Arm J P, Bottoli I, Skerjanec A, Floch D, Groenewegen A, Maahs S, Owen C E, Jones I, Lowe P J
Translational Medicine, Novartis Institute for Biomedical Research, Cambridge, MA, USA.
Clin Exp Allergy. 2014 Nov;44(11):1371-85. doi: 10.1111/cea.12400.
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.
使用一种对IgE亲和力高于奥马珠单抗的单克隆抗体，我们研究了更完全地抑制IgE是否能产生更大的药效学效应，包括抑制对变应原的皮肤点刺反应。
探讨新型高亲和力人源化单克隆IgG1κ抗IgE抗体QGE031（利吉珠单抗）的药代动力学、药效学及安全性。
在特应性受试者中进行了临床前评估以及两项随机、安慰剂对照、双盲临床试验。第一项试验静脉注射单剂量的QGE031（0.1 - 10mg/kg）或安慰剂，而第二项试验每2周皮下注射两至四剂QGE031（0.2 - 4mg/kg）或安慰剂。两项试验均包括一个开放标签的奥马珠单抗组。
73名受试者中有60名（82%）和110名受试者中有96名（87%）分别完成了静脉和皮下研究。QGE031的暴露量及其半衰期取决于QGE031剂量和血清IgE水平。静脉注射后，QGE031具有双指数药代动力学特征，终末半衰期约为20天。QGE031对游离IgE、嗜碱性粒细胞FcεRI和嗜碱性粒细胞表面IgE的抑制呈剂量和时间依赖性，在程度（游离IgE和表面IgE）和持续时间上均优于奥马珠单抗。在第85天，即最后一剂后的6周，皮下注射QGE031（2mg/kg）或奥马珠单抗的受试者对变应原的皮肤点刺风团反应分别被抑制>95%和41%（P<0.001）。在接受QGE031和安慰剂治疗的受试者中均观察到荨麻疹，在一名静脉注射10mg/kg QGE031治疗的受试者中伴有全身症状。未发生严重不良事件。
这些关于高亲和力IgG1κ抗IgE抗体QGE031的首批临床数据表明，与奥马珠单抗相比，QGE031对游离IgE的抑制增强在特应性受试者（包括高IgE水平者）中转化为更优的药效学效应。因此，QGE031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不佳的患者受益。
