Eritoran (E5564), a TLR4 antagonist, as a novel therapeutic for influenza

Eritoran (E5564)，一种 TLR4 拮抗剂，作为流感的新型治疗剂

基本信息

批准号：
8884533
负责人：
JORGE C BLANCO
金额：
$ 86.55万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-03 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8884533
关键词：
Acids Acute Lung Injury Adult Respiratory Distress Syndrome Agonist Animal Model Animals Antiviral Agents Avian Influenza Bacteria Categories Chemicals Clinical Trials Cotton Rats Coupled Data Death Rate Deposition Development Plans Dose Economics Epitopes Exposure to Ferrets Future Gene Expression Generations Genomics Gold Health Human Immune response Immunocompromised Host In Vitro Infection Inflammatory Influenza Influenza A Virus, H5N1 Subtype Influenza A virus Influenza B Virus Interleukin-6 Laboratories Lead Lipopolysaccharides Lung Inflammation Maryland Mediating Modeling Molecular Mus Mutation Neuraminidase inhibitor Oxidative Stress Paper Pharmaceutical Preparations Phase Phospholipids Population Production Publishing Refractory Reporting Resistance Safety Science Seasons Septic Shock Sigmodon Signal Pathway Signal Transduction Signaling Molecule Stimulus TRAF6 gene Testing Therapeutic Therapeutic Agents Transgenic Mice Treatment Protocols Universities Vaccination Veterinary Medicine Virulent Virus aged base biothreat college comparative efficacy cytokine efficacy testing human TLR4 protein human disease immunogenic immunosuppressed in vivo influenza virus vaccine killings medical schools microbial mortality mouse model novel strategies novel therapeutics pandemic disease pandemic influenza pathogen product development prototype research study resistant strain respiratory infection virus response seasonal influenza seropositive toll-like receptor 4 vaccination strategy vaccine development

项目摘要

DESCRIPTION (provided by applicant): Seasonal influenza is associated with significant mortality worldwide, but pandemic strains that arise unexpectedly from genomic reassortment between influenza strains from diverse species can lead to pandemics and global devastation. While vaccination against influenza is effective, the science of predicting which antigenic epitopes are likely to appear in the next influenza season is an imprecise one and can be further compromised by logistical problems of manufacturing and distribution. Antiviral agents, such as neuraminidase inhibitors (NAIs), are hampered by the increasing resistance of many influenza strains to such agents and the need to be administered very soon after infection. Both of these approaches focus on targeting the virus, rather than the host response to infection. Evidence by Imai et al. (2008) suggested that acute lung injury (ALI) caused by chemical or microbial insults causes oxidative stress that results in generation of an oxidized phospholipid, OxPAPC, a potent agonist of Toll-like Receptor 4 (TLR4)-induced lung inflammation. This observation was extended in the laboratories of the PIs by experiments in which mice with a targeted mutation in TLR4 were shown to be highly refractory to infection with mouse-adapted influenza strain A/PR/8/24 ("PR8"). The central hypothesis to be tested is that blocking TLR4 signaling therapeutically will protect against influenza infection. We provide compelling evidence in our proposal that the synthetic TLR4 antagonist, Eritoran (E5564), produced by Eisai Inc., and shown to have an excellent safety record in humans through Phase 1-3 clinical trials, blocks influenza infection in mice when administered therapeutically, even later than required for antiviral administration. The proposed plan is a partnership between Eisai Inc. and the University of Maryland, School of Medicine, Sigmovir Biosystems, Inc., and University of Maryland, College of Veterinary Medicine to optimize treatment with Eritoran and NAIs as a therapeutic for influenza infection using mice to optimize treatment regimens and further delineate the effect of influenza infection and Eritoran on the innate immune response, cotton rats to explore efficacy against non-adapted human strains of virus and in a model of aged/immunocompromised animals, and finally, in ferrets, to confirm and extend the use of Eritoran using pandemic strains of influenza under ABSL3 conditions. A Product Development Plan is presented that delineates future plans for moving Eritoran to clinical trial as a therapeutc for influenza.

描述（由申请人提供）：季节性流感与全球范围内的显着死亡率相关，但来自不同物种的流感毒株之间的基因组重配意外产生的大流行毒株可能导致大流行和全球性破坏。虽然流感疫苗接种是有效的，但预测下一个流感季节可能出现哪些抗原表位的科学是不精确的，并且可能会因制造和分销的后勤问题而进一步受到损害。抗病毒药物，例如神经氨酸酶抑制剂（NAIs），由于许多流感毒株对此类药物的耐药性不断增加以及需要在感染后立即施用而受到阻碍。这两种方法都侧重于针对病毒，而不是宿主对感染的反应。 Imai 等人的证据。 (2008) 表明，化学或微生物损伤引起的急性肺损伤 (ALI) 会导致氧化应激，从而导致氧化磷脂 OxPAPC 的产生，OxPAPC 是 Toll 样受体 4 (TLR4) 诱导的肺部炎症的有效激动剂。这一观察结果在 PI 实验室中通过实验得到了扩展，在这些实验中，TLR4 具有靶向突变的小鼠被证明对小鼠适应性流感毒株 A/PR/8/24（“PR8”）的感染具有高度抵抗力。待检验的中心假设是，通过治疗性阻断 TLR4 信号传导可以预防流感感染。我们在提案中提供了令人信服的证据，证明由卫材公司生产的合成 TLR4 拮抗剂 Eritoran (E5564)，通过 1-3 期临床试验显示在人类中具有出色的安全性记录，在治疗时可阻断小鼠的流感感染，甚至晚于抗病毒给药所需的时间。拟议的计划是卫材公司与马里兰大学医学院、Sigmovir Biosystems, Inc. 和马里兰大学兽医学院之间的合作伙伴关系，旨在优化使用 Eritoran 和 NAI 作为小鼠流感感染的治疗方法为了优化治疗方案并进一步阐明流感感染和依立托伦对先天免疫反应的影响，棉鼠探索对非适应性人类病毒株的功效，并在模型中老年/免疫功能低下的动物，最后在雪貂中，在 ABSL3 条件下使用大流行性流感株来确认和扩展 Eritoran 的使用。提出了一项产品开发计划，描述了将 Eritoran 作为流感治疗药物进入临床试验的未来计划。