelial cytokines has identified them as strong potential therapeutic targets to prevent exacerbations and improve lung function in patients with T2-high and T2-low asthma. This article describes the effects of alarmins and discusses the potential role of anti-alarmins in the context of existing biologics. Clinical phenotypes of patients who may benefit from these treatments are also discussed, including how biomarkers may help identify potential responders.

Footnotes

This manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.

Conflict of interest: Dr. Porsbjerg reports grants and personal fees from AstraZeneca, grants and personal fees from Boehringer Ingelheim, grants and personal fees from GlaxoSmithKline, grants and personal fees from Icepharma, grants and personal fees from Janssen, grants and personal fees from Nigaard, grants and personal fees from Nopharma, grants and personal fees from Novartis, grants and personal fees from Pharmaxis, grants and personal fees from Roche, grants and personal fees from Sandoz, grants and personal fees from Sanofi, grants and personal fees from Teva, outside the submitted work.

Conflict of interest: Dr. Sverrild reports personal fees from AstraZeneca, from Sanofi Genzyme, personal fees from Novartis, outside the submitted work.

Conflict of interest: Dr. Lloyd reports and Clare M Lloyd is a Wellcome Senior Fellow in Basic Biomedical Science (107059/15/Z).

Conflict of interest: Dr. Menzies-Gow reports grants and personal fees from AstraZeneca, personal fees from Boehringer Ingelheim, personal fees from GlaxoSmithKline, personal fees from Novartis, personal fees from Sanofi, personal fees from Teva, personal fees from Roche, personal fees from Vectura, outside the submitted work.

Conflict of interest: Dr. Bel reports personal fees from AstraZeneca, personal fees from Chiesi, personal fees from GlaxoSmithKline, personal fees from Novartis, personal fees from Sanofi, personal fees from Sterna, personal fees from Teva, outside the submitted work.

This is a PDF-only article. Please click on the PDF link above to read it.

  • Received February 6, 2020.
  • Accepted June 6, 2020.
  • Copyright ©ERS 2020
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Anti-alarmins in asthma: targeting the airway epithelium with next-generation biologics
Celeste M. Porsbjerg, Asger Sverrild, Clare M. Lloyd, Andrew N. Menzies-Gow, Elisabeth H. Bel
European Respiratory Journal Jan 2020, 2000260; DOI: 10.1183/13993003.00260-2020

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Anti-alarmins in asthma: targeting the airway epithelium with next-generation biologics
Celeste M. Porsbjerg, Asger Sverrild, Clare M. Lloyd, Andrew N. Menzies-Gow, Elisabeth H. Bel
European Respiratory Journal Jan 2020, 2000260; DOI: 10.1183/13993003.00260-2020
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