An immunotherapeutic IgY formulation against norovirus diarrhea

STTRI期应用项目摘要/摘要：一种免疫治疗性卵黄抗体制剂 治疗诺如病毒腹泻 人类诺如病毒(HuNoV)每年感染全球数百万人，导致腹泻疾病 每年造成20多万人死亡，特别是在非常年轻的，非常年长的和 免疫功能受损。目前既没有有效的疫苗，也没有有效的治疗方法 新城疫病毒感染。使问题变得更加复杂的是，HuNov毒株迅速突变和 不可预测，这可以减少任何靶向治疗的影响，当面对新的 新出现的菌株。这项提案的长期目标是评估一种新的方法来 预防或治疗新城疫病毒腹泻：使用从鸡蛋中提纯的抗新城疫病毒抗体 用代表多个HuNov毒株的纳米颗粒免疫，以提供“被动免疫” 进入肠道。这些抗体被称为“卵黄抗体”，表明它们是来自 蛋黄。申请人已经证明了抗HuNoV IgY可以阻止HuNoV病毒 在人类肠道细胞模型中复制，而这个项目是这项工作的自然延伸。 该项目的具体目标1是生产和彻底表征针对三种卵黄抗体生产的卵黄 不同毒株优势的HuNov病毒基因，GII.4。通过使用所谓的“P24” 代表这三个菌株的纳米颗粒作为免疫抗原，产生的IgY将靶向 所有这三种变种，都提供了一个证据，证明可以使用廉价的 和容易产生的抗原。一旦抗体的特性和它们的结合能力 已经确定了对所有三种病毒株的抑制，该项目的具体目标2将是 评价抗人新城疫病毒抗体在已建立的生猪模型中的保护作用 显示为人类HuNov腹泻的概括。猪将用活性成分进行为期一天的预处理 抗体或对照(未免疫)抗体，然后会感染大剂量的一种 HuNov GII.4变种。这些动物的腹泻体征和症状将被监测是否有额外的 七天，帮助我们了解治疗预防腹泻的效果，以及在 腹泻的动物，它在多大程度上将疾病的严重性或持续时间降至最低。如果该项目 在这种模式下，成功地展示了对HNOV的显著保护，人类安全， 将进行耐受性和有效性研究，最终导致监管部门批准 使用抗HuNov IgY预防和/或治疗HuNov腹泻。这样一种现成的治疗方法是 预计将显著减少人类痛苦，并提供巨大的社会效益，特别是 在美国和世界各地最脆弱的人群中。

Project Summary/Abstract for STTR Phase I Application: An immunotherapeutic IgY formulation against norovirus diarrhea Human norovirus (HuNoV) infects millions of people globally each year, causing diarrheal illness resulting in more than 200,000 deaths annually, particularly in the very young, the very old, and the immunocompromised. There is currently neither an effective vaccine nor effective treatment for HuNoV infections. Compounding the problem is the fact that HuNoV strains mutate rapidly and unpredictably, which can reduce the impact of any targeted therapeutic when faced with novel emerging strains. This proposal’s long-term objective is to evaluate a novel approach to the prevention or treatment of HuNoV diarrhea: using anti-HuNoV antibodies, purified from eggs of hens immunized with nanoparticles representing multiple strains of HuNoV, to provide “passive immunity” to the intestinal tract. These antibodies are called “IgY” to indicate that they are immunoglobulins from egg yolks. The applicant has already demonstrated that anti-HuNoV IgY can stop HuNoV viruses from replicating in a human intestinal cell model, and this project is the natural extension of that work. The project’s Specific Aim 1 is to produce and thoroughly characterize IgY produced against three different strains of the predominant HuNoV viral genotype, GII.4. By using so-called “P24” nanoparticles representing all three strains as the immunizing antigens, the IgY produced will target all three variants, offering a proof that broad-spectrum protection can be achieved using inexpensive and readily-produced antigens. Once the antibodies have been characterized and their ability to bind to and inhibit all three viral strains has been established, the project’s Specific Aim 2 will be to evaluate the protective effect of the anti-HuNoV antibodies in a gnotobiotic pig model that has been shown to recapitulate human HuNoV diarrhea. Pigs will be pre-treated for one day with the active antibodies or control (unimmunized) antibodies, and then will be infected with a large dose of one HuNoV GII.4 variant. The animals’ signs and symptoms of diarrhea will be monitored for an additional seven days, to help us understand both how well the treatment prevented diarrhea, and in those animals that develop diarrhea, how well it minimizes the disease severity or duration. If the project successfully demonstrates significant protection against HuNoV in this model, human safety, tolerability, and effectiveness studies will be performed, ultimately resulting in regulatory approval to use anti-HuNoV IgY to prevent and/or treat HuNoV diarrhea. Such a readily available treatment is expected to significantly reduce human suffering and provide substantial societal benefit, especially among the most vulnerable populations in the US and around the world.