Development of IFN-lambda3 for the Prevention and Treatment of Virus Infection

描述(申请人提供)：越来越多的人担心，人类种群中自然存在的良性病毒或通常居住在非人类宿主中的病毒，在获得野生环境中的零星突变或在实验室环境中进行转基因以用于生物恐怖主义后，可能演变成有效地感染并在人类种群中传播。即使在诊断技术的发展方面取得了巨大的进步，也可能需要几周的时间才能识别出新出现的病毒；可能需要几个月(或几年)的时间来开发有效的病毒特异性治疗方法。因此，在使用未知性质的生物武器攻击平民或军事人员的威胁下，或在攻击之后立即攻击，只有广谱抗病毒药物可用作预防和/或治疗感染不明病毒剂的预防性治疗。数百种不同的病毒能够感染人类；疾病的严重程度可能从无症状的机会性感染到危及生命的病毒性疾病。尽管不同病毒的生物学、生命周期和致病机制存在很大差异，但免疫系统主要使用相同的抗病毒保护机制来对抗任何类型的病毒。这一机制完全依赖于 干扰素(IFN)。这些小的分泌蛋白由感染病毒的细胞释放，以警告邻近细胞病毒的存在，并迫使这些细胞部署各种抗病毒保护手段。因此，我们认为，应对病毒感染的最佳治疗策略是加强免疫系统的保护性抗病毒力量，而不是针对单个病毒进行治疗干预。有两种类型的IFN，即I型IFN(干扰素-α/？)和新近发现的III型IFN(干扰素-λS)，它们可以独立地激活各种器官的快速天然抗病毒保护。重要的是，最近的研究已经开始揭示干扰素-λS独特的生物学特性，这可能使它们成为比I型IFN更好的抗病毒治疗药物。我们组建了一支强大的研究团队，有一家制药公司参与，该团队拥有必要的专业知识、知识产权和能力，可以开发和测试基于干扰素-λ的生物防御疗法。在目标1中，我们将制定程序来优化和扩大干扰素-λ3及其衍生物的生产，以进行广泛的体外和体内试验，以确定其临床前疗效。这将包括将干扰素-λ3进行聚乙二醇化，以提高干扰素-λ3的稳定性、递送性和安全性。另外，我们将在动物感染模型中测试干扰素-λ3抗病毒药物的抗病毒性能和作用机制，首先在生物安全级别2，然后在生物安全级别3设施中。该项目的长期目标是开发基于干扰素-λ的广谱抗病毒药物，并将其推向临床。

DESCRIPTION (provided by applicant): There is a growing concern that naturally existing benign viruses within human population or viruses normally residing in non-human hosts may evolve to efficiently infect and spread through the human population after acquiring sporadic mutations in the wild or being genetically modified in laboratory settings for bioterrorism. Even with enormous advances in the development of diagnostic techniques, several weeks may pass before a novel emerging virus can be identified; and it may take several months (or years) to develop effective virus- specific therapy. Therefore, under the threat of an attack to civilian or military personnel with bioweapons of unknown nature, or immediately after an attack, only broad-spectrum antivirals can be used as a prophylactic treatment to prevent and/or treat infection with an unidentified viral agent. Hundreds of different viruses are able to infect humans; and the severity of the disease may range from asymptomatic opportunistic infections to life-threatening viral diseases. Although the biology, life cycle and pathogenesis of different viruses are widely divergent, the immune system employs mainly the same mechanism of antiviral protection to battle any type of viruses. This mechanism relies entirely on the action of interferons (IFNs). These small secreted proteins are released by virus-infected cells to warn neighboring cells about viral presence and to force these cells to deploy various means of antiviral protection. Thus, we believe that the best therapeutic strategy to deal with viral infections is to enhance protective antiviral forces of the immune system, rather than target an individual virus for therapeutic intervention. There are two types of IFNs, type I IFNs (IFN-α/ß) and recently identified type III IFNs (IFN-λs), that can independently activate rapid innate antiviral protection in various organs. Importantly, recent studies have started to reveal unique biological features of IFN-λs that may make them better antiviral therapeutics than type I IFNs. We have assembled a strong team of investigators with the participation of a pharmaceutical company, the team that has necessary expertise, intellectual property and capability to develop and test IFN-λ- based therapeutics for biodefense. In aim 1, we will develop procedures to optimize and scale up production of IFN-λ3 and its derivatives for the extensive in vitro and in vivo testing needed to establish its preclinical efficacy. This will include pegylation of IFN-λ3 t improve the stability, deliverability and increase safety of IFN-λ3. In other aims, we will test antiviral properties and mechanisms of action of IFN-λ3-base antivirals against various viruses in animal models of infection, first at biosafety level 2 (BSL2) and then at BSL3 facilities. The long-term goal of this project is to develop IFN-λ-based broad-spectrum antiviral therapeutics and bring them into the clinic.