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

Silkoff, Philip E; Flavin, Susan; Gordon, Robert; Loza, Mathew J.; Sterk, Peter J; Lutter, Rene; Diamant, Zuzana LU ; Turner, Ronald B.; Lipworth, Brian J. and Proud, David, et al. (2017) In Journal of Allergy and Clinical Immunology
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... (More)

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.

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keywords
Asthma, Inflammation, Toll-like receptor 3, Viral infection
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Journal of Allergy and Clinical Immunology
publisher
Elsevier
external identifiers
  • scopus:85027506884
ISSN
0091-6749
DOI
10.1016/j.jaci.2017.06.027
language
English
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no
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008e7af4-f80e-4798-9975-8ee09af31b83
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2017-09-04 17:35:57
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2017-09-05 03:00:03
@article{008e7af4-f80e-4798-9975-8ee09af31b83,
  abstract     = {<p>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<sub>1</sub> during 10 days after inoculation. Results: In asthmatic patients (n = 63) CNTO3157 provided no protection against FEV<sub>1</sub> 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.</p>},
  author       = {Silkoff, Philip E and Flavin, Susan and Gordon, Robert and Loza, Mathew J. and Sterk, Peter J and Lutter, Rene and Diamant, Zuzana and Turner, Ronald B. and Lipworth, Brian J. and Proud, David and Singh, Dave and Eich, Andreas and Backer, Vibeke and Gern, James E. and Herzmann, Christian and Halperin, Scott A. and Mensinga, Tjeert T. and Del Vecchio, Alfred M. and Branigan, Patrick and San Mateo, Lani and Baribaud, Frédéric and Barnathan, Elliot S. and Johnston, Sebastian L.},
  issn         = {0091-6749},
  keyword      = {Asthma,Inflammation,Toll-like receptor 3,Viral infection},
  language     = {eng},
  month        = {07},
  publisher    = {Elsevier},
  series       = {Journal of Allergy and Clinical Immunology},
  title        = {Toll-like receptor 3 blockade in rhinovirus-induced experimental asthma exacerbations : A randomized controlled study},
  url          = {http://dx.doi.org/10.1016/j.jaci.2017.06.027},
  year         = {2017},
}