Evaluation of Safe and Immunogenic Dose of AD Vaccine in aged non-human primates: Prelude to Phase 1 Preventive Vaccinations

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，甚至在无症状的健康人在AD的风险。FDA最近宣布， 紧急加速批准mAb Aducanumab用于治疗早期AD。但据 使用非常昂贵的mAb作为健康受试者的预防性治疗是不切实际的， 需要频繁（每月）给予高浓度（700- 800 mg/IV注射）的 这种免疫力。相比之下，几乎所有有效的疫苗在使用时都是有效的 作为预防性治疗。因此，在U 01 AG 060965的行政补充中，我们 拟检测靶向Aβ的双联疫苗（DUVAC）的总体安全性和免疫原性 和Tau在非人类灵长类动物中更接近于人类免疫系统。这些 数据将支持向FDA提交IND，用于未来的临床试验， 用极免疫原性Aβ和tau治疗有MCI风险的无症状健康受试者 基于相同和非常免疫原性的MultiTEP平台和新型佐剂的疫苗 AdvaxCpG。我们专有的疫苗平台可以刺激适应性免疫，提供广泛的 覆盖人类MHC多态性并激活幼稚Th细胞和预先存在的Th细胞， 响应于常规疫苗和/或各种感染而产生的记忆Th细胞 病原体在一个人的寿命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细胞并诱导产生治疗上有效的 人类中对病理性Aβ和Tau具有特异性的抗体，类似于非人灵长类动物中的抗体。 沿着在老年猴中完成研究，并获得AG 060965安全性/毒理学研究的数据， 患病小鼠应该强烈支持我们的IND提交的第一个在人类预防双重 Aβ/tau疫苗用于有MCI或更早风险的健康人群，基于研究血液、CSF、脑 生物标志物。

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 or even in asymptomatic healthy people at risk of AD. Recently FDA announced emergency accelerated approval of mAb Aducanumab for treatment of early AD. However, 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 effective vaccines are effective when they are used as a preventive treatment. Accordingly, in this administrative supplement to U01 AG060965, we propose to test the overall safety and immunogenicity of a dual vaccine (DUVAC) targeting Aβ and Tau in non-human primates that more closely resemble the human immune system. These data will support the submission of INDs to the FDA for future clinical trials that will allow us to treat asymptomatic healthy subjects at risk to MCI with extremely immunogenic Aβ and tau vaccines based on the same and very immunogenic MultiTEP platform and novel adjuvant AdvaxCpG. 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 in non-human primates. Completing studies in aged monkeys along with data from AG060965 safety/toxicology studies in diseased mice should strongly support our IND submission for the first-in-human preventive dual Aβ/tau vaccine with healthy people at risk of MCI or earlier based on research blood, CSF, brain biomarkers.