Pharmacokinetics, pharmacodynamics and safety of QGE031 (ligelizumab), a novel high-affinity anti-IgE antibody, in atopic subjects.
Pharmacokinetics, pharmacodynamics and safety of QGE031 (ligelizumab), a novel high-affinity anti-IgE antibody, in atopic subjects.
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DOI：
10.1111/cea.12400
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发表时间：
2014-11
期刊：
影响因子：
--
通讯作者：
Lowe PJ
中科院分区：
文献类型：
--
作者：
Arm JP;Bottoli I;Skerjanec A;Floch D;Groenewegen A;Maahs S;Owen CE;Jones I;Lowe PJ
使用对IgE具有比奥马珠单抗更大亲和力的单克隆抗体，我们检查了是否更完全地抑制IgE提供更大的药效学效应，包括抑制对过敏原的皮肤刺痛反应。探讨新型高亲和力人源化单克隆IgG 1 κ抗IgE抗体QGE 031（ligelizumab）的药代动力学、药效学和安全性。在特应性受试者中进行了临床前评估和两项随机、安慰剂对照、双盲临床试验。第一项试验单次静脉注射QGE 031（0.1-10 mg/kg）或安慰剂，第二项试验皮下注射QGE 031（0.2- 4 mg/kg）或安慰剂2 - 4次，间隔2周。两项试验均包括开放标签的omalizumab组，分别有60/73（82%）和96/110（87%）的受试者完成了静脉注射和皮下注射研究。QGE 031的暴露量及其半衰期取决于QGE 031剂量和血清IgE水平。静脉给药后，QGE 031具有双指数药代动力学特征，终末半衰期约为20天。QGE 031对游离IgE、嗜碱性粒细胞FcεRI和嗜碱性粒细胞表面上级的剂量和时间依赖性抑制在程度（游离IgE和表面IgE）和持续时间方面优于奥马珠单抗。在第85天，末次给药后6周，皮下注射QGE 031（2 mg/kg）或奥马珠单抗的受试者对变应原的皮肤刺痛风团反应分别被抑制> 95%和41%（P < 0.001）。在接受QGE 031和安慰剂治疗的受试者中观察到荨麻疹，并在接受10 mg/kg静脉注射QGE 031治疗的1例受试者中伴有全身症状。未发生严重不良事件。QGE 031（一种高亲和力IgG 1 κ抗IgE抗体）的这些首次临床数据表明，与奥马珠单抗相比，QGE 031对游离IgE的抑制作用增强，在特应性受试者（包括IgE水平较高的受试者）中转化为上级药效学效应。因此，QGE 031可能使无法接受奥马珠单抗治疗或接受奥马珠单抗治疗效果欠佳的患者受益。
Using a monoclonal antibody with greater affinity for IgE than omalizumab, we examined whether more complete suppression of IgE provided greater pharmacodynamic effects, including suppression of skin prick responses to allergen. To explore the pharmacokinetics, pharmacodynamics and safety of QGE031 (ligelizumab), a novel high-affinity humanized monoclonal IgG1κ anti-IgE. Preclinical assessments and two randomized, placebo-controlled, double-blind clinical trials were conducted in atopic subjects. The first trial administered single doses of QGE031 (0.1–10 mg/kg) or placebo intravenously, while the second trial administered two to four doses of QGE031 (0.2– 4 mg/kg) or placebo subcutaneously at 2-week intervals. Both trials included an open-label omalizumab arm. Sixty of 73 (82%) and 96 of 110 (87%) subjects completed the intravenous and subcutaneous studies, respectively. Exposure to QGE031 and its half-life depended on the QGE031 dose and serum IgE level. QGE031 had a biexponential pharmacokinetic profile after intravenous administration and a terminal half-life of approximately 20 days. QGE031 demonstrated dose- and time-dependent suppression of free IgE, basophil FcεRI and basophil surface IgE superior in extent (free IgE and surface IgE) and duration to omalizumab. At Day 85, 6 weeks after the last dose, skin prick wheal responses to allergen were suppressed by > 95% and 41% in subjects treated subcutaneously with QGE031 (2 mg/kg) or omalizumab, respectively (P < 0.001). Urticaria was observed in QGE031- and placebo-treated subjects and was accompanied by systemic symptoms in one subject treated with 10 mg/kg intravenous QGE031. There were no serious adverse events. These first clinical data for QGE031, a high-affinity IgG1κ anti-IgE, demonstrate that increased suppression of free IgE compared with omalizumab translated to superior pharmacodynamic effects in atopic subjects, including those with high IgE levels. QGE031 may therefore benefit patients unable to receive, or suboptimally treated with, omalizumab.
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影响因子：
14.2
作者：
Eckman, John A.;Sterba, Patricia M.;Kelly, Denise;Alexander, Val;Liu, Mark C.;Bochner, Bruce S.;MacGlashan, Donald W., Jr.;Saini, Sarbjit S.
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