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

Authors :
Silkoff, Philip E.
Flavin, Susan
Gordon, Robert
Loza, Mathew J.
Sterk, Peter J.
Lutter, Rene
Diamant, Zuzana
Turner, Ronald B.
Lipworth, Brian J.
Proud, David
Singh, Dave
Eich, Andreas
Backer, Vibeke
Gern, James E.
Herzmann, Christian
Halperin, Scott A.
Mensinga, Tjeert T.
Del Vecchio, Alfred M.
Branigan, Patrick
San Mateo, Lani
Source :
Journal of Allergy & Clinical Immunology; Apr2018, Vol. 141 Issue 4, p1220-1230, 11p
Publication Year :
2018

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 FEV 1 during 10 days after inoculation. Results In asthmatic patients (n = 63) CNTO3157 provided no protection against FEV 1 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. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
00916749
Volume :
141
Issue :
4
Database :
Supplemental Index
Journal :
Journal of Allergy & Clinical Immunology
Publication Type :
Academic Journal
Accession number :
128740849
Full Text :
https://doi.org/10.1016/j.jaci.2017.06.027