Hans Jürgen Hoffmann

RORγt inhibitors block both IL-17 and IL-22 conferring a potential advantage over anti-IL-17 alone to treat severe asthma

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

  • David Lamb, Boehringer Ingelheim Pharma GmbH & Co KG, Boehringer Ingelheim, Translat Med & Clin Pharmacol, Germany
  • Dorothy De Sousa, Boehringer Ingelheim Ltd, Burlington, Canada
  • ,
  • Karsten Quast, Boehringer Ingelheim Pharma GmbH & Co KG, Boehringer Ingelheim, Translat Med & Clin Pharmacol
  • ,
  • Katrin Fundel-Clemens, Boehringer Ingelheim Pharma GmbH & Co KG, Boehringer Ingelheim, Translat Med & Clin Pharmacol
  • ,
  • Jonas S Erjefält, Medetect AB, Lund University
  • ,
  • Caroline Sandén, Medetect AB
  • ,
  • Hans Jürgen Hoffmann
  • Marc Kästle, Boehringer Ingelheim Pharma GmbH & Co KG, Boehringer Ingelheim, Translat Med & Clin Pharmacol
  • ,
  • Ramona Schmid, Boehringer Ingelheim Pharma GmbH & Co KG, Boehringer Ingelheim, Translat Med & Clin Pharmacol
  • ,
  • Kevin Menden, Boehringer Ingelheim Pharma GmbH & Co KG, Boehringer Ingelheim, Translat Med & Clin Pharmacol
  • ,
  • Denis Delic, Boehringer Ingelheim Pharma GmbH & Co KG, Boehringer Ingelheim, Translat Med & Clin Pharmacol

BACKGROUND: RORγt is a transcription factor that enables elaboration of Th17-associated cytokines (including IL-17 and IL-22) and is proposed as a pharmacological target for severe asthma.

METHODS: IL-17 immunohistochemistry was performed in severe asthma bronchial biopsies (specificity confirmed with in situ hybridization). Primary human small airway epithelial cells in air liquid interface and primary bronchial smooth muscle cells were stimulated with recombinant human IL-17 and/or IL-22 and pro-inflammatory cytokines measured. Balb/c mice were challenged intratracheally with IL-17 and/or IL-22 and airway hyperreactivity, pro-inflammatory cytokines and airway neutrophilia measured. Balb/c mice were sensitized intraperitoneally and challenged intratracheally with house dust mite extract and the effect of either a RORγt inhibitor (BIX119) or an anti-IL-11 antibody assessed on airway hyperreactivity, pro-inflammatory cytokines and airway neutrophilia measured.

RESULTS: We confirmed in severe asthma bronchial biopsies both the presence of IL-17-positive lymphocytes and that an IL-17 transcriptome profile in a severe asthma patient sub-population. Both IL-17 and IL-22 stimulated the release of pro-inflammatory cytokine and chemokine release from primary human lung cells and in mice. Furthermore, IL-22 in combination with IL-17, but neither alone, elicits airway hyperresponsiveness (AHR) in naïve mice. A RORγt inhibitor specifically blocked both IL-17 and IL-22, AHR and neutrophilia in a mouse house dust mite model unlike other registered or advanced pipeline modes of action. Full efficacy versus these parameters was associated with 90% inhibition of IL-17 and 50% inhibition of IL-22. In contrast, anti-IL-17 also blocked IL-17, but not IL-22, AHR or neutrophilia. Moreover, the deregulated genes in the lungs from these mice correlated well with deregulated genes from severe asthma biopsies suggesting that this model recapitulates significant severe asthma-relevant biology. Furthermore, these genes were reversed upon RORγt inhibition in the HDM model. Cell deconvolution suggested that the responsible cells were corticosteroid insensitive γδ-T-cells.

CONCLUSION: These data strongly suggest that both IL-17 and IL-22 are required for Th2-low endotype associated biology and that a RORγt inhibitor may provide improved clinical benefit in a severe asthma sub-population of patients by blocking both IL-17 and IL-22 biology compared with blocking IL-17 alone.

Original languageEnglish
Article number158
JournalRespiratory Research
Volume22
ISSN1178-6205
DOIs
Publication statusPublished - May 2021

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