Tolerability in man following inhalation dosing of the selective TLR7 agonist, AZD8848.
Tolerability in man following inhalation dosing of the selective TLR7 agonist, AZD8848.
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DOI：
10.1136/bmjresp-2015-000113
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发表时间：
2016
影响因子：
4.1
通讯作者：
Keeling D
中科院分区：
文献类型：
--
作者：
Delaney S;Biffen M;Maltby J;Bell J;Asimus S;Aggarwal A;Kraan M;Keeling D
许多哮喘患者具有辅助性T细胞2型（Th2）驱动的肺部炎症，而Toll样受体7（TLR7）激动剂通过诱导I型干扰素来抑制Th2应答。在人类中，口服或胃肠外TLR7激动剂可通过全身诱导I型干扰素诱导流感样症状。设计一种仅在肺部有活性的TLR7激动剂可以降低副作用的风险，并为治疗哮喘提供一种新的手段。我们开发了一种TLR7激动剂前药AZD 8848，以确定其在临床前模型和人体中的局部和全身作用。在大鼠过敏模型中，我们沿着测定了TLR7前药激动剂AZD 8848的体外细胞效力以及药代动力学和疗效。在AZD 8848吸入给药后，在单次给药剂量递增和多次给药剂量递增临床研究中测量了痰液和血液生物标志物，并评估了耐受性。AZD 8848在细胞试验中具有强效作用，药代动力学证实AZD 8848无全身暴露。在动物模型中，每周一次肺部给药在最终给药后26天显示出疗效。 在健康志愿者中，AZD 8848最初耐受性良好，通过诱导痰液中的CXCL10证实了靶向结合。一周后给予第二次吸入剂量，放大了超过一半参与者的全身干扰素信号，并导致明显的流感样症状。 前药设计限制了AZD 8848对肺部的直接作用。然而，由TLR7局部诱导的I型干扰素溢出全身，限制了这种吸入前药方法的实用性。NCT 01560234、NCT 01818869。
Many patients with asthma have a T-helper type 2 (Th2) driven inflammation of the lung, whereas toll-like receptor 7 (TLR7) agonists, by inducing type I interferons, inhibit Th2 responses. In man, oral or parenteral TLR7 agonists can induce influenza-like symptoms through systemic induction of type I interferons. Design of a TLR7 agonist that is only active in the lung could reduce the risk of side effects and offer a new means for treating asthma. We developed a TLR7 agonist antedrug, AZD8848, to determine its local and systemic effects in preclinical models and man. In vitro cellular potencies for the TLR7 antedrug agonist, AZD8848, were determined along with pharmacokinetics and efficacy in a rat allergy model. Sputum and blood biomarkers were measured in single ascending and multiple ascending dose clinical studies following inhalation delivery of AZD8848 and tolerability assessed. AZD8848 was potent in cellular assays and pharmacokinetics confirmed lack of systemic exposure to AZD8848. Weekly lung dosing in an animal model showed efficacy 26 days beyond the final dose. In healthy volunteers, AZD8848 was initially well tolerated with target engagement being demonstrated by induction of CXCL10 in sputum. A second inhaled dose, given 1 week later, amplified the systemic interferon signal in more than half the participants and resulted in significant influenza-like symptoms. The antedrug design restricted the direct actions of AZD8848 to the lung. However, the type I interferon induced locally by TLR7 spilled over systemically, limiting the utility of this inhaled antedrug approach. NCT01560234, NCT01818869.