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

J Allergy Clin Immunol. 2018 Apr;141(4):1220-1230. doi: 10.1016/j.jaci.2017.06.027. Epub 2017 Jul 20.

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.

Trial registration: ClinicalTrials.gov NCT01704040.

Keywords: Asthma; Toll-like receptor 3; inflammation; viral infection.

Publication types

  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Anti-Inflammatory Agents / therapeutic use*
  • Antibodies, Monoclonal / therapeutic use*
  • Asthma / diagnosis
  • Asthma / drug therapy*
  • Asthma / immunology
  • Asthma / virology*
  • Disease Progression
  • Double-Blind Method
  • Female
  • Healthy Volunteers
  • Humans
  • Male
  • Middle Aged
  • Picornaviridae Infections / complications*
  • Picornaviridae Infections / drug therapy
  • Picornaviridae Infections / immunology
  • Rhinovirus*
  • Severity of Illness Index
  • Toll-Like Receptor 3 / antagonists & inhibitors*
  • Treatment Outcome
  • Young Adult

Substances

  • Anti-Inflammatory Agents
  • Antibodies, Monoclonal
  • CNTO3157
  • Toll-Like Receptor 3

Associated data

  • ClinicalTrials.gov/NCT01704040
  • EudraCT/2011-005369-19