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

描述（由申请人提供）：季节性流感在全球范围内与显著的死亡率相关，但来自不同物种的流感毒株之间的基因组重组意外产生的大流行毒株可能导致大流行和全球破坏。虽然预防流感的疫苗接种是有效的，但预测在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，并且可能因生产和分销的后勤问题而进一步受到损害。许多流感毒株对神经氨酸酶抑制剂等抗病毒药物的耐药性日益增强，而且需要在感染后很快给予这些药物，这阻碍了它们的使用。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（2008）的证据表明，由化学或微生物损伤引起的急性肺损伤（ALI）引起氧化应激，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的实验室中得到了扩展，在实验中，TLR4靶向突变的小鼠对小鼠适应流感毒株a /PR/8/24（“PR8”）的感染表现出高度的耐受性。待验证的中心假设是，从治疗上阻断TLR4信号传导将预防流感感染。在我们的提案中，我们提供了令人信服的证据，证明卫材公司生产的合成TLR4拮抗剂itoran (E5564)，通过1-3期临床试验显示在人类中具有出色的安全记录，在治疗性给药时阻断小鼠流感感染，甚至比抗病毒给药所需的时间晚。拟议的计划是卫材公司与马里兰大学医学院、西格莫维尔生物系统公司和马里兰大学兽医学院之间的合作伙伴关系，以优化利用厄立托兰和NAIs作为流感感染治疗药物的治疗方法，利用小鼠优化治疗方案，并进一步描述流感感染和厄立托兰对先天免疫反应的影响。在棉花大鼠和衰老/免疫功能低下动物模型中探索对非适应性人类病毒株的疗效，最后在雪貂中证实并扩大在ABSL3条件下使用厄立特里亚流感大流行毒株的使用。提出了一项产品开发计划，描述了将厄立特里亚作为流感治疗药物进行临床试验的未来计划。

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.