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

项目摘要 免疫疗法仍然被认为是预防AD的非常有前途的治疗策略， 满足某些条件。来自各种免疫学研究的数据支持我们的长期- 免疫原性AD疫苗至少可以延缓疾病进展， 在AD之前的疾病早期阶段靶向Aβ和Tau病理分子 表现。使用非常昂贵的单克隆抗体作为健康人的预防性治疗是不切实际的。 由于需要频繁（每月）给予高浓度（700- 800 mg）的受试者 静脉注射）。几乎所有的疫苗都是有效的， 预防性设置。因此，我们寻求对U 01 AG 060965的行政补充， 将支持编制并向FDA提交监管文件，以支持 启动双重预防疫苗的1期临床试验。我们的专利疫苗平台 可以刺激适应性免疫，广泛覆盖人类MHC多态性， 激活初始Th细胞和预先存在的记忆Th细胞， 常规疫苗和/或在人的寿命期间感染各种病原体，而没有 激活有害的自身反应性T细胞。这些“非自身”Th细胞应激活B细胞， 诱导产生特异于病理性Aβ和Tau的治疗有效抗体， 与我们在近交系WT和Tg小鼠以及远交系兔中观察到的相似， 猴子如果在I期试验中安全且具有免疫原性，则AV-1959 R/A和AV-1980 R/A的组合 疫苗可作为预防措施用于有MCI风险的健康人群（基于 生物标志物）以延迟AD。

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.