首页 >  专业园地 >  文献导读 >  临床观察 > 正文

Elarekibep(PRS-060/AZD1402):以IL-4ra为靶点治疗T2内型哮喘的新型吸入型抗哮喘药物

2023/02/01

   摘要
   背景:T2内型哮喘通过IL-4Ra介导的 IL-4和IL-13信号通路所驱动,IL-4Ra在气道上皮细胞、气道平滑肌和呼吸道黏膜免疫细胞上高度表达,提示其作为吸入拮抗剂的潜在优势。脂质运载蛋白1 (Lcn1)是一种富含于人类睫状液的16kD蛋白质,具有非常适合蛋白质工程的药物样结构,但从未被用于制造吸入性“Anticalin”蛋白治疗。
   目的:将Lcn1重组入可吸入的IL-4Ra拮抗剂,并评估其药效学/动力学特征。
   方法:采用定向蛋白诱变的方法对Lcn1进行了系统的修饰,产生了一种高亲和力、缓慢解离、长效的IL-4Ra完全拮抗剂,命名为‘PRS-060’,其性质类似于dupilumab,在体外竞争性地拮抗IL-4Ra依赖的细胞增殖、粘液诱导和嗜酸性粒细胞趋化因子的表达。由于PrS-060对人IL-4Ra具有良好的特异性,与啮齿动物或高等灵长类动物无交叉反应,我们建立了一种新的三人源化小鼠模型,在正确的同线基因座上替代hIL-4Ra、hIL-4和hIL-13来模拟临床用药。
   结果:吸入的PRS-060对三种人源化小鼠的急性变态反应性炎症指标有较强的抑制作用,其作用持续时间长于其整体清除时间,提示它可能在肺内起作用。
   结论:Lcn1可被重组入抗磷脂拮抗剂PRS-060,成为治疗T2内型哮喘的新型吸入外用、长效治疗药物。


 
 (中日友好医院呼吸与危重症医学科 万静萱 摘译 林江涛 审校)
(J Allergy Clin Immunol. 2022 Dec 30;doi: 10.1016/j.jaci.2022.12.815. IF: 10.228)


 
Elarekibep (PRS-060/AZD1402): a new class of inhaled Anticalin medicine targeting IL-4Ra for T2 endotype asthma.
 
Matschiner G, Fitzgerald MF, Moebius U,
 
Abstrast
Background: T2 endotype asthma is driven by IL-4 and IL-13 signaling via IL-4Ra, which is highly expressed on airway epithelium, airway smooth muscle and immunocytes in the respiratory mucosa, suggesting potential advantages of an inhalable antagonist. Lipocalin 1 (Lcn1), a 16kD protein abundant in human periciliary fluid, has a robust drug-like structure well-suited to protein engineering, but has never been used to make an inhaled "Anticalin" protein therapeutic.
Objectives: To re-engineer Lcn1 into an inhalable IL-4Ra antagonist and assess its pharmacodynamic/kinetic profile.
Methods: Lcn1 was systematically modified by directed protein mutagenesis yielding a high affinity, slowly dissociating, long-acting full antagonist of IL-4Ra designated 'PRS-060' with properties analogous to dupilumab, competitively antagonizing IL-4Ra dependent cell proliferation, mucus induction and eotaxin expression in vitro. As PRS-060 displayed exquisite specificity for human IL-4Ra, with no cross-reactivity to rodents or higher primates, we created a new triple-humanized mouse model substituting hIL-4Ra, hIL-4, and hIL-13 at their correct syntenic murine loci to model clinical dosing.
Results: Inhaled PRS-060 strongly suppressed acute allergic inflammation indices in triple humanized mice with a duration of action longer than its bulk clearance suggesting it may act locally in the lung.
Conclusions: Lcn1 can be re-engineered into the Anticalin antagonist PRS-060, exemplifying a new class of inhaled topical, long-acting therapeutic with potential to treat T2 endotype asthma.
 
 


上一篇: 在严重未控制的嗜酸性粒细胞性哮喘患者中,使用贝那利珠单抗后嗜酸性粒细胞耗竭与甘露醇诱导的气道高反应性减弱相关
下一篇: 描述间歇性口服皮质类固醇处方模式及其与哮喘不良结局的相关性的英国观察队列研究

用户登录