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

描述（由申请人提供）：季节性流感与全球范围内的显著死亡率相关，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破坏。虽然针对流感的疫苗接种是有效的，但预测哪些抗原表位可能在下一个流感季节出现的科学是不精确的，并且可能进一步受到生产和分销的物流问题的影响。抗病毒剂，如神经氨酸酶抑制剂（NAI），由于许多流感病毒株对此类药物的耐药性增加以及需要在感染后很快施用而受到阻碍。这两种方法都侧重于靶向病毒，而不是宿主对感染的反应。Imai et al.（2008）的证据表明，化学或微生物损伤引起的急性肺损伤（ALI）会导致氧化应激，导致氧化磷脂OxPAPC的产生，OxPAPC是Toll样受体4（TLR 4）诱导的肺部炎症的强效激动剂。在PI的实验室中，通过实验扩展了这一观察结果，在这些实验中，具有TLR 4靶向突变的小鼠显示出对小鼠适应性流感病毒株A/PR/8/24（“PR 8”）的感染高度难治。有待检验的中心假设是，阻断TLR 4信号传导治疗将防止流感感染。我们在我们的提案中提供了令人信服的证据，即合成的TLR 4拮抗剂，E5564，由Dallai Inc.生产，并且通过1-3期临床试验显示在人类中具有优异的安全记录，当治疗性施用时，甚至比抗病毒施用所需的时间更晚地阻断小鼠中的流感感染。拟议中的计划是一个合作伙伴关系之间的martai公司。以及马里兰州大学医学院、Sigmovir生物系统公司，和马里兰州大学兽医学院，使用小鼠优化治疗方案并进一步描述流感感染和NAI对先天免疫应答的影响，使用棉鼠探索对非适应性人类病毒株的功效，并在老年/免疫受损动物模型中，最后，在雪貂中，在ABSL 3条件下使用流感大流行株确认和扩大使用阿托洛尔。提出了一个产品开发计划，描绘了未来的计划，将阿托洛尔作为流感的治疗药物进行临床试验。

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.