Toll-like receptor 3 blockade in rhinovirus-induced experimental asthma exacerbations: A randomized controlled study - 05/04/18
, Susan Flavin, PhD a, Robert Gordon, MS a, Mathew J. Loza, PhD a, Peter J. Sterk, MD b, Rene Lutter, MD c, Zuzana Diamant, MD d, Ronald B. Turner, MD e, Brian J. Lipworth, MD f, David Proud, PhD g, Dave Singh, MD h, Andreas Eich, MD i, Vibeke Backer, MD j, James E. Gern, MD k, Christian Herzmann, MD l, Scott A. Halperin, MD m, Tjeert T. Mensinga, MD n, Alfred M. Del Vecchio, PhD a, Patrick Branigan, MS a, Lani San Mateo, PhD a, Frédéric Baribaud, PhD a, Elliot S. Barnathan, MD a, Sebastian L. Johnston, MD oAbstract |
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.
El texto completo de este artículo está disponible en PDF.Key words : Asthma, viral infection, inflammation, Toll-like receptor 3
Abbreviations used : ACQ7, AE, AUC, CCSS, CSAS, Feno, HRV, HSV-1, ICS, mITT, PD, PEFR, PK, poly-I:C, RIG-I, sIL-33R, TLR
Esquema
| Supported by Janssen R&D, Spring House, Pa. |
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| Disclosure of potential conflict of interest: P. E. Silkoff is an employee of Janssen R&D. S. Flavin is an employee of Janssen R&D. R. Gordon is an employee of Janssen R&D. M. J. Loza is an employee of Johnson & Johnson and holds stock with Johnson & Johnson. P. J. Sterk receives grant support from Johnson & Johnson. Z. Diamant is an employee of QPS Netherlands. R. B. Turner receives travel support from Janssen Research and Development; receives grant support from Janssen Research and Development, Danisco Sweetners; and serves as a consultant for Pfizer, PrEP Biopharm, and GlaxoSmithKline. B. J. Lipworth receives grant support from Teva and Cheisi; serves as a consultant for Chiesi, Dr Reddy, and Sandoz; receives speakers' fees from Meda and Boehringer Ingelheim; and receives travel support from NAPP. D. Proud serves on the advisory board from Janssen, AstraZeneca, and Pfizer and serves as a consultant from Procter & Gamble. D. Singh receives grant support from Johnson & Johnson, Almirall, AstraZeneca, Boehringer Ingleheim, Chiesi, GlaxoSmithKline, Glenmark, Merck, NAPP, Novartis, Pfizer, Takeda, Teva, Therevance, Verona, Genentech, and Skyepharma. J. E. Gern serves as a consultant for Janssen, Genentech, Amgen, Novartis, PREP Biopharm, Regeneron, and GlaxoSmithKline; receives grant support from GlaxoSmithKline; receives payment for development of educational presentations Boehringer Ingelheim; and receives travel support from Boehringer Ingelheim. C. Herzmann reports grant support from Janssen and receives personal fees from Genzyme, Hexal, and Abbvie. T. T. Mensinga is an employee of QPS. A. M. Del Vecchio is an employee of and holds stock in Janssen Pharmaceuticals. P. Branigan is an employee of Janssen R&D. L. San Mateo is an employee of Janssen R&D and holds a US patent 9,238,693. F. Baribaud is an employee of Janssen R&D. E. S. Barnathan is an employee of and holds stock in Janssen R&D LLC. S. L. Johnston receives grant support from Centocor, Sanofi Pasteur, GlaxoSmithKline, Chiesi, Boehringer Ingelheim, Grunenthal, Novartis, and Sunairgen and holds patents PCT/EP2003/007939, GB 0405634.7, 12, PCT/GB05/50031, 12, 0518425.4, 9, 7569216, 1734987, 1097181, 4807526, 11100187.0, and 13305152. The rest of the authors declare that they have no relevant conflicts of interest. |
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| The study was registered on the clinicaltrials.gov Web site (US registration no. NCT01704040) and the EU registration site (EudraCT; registration no. 2011-005369-19). |
Vol 141 - N° 4
P. 1220-1230 - avril 2018 Regresar al número
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