Toll-like receptor 3 blockade in rhinovirus-induced experimental asthma exacerbations: A randomized controlled study

Research output: Contribution to journalArticle

Abstract

Background: Human rhinoviruses (HRVs) commonly precipitate asthma exacerbations. Toll-like receptor 3, an innate pattern recognition receptor, is triggered by HRV, driving inflammation that can worsen asthma. Objective: We sought to evaluate an inhibitory mAb to Toll-like receptor 3, CNTO3157, on experimental HRV-16 inoculation in healthy subjects and asthmatic patients. Methods: In this double-blind, multicenter, randomized, parallel-group study in North America and Europe, healthy subjects and patients with mild-to-moderate stable asthma received single or multiple doses of CNTO3157 or placebo, respectively, and were then inoculated with HRV-16 within 72 hours. All subjects were monitored for respiratory symptoms, lung function, and nasal viral load. The primary end point was maximal decrease in FEV1 during 10 days after inoculation. Results: In asthmatic patients (n = 63) CNTO3157 provided no protection against FEV1 decrease (least squares mean: CNTO3157 [n = 30] = -7.08% [SE, 8.15%]; placebo [n = 25] = -5.98% [SE, 8.56%]) or symptoms after inoculation. In healthy subjects (n = 12) CNTO3157 versus placebo significantly attenuated upper (P = .03) and lower (P = .02) airway symptom scores, with area-under-the-curve increases of 9.1 (15.1) versus 34.9 (17.6) and 13.0 (18.4) versus 50.4 (25.9) for the CNTO3157 (n = 8) and placebo (n = 4) groups, respectively, after inoculation. All of the severe and 4 of the nonserious asthma exacerbations occurred while receiving CNTO3157. Conclusion: In summary, CNTO3157 was ineffective in attenuating the effect of HRV-16 challenge on lung function, asthma control, and symptoms in asthmatic patients but suppressed cold symptoms in healthy subjects. Other approaches, including blockade of multiple pathways or antiviral agents, need to be sought for this high unmet medical need.

Details

Authors
  • Philip E Silkoff
  • Susan Flavin
  • Robert Gordon
  • Mathew J. Loza
  • Peter J Sterk
  • Rene Lutter
  • Ronald B. Turner
  • Brian J. Lipworth
  • David Proud
  • Dave Singh
  • Andreas Eich
  • Vibeke Backer
  • James E. Gern
  • Christian Herzmann
  • Scott A. Halperin
  • Tjeert T. Mensinga
  • Alfred M. Del Vecchio
  • Patrick Branigan
  • Lani San Mateo
  • Frédéric Baribaud
  • Elliot S. Barnathan
  • Sebastian L. Johnston
External organisations
  • Academic Medical Center
  • Skåne University Hospital
  • QPS-Netherlands
  • University of Virginia School of Medicine
  • University of Dundee
  • University of Calgary
  • University Hospital of South Manchester NHS Foundation Trust
  • Imperial College London
  • Janssen Research & Development LLC
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Respiratory Medicine and Allergy

Keywords

  • Asthma, Inflammation, Toll-like receptor 3, Viral infection
Original languageEnglish
JournalJournal of Allergy and Clinical Immunology
Publication statusE-pub ahead of print - 2017 Jul 20
Publication categoryResearch
Peer-reviewedYes
Externally publishedYes