Cooperative program U01 AG060965 Supplement: "Preparation of IND for Dual Aβ/Tau AD Vaccine for submission to FDA"

合作计划 U01 AG060965 补充：“双 Aβ/Tau AD 疫苗 IND 的准备以提交给 FDA”

• 批准号: 10505652
• 负责人: Michael G Agadjanyan
• 金额: $ 29.77万
• 依托单位: INSTITUTE FOR MOLECULAR MEDICINE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10505652
• 关键词: Adjuvant; Administrative Supplement; Alzheimer disease prevention; Alzheimer' s disease model; Amyloid beta-Protein; Antibodies; B-Lymphocytes; Biological; Biological Markers; Cells; Certification; Chemicals; Chemistry; Clinical Data; Clinical Protocols; Clinical Research; Cyclic GMP; Data; Disease; Disease Progression; Genetic Polymorphism; Goals; Guidelines; Human; Immunotherapeutic agent; Immunotherapy; Inbreeding; Infection; Inflammation; Injections; Instruction; Investigation; Investigational Drugs; Investigational New Drug Application; Longevity; Memory; Monkeys; Monoclonal Antibodies; Mus; Nerve Degeneration; Neurologist; Oryctolagus cuniculus; Pamphlets; Pathologic; Pathologic Processes; Persons; Pharmaceutical Preparations; Pharmacology and Toxicology; Phase I Clinical Trials; Placebos; Preparation; Preventive; Preventive measure; Preventive treatment; Preventive vaccine; Product Labeling; Production; Psychiatrist; Publishing; Reporting; Research Personnel; Risk; Safety; Scientist; Specialist; Therapeutic; Toxic effect; Toxicology; Vaccines; adaptive immunity; autoreactive T cell; base; cGMP production; disorder risk; immunogenic; immunogenicity; medication safety; mouse model; nonhuman primate; pathogen; phase I trial; pre-clinical; preclinical study; programs; response; tau Proteins; vaccine evaluation; vaccine platform; vaccine trial

Project Summary Immunotherapy is still considered a very promising therapeutic strategy for AD prevention when certain conditions are met. Data from various immunotherapeutic studies support our long- standing tenet that immunogenic AD vaccines could at least delay disease progression when they target both Aβ and Tau pathological molecules at an early stage of the disease before AD manifestation. It is impractical to use very expensive mAbs as a preventive treatment of healthy subjects due to the need for frequent (monthly) administration of high concentrations (700-800mg per IV injection) of this immunotherapeutic. In contrast, almost all vaccines are effective in preventive settings. Accordingly, we seek an administrative supplement to U01 AG060965 that will support the preparation and submission of regulatory documents to the FDA to support the initiation of Phase 1 clinical trial of the dual preventive vaccine. Our proprietary vaccine platform can stimulate adaptive immunity, providing broad coverage of human MHC polymorphisms and activating both naive Th cells and pre-existing memory Th cells generated in response to conventional vaccines and/or infections with various pathogens during one's lifespan without the activation of harmful autoreactive T cells. These "non-self" Th cells should activate B cells and induce the production of therapeutically potent antibodies specific to pathological Aβ and Tau in humans similar to that we observed in inbred WT and Tg mice as well as outbred rabbits and monkeys. If safe and immunogenic in Phase 1 trials, the combined AV-1959R/A, and AV-1980R/A vaccines could be used as a preventive measure in healthy people at risk of MCI (based on biomarkers) to delay AD.

项目摘要 免疫疗法仍然被认为是预防阿尔茨海默病的一种非常有前途的治疗策略 满足某些条件。来自各种免疫治疗研究的数据支持我们的长期- 坚持的原则是，免疫原性AD疫苗至少可以延缓疾病的进展，当它们 在AD之前的疾病早期阶段同时靶向Aβ和Tau病理分子 显化。用非常昂贵的单抗作为健康的预防性治疗是不切实际的。 受试者需要经常(每月)服用高浓度药物(700-800毫克 每次静脉注射)这种免疫疗法。相比之下，几乎所有的疫苗都有效 预防性设置。因此，我们要求对U01 AG060965作出行政补充，即 将支持编写并向FDA提交监管文件，以支持 启动双重预防疫苗的第一阶段临床试验。我们的专有疫苗平台 可以刺激适应性免疫，提供广泛的人类MHC基因多态和 激活幼稚的Th细胞和预先存在的记忆Th细胞 在一个人的一生中接种常规疫苗和/或感染各种病原体 激活有害的自身反应性T细胞。这些“非自身”Th细胞应该能激活B细胞并 诱导小鼠产生抗病理Aβ和Tau的治疗性抗体 与我们在近交系WT和TG小鼠以及近交系兔子和Tg小鼠中观察到的人类相似 猴子。如果在第一阶段试验中是安全的和免疫原性的，则联合使用AV-1959R/A和AV-1980R/A 疫苗可以作为预防措施用于有MCI风险的健康人(基于 生物标志物)来延缓AD。