OX40L blockade and allergen-induced airway responses in subjects with mild asthma
OX40L blockade and allergen-induced airway responses in subjects with mild asthma
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DOI：
10.1111/cea.12235
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发表时间：
2014-01-01
影响因子：
6.1
通讯作者：
O'Byrne, P. M.
中科院分区：
文献类型：
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作者：
Gauvreau, G. M.;Boulet, L. -P.;O'Byrne, P. M.
背景 OX40/OX40L 相互作用有助于过敏刺激后 T 细胞的最佳反应，并在记忆 T 效应细胞的维持和重新激活中发挥重要作用。目的我们测试了抗 OX40L 单克隆抗体 (MAb) 治疗是否会抑制哮喘受试者过敏原诱导的反应。方法招募了 28 名轻度特应性哮喘受试者进行双盲、随机、安慰剂对照、平行组试验（ClinicalTrials.gov 标识符 NCT00983658）比较使用人源化抗 OX40L MAb 与安慰剂在 3 个月内静脉注射 4 剂对 OX40L 的阻断作用。在首次服用研究药物后 56 天和 113 天进行过敏原吸入挑战。主要结果变量是晚期哮喘反应。其他结局包括早期哮喘反应、气道高反应性、血清 IgE 水平、血液和痰嗜酸性粒细胞、安全性和耐受性。 结果与安慰剂相比，抗 OX40L MAb 治疗并没有减弱第 56 天或第 113 天的早期或晚期哮喘反应。在抗 OX40L MAb 治疗组中，到第 113 天时，总 IgE 较给药前水平减少 17%，痰嗜酸性粒细胞减少 75%（均 P=0.04）。抗 OX40L MAb 对气道高反应性或血液嗜酸性粒细胞没有影响。两组的AE发生率相似。结论和临床相关性通过给药后16周血清总IgE和气道嗜酸性粒细胞的减少观察抗OX40L MAb的药理活性，但对过敏原诱导的气道反应没有影响。抗体的治疗持续时间或剂量可能不足以影响气道反应。
BackgroundThe OX40/OX40L interaction contributes to an optimal T cell response following allergic stimuli and plays an important role in the maintenance and reactivation of memory T effector cells.ObjectiveWe tested whether treatment with an anti-OX40L monoclonal antibody (MAb) would inhibit allergen-induced responses in subjects with asthma.MethodsTwenty-eight mild, atopic asthmatic subjects were recruited for a double-blind, randomized, placebo-controlled, parallel-group trial (ClinicalTrials.gov identifier NCT00983658) to compare blockade of OX40L using a humanized anti-OX40L MAb to placebo-administered intravenously in 4 doses over 3months. Allergen inhalation challenges were carried out 56 and 113days after the first dose of study drug. The primary outcome variable was the late-phase asthmatic response. Other outcomes included the early-phase asthmatic response, airway hyperresponsiveness, serum IgE levels, blood and sputum eosinophils, safety and tolerability.ResultsTreatment with anti-OX40L MAb did not attenuate the early- or late-phase asthmatic responses at days 56 or 113 compared with placebo. In the anti-OX40L MAb treatment group, total IgE was reduced 17% from pre-dosing levels, and sputum eosinophils decreased 75% by day 113 (both P=0.04). There was no effect of anti-OX40L MAb on airway hyperresponsiveness or blood eosinophils. The frequency of AEs was similar in both groups.Conclusion and Clinical RelevancePharmacological activity of anti-OX40L MAb was observed by decreases in serum total IgE and airway eosinophils at 16weeks post-dosing, but there was no effect on allergen-induced airway responses. It is possible that the treatment duration or dose of antibody was insufficient to impact the airway responses.