Safety profile, pharmacokinetics, and biologic activity of MEDI-563, an anti-IL-5 receptor α antibody, in a phase I study of subjects with mild asthma
Safety profile, pharmacokinetics, and biologic activity of MEDI-563, an anti-IL-5 receptor α antibody, in a phase I study of subjects with mild asthma
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DOI：
10.1016/j.jaci.2010.04.005
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发表时间：
2010-06-01
影响因子：
14.2
通讯作者：
Molfino, Nestor A.
中科院分区：
文献类型：
--
作者：
Busse, William W.;Katial, Rohit;Molfino, Nestor A.
背景：嗜酸性粒细胞水平升高与气道炎症和哮喘恶化有关。IL-5负责嗜酸性粒细胞的分化、增殖和活化; IL-5受体在嗜酸性粒细胞及其祖细胞上表达，靶向这些受体可诱导嗜酸性粒细胞凋亡。目的：评价靶向IL-5受体α链的人源化mAb MEDI-563的安全性、药代动力学和药效学。在这项开放标签研究中，轻度特应性哮喘受试者（n = 44）接受MEDI-563单次、递增、静脉给药（0.0003-3 mg/kg），给药时间为3 - 30分钟。对肺功能、症状评分、不良事件、MEDI-563药代动力学、C反应蛋白（CRP）、IL-6、嗜酸性粒细胞阳离子蛋白（ECP）和嗜酸性粒细胞水平进行了评价。（基线+/- SD，0.27 +/- 0.2 x 10（3）/mu L;给药后24小时，0.01 +/- 0.0 x 10（3）/mu L）; 94.0%接受≥ 0.03 mg/kg的受试者显示水平在0.00 x 10（3）/mu L和0.01 x 10（3）/mu L之间。在0.03 - 0.1和0.3 - 3 mg/kg剂量下，嗜酸性粒细胞减少症分别持续至少8周或12周。ECP水平从21.4 +/- 17.2 μ g/L（基线）降至10.3 +/- 7.0 μ g/L（给药后24小时）。最常报告的不良事件为白色细胞计数降低（34.1%）、鼻咽炎（27.3%）和血肌酸磷酸激酶升高（25.0%）。给药后24小时，平均C反应蛋白水平升高至5.5倍，但在研究结束时恢复至基线水平;给药后6至12小时，平均IL-6水平升高至3.9倍至4.7倍。药代动力学活性与剂量成比例，剂量为0.03至3 mg/kg.Conclusion：MEDI-563的单次递增剂量具有可接受的安全性特征，并导致给药后24小时内PB嗜酸性粒细胞计数显著减少。（J Allergy Clin Immunol 2010;125：1237-44.）
Background: Increased eosinophil levels have been linked to airway inflammation and asthma exacerbations. IL-5 is responsible for eosinophil differentiation, proliferation, and activation; IL-5 receptors are expressed on eosinophils and their progenitors, and targeting such receptors induces eosinophil apoptosis.Objective: To evaluate the safety profile, pharmacokinetics, and pharmacodynamics of MEDI-563, a humanized mAb targeting the IL-5 receptor alpha chain.Methods: Single, escalating, intravenous doses (0.0003-3 mg/kg) of MEDI-563 were administered to subjects with mild atopic asthma (n = 44) over similar to 3 to 30 minutes in this open-label study. Pulmonary function, symptom scores, adverse events, MEDI-563 pharmacokinetics, and levels of C-reactive protein (CRP), IL-6, eosinophil cationic protein (ECP), and eosinophils were evaluated.Results: Mean peripheral blood (PB) eosinophil levels decreased in a dose-dependent fashion (baseline +/- SD, 0.27 +/- 0.2 x 10(3)/mu L; 24 hours postdose, 0.01 +/- 0.0 x 10(3)/mu L); 94.0% of subjects receiving >= 0.03 mg/kg exhibited levels between 0.00 x 10(3)/mu L and 0.01 x 10(3)/mu L. Eosinopenia lasted at least 8 or 12 weeks with doses of 0.03 to 0.1 and 0.3 to 3 mg/kg, respectively. ECP levels were reduced from 21.4 +/- 17.2 mu g/L (baseline) to 10.3 +/- 7.0 mu g/L (24 hours postdose). The most frequently reported adverse events were reduced white blood cell counts (34.1%), nasopharyngitis (27.3%), and increased blood creatine phosphokinase (25.0%). Mean C-reactive protein levels increased similar to 5.5-fold at 24 hours postdose but returned to baseline by study end; mean IL-6 levels increased, similar to 3.9-fold to 4.7-fold at 6 to 12 hours postdose, respectively. Pharmacokinetic activity was dose proportional at doses of 0.03 to 3 mg/kg.Conclusion: Single escalating doses of MEDI-563 had an acceptable safety profile and resulted in marked reduction of PB eosinophil counts within 24 hours after dosing. (J Allergy Clin Immunol 2010;125:1237-44.)