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。
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.
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)
(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.
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