An immunotherapeutic IgY formulation against norovirus diarrhea

一种针对诺如病毒腹泻的免疫治疗 IgY 制剂

• 批准号: 10693530
• 负责人: Julius G Goepp
• 金额: $ 30万
• 依托单位: SCALED MICROBIOMICS, LLC
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-11 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10693530
• 关键词: Accounting; Acute; Affect; Affinity Chromatography; Age; Allergens; Animals; Antibodies; Antigen Presentation; Antigens; Binding; Biological Assay; Birds; Cattle; Cell model; Cessation of life; Child; Chronic; Chronic diarrhea; Clinical; Colostrum; Complex; Control Groups; Dependence; Development; Diarrhea; Direct Costs; Disease; Dose; Egg Yolk; Evaluation; Evolution; Exposure to; Family member; Family suidae; Formulation; Future; Gastroenteritis; Genetic Recombination; Genotype; Gnotobiotic; Harvest; Hospitalization; Human; IgY; Immune; Immunize; Immunocompromised Host; Immunoglobulin G; Immunoglobulins; Immunotherapeutic agent; In Vitro; Infection; Intervention; Intestines; Investigational New Drug Application; Legal patent; Licensing; Life Style; Medical; Military Personnel; Modeling; Monitor; Monoclonal Antibodies; Morbidity - disease rate; Mutate; Norovirus; Oral; Oral Administration; Passive Immunity; Passive Immunotherapy; Persons; Phase; Population; Populations at Risk; Prevention; Prevention approach; Production; Property; Prophylactic treatment; Proteins; Research; Safety; Serum; Severities; Severity of illness; Signs and Symptoms; Small Business Technology Transfer Research; Standardization; Surface Antigens; System; Tablets; Technology; Therapeutic; Therapeutic Effect; Update; Vaccines; Variant; Viral; Virus Replication; Virus Shedding; Virus-like particle; Vomiting; Vulnerable Populations; Work; aqueous; attributable mortality; burden of illness; capsule; commercial application; cost; cross reactivity; diarrheal disease; disorder prevention; effective intervention; effective therapy; effectiveness study; egg; first-in-human; flexibility; high risk; human model; human subject; illness length; innovation; low and middle-income countries; microbiome research; mutant; nanoparticle; neutralizing antibody; novel; novel strategies; older patient; pathogen; pediatric patients; phase 1 study; phase 2 study; porcine model; prevent; primary outcome; productivity loss; protective effect; secondary outcome; targeted treatment

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.

STTR第一阶段应用的项目总结/摘要：免疫球蛋白IgY制剂 对抗诺如病毒腹泻 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，非常年老的， 免疫力低下目前既没有有效的疫苗，也没有有效的治疗方法。 HuNoV感染使问题更加复杂的是，HuNoV毒株迅速突变， 不可预测的，这可以减少任何靶向治疗的影响时，面对新的 新出现的菌株该提案的长期目标是评估一种新的方法， 预防或治疗HuNoV腹泻：使用从鸡蛋中纯化的抗HuNoV抗体 用代表多种HuNoV毒株的纳米颗粒免疫，以提供“被动免疫” 到肠道。这些抗体被称为“IgY”，以表明它们是来自 蛋黄。申请人已经证明抗HuNoV IgY可以阻止HuNoV病毒 在人类肠道细胞模型中复制，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IgY生产的三个 主要HuNoV病毒基因型GII.4的不同毒株。通过使用所谓的“P24” 代表所有三种菌株的纳米颗粒作为免疫抗原，产生的IgY将靶向 所有这三种变体，提供了一个证据，证明广谱保护可以实现使用廉价的 和容易产生的抗原。一旦抗体被鉴定并且它们的结合能力 该项目的具体目标2将是， 评估抗HuNoV抗体在已被感染的无菌猪模型中的保护作用。 显示重现人HuNoV腹泻。猪将用活性成分预处理一天。 抗体或对照（未免疫的）抗体，然后将感染大剂量的一种 HuNoV GII.4变体。将监测动物的腹泻体征和症状，以进行额外的 七天，以帮助我们了解治疗如何预防腹泻， 发生腹泻的动物，它在多大程度上最大限度地减少了疾病的严重程度或持续时间。如果项目 成功地证明了在该模型中对HuNoV的显著保护，人类安全， 将进行耐受性和有效性研究，最终获得监管机构批准， 使用抗HuNoV IgY预防和/或治疗HuNoV腹泻。这种现成的治疗方法是 预计将大大减少人类痛苦，并提供巨大的社会效益，特别是 在美国和全世界最脆弱的人群中。