Toll-like receptor 3 blockade in rhinovirus-induced experimental asthma exacerbations: A Randomized Controlled Study

Philip E. Silkoff (Lead / Corresponding author), Susan Flavin, Robert Gordon, Mathew J. Loza, Peter J. Sterk, Rene Lutter, Zuzana Diamant, 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 MateoFrédéric Baribaud, Elliot S. Barnathan, Sebastian L. Johnston

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Abstract

Background: Human rhinoviruses (HRV) commonly precipitate asthma exacerbations. TLR3, an innate pattern-recognition receptor, is triggered by HRV driving inflammation that may worsen asthma.

Objective: To evaluate an inhibitory monoclonal antibody to TLR3, CNTO3157, on experimental HRV-16 inoculation in healthy and asthmatic subjects.

Methods: In this double-blind multicenter randomized parallel-group study in North America and Europe, healthy and mild-moderate stable asthmatic subjects received single or multiple doses of CNTO 3157 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 endpoint was maximal decline in forced expired volume in 1 second (FEV1) during 10-days post-inoculation.

Results: In asthmatic subjects (N=63), CNTO3157 provided no protection against FEV1 decline (LS mean [SE]: CNTO3157 (n=30) = -7.08 [8.15] % and placebo (n=25) = -5.98 [8.56] %), or symptoms post- inoculation. In healthy subjects (N=12), CNTO3157 versus placebo significantly attenuated upper (p=0.03) and lower (p=0.02) airway symptom scores, with area-under-the-curve increases of 9.1(15.1) vs 34.9 (17.6) and 13.0 (18.4) vs 50.4 (25.9) for the CNTO3157 group (n=8) and placebo group (n=4), respectively, after inoculation. All of the severe and three of the four non-serious asthma exacerbations occurred on CNTO3157.

Conclusion: In summary, CNTO3157 was ineffective in attenuating the impact of HRV-16 challenge on lung function, asthma control, and symptoms in asthma, 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.

Original languageEnglish
Pages (from-to)1220-1230
Number of pages11
JournalJournal of Allergy and Clinical Immunology
Volume141
Issue number4
Early online date20 Jul 2017
DOIs
Publication statusPublished - Apr 2018

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Keywords

  • Asthma
  • Viral infection
  • inflammation
  • TLR3

Cite this

Silkoff, P. E., Flavin, S., Gordon, R., Loza, M. J., Sterk, P. J., Lutter, R., Diamant, Z., Turner, R. B., Lipworth, B. J., Proud, D., Singh, D., Eich, A., Backer, V., Gern, J. E., Herzmann, C., Halperin, S. A., Mensinga, T. T., Del Vecchio, A. M., Branigan, P., ... Johnston, S. L. (2018). Toll-like receptor 3 blockade in rhinovirus-induced experimental asthma exacerbations: A Randomized Controlled Study. Journal of Allergy and Clinical Immunology, 141(4), 1220-1230. https://doi.org/10.1016/j.jaci.2017.06.027