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.

中文翻译：

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鼻病毒诱导的实验性哮喘发作中的 Toll 样受体 3 阻断：一项随机对照研究

背景

人鼻病毒 (HRV) 通常会导致哮喘恶化。Toll 样受体 3 是一种先天模式识别受体，由 HRV 触发，引发炎症，从而加重哮喘。

客观的

我们试图在健康受试者和哮喘患者的实验性 HRV-16 接种中评估 Toll 样受体 3 CNTO3157 的抑制性 mAb。

方法

在北美和欧洲的这项双盲、多中心、随机、平行组研究中，健康受试者和轻度至中度稳定哮喘患者分别接受单剂或多剂 CNTO3157 或安慰剂，然后接种 HRV -16 在 72 小时内。监测所有受试者的呼吸症状、肺功能和鼻病毒载量。主要终点是接种后 10 天内FEV _{1的最大降低。}

结果

在哮喘患者 (n = 63) 中，CNTO3157 对 FEV ₁降低没有提供保护（最小二乘均值：CNTO3157 [n = 30] = -7.08% [SE, 8.15%]；安慰剂 [n = 25] = -5.98% [SE , 8.56%]) 或接种后出现症状。在健康受试者 (n = 12) 中，与安慰剂相比，CNTO3157 显着减弱了上 ( P  = .03) 和下 ( P  = .02) 气道症状评分，曲线下面积分别增加了 9.1 (15.1) 和 34.9 (17.6) ) 和 13.0 (18.4) 与 CNTO3157 (n = 8) 和安慰剂 (n = 4) 组在接种后分别为 50.4 (25.9)。在接受 CNTO3157 时，所有的严重哮喘发作和 4 次非严重哮喘发作都发生了。

结论

总之，CNTO3157 在减弱 HRV-16 攻击对哮喘患者肺功能、哮喘控制和症状的影响方面无效，但在健康受试者中抑制了感冒症状。对于这种高度未满足的医疗需求，需要寻求其他方法，包括阻断多种途径或抗病毒药物。