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

AD 疫苗在老年非人灵长类动物中的安全和免疫原性剂量评估：第一阶段预防性疫苗接种的前奏

• 批准号: 10433497
• 负责人: Michael G Agadjanyan
• 金额: $ 41.95万
• 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 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10433497
• 关键词: Active Immunotherapy; Adjuvant; Administrative Supplement; Aducanumab; Alzheimer disease prevention; Alzheimer' s disease model; Alzheimer' s disease related dementia; Amyloid; Amyloid beta-42; Amyloid beta-Protein; Antibodies; Antibody titer measurement; B-Lymphocyte Epitopes; B-Lymphocytes; Behavioral; Biochemistry; Biological Assay; Biological Markers; Biological Process; Blood; Brain; C-reactive protein; Clinical; Clinical Data; Clinical Trials; Combined Modality Therapy; Cyclic GMP; Data; Disease; Disease Progression; Disease model; Dose; Early Intervention; Early treatment; Emergency Situation; Enzyme-Linked Immunosorbent Assay; Evaluation; Female; Future; Genetic Polymorphism; Goals; Helper-Inducer T-Lymphocyte; Human; Immune system; Immunization; Immunize; Immunotherapeutic agent; Immunotherapy; In Vitro; Infection; Inflammation; Injections; Interferon Type II; Intramuscular; Longevity; Macaca fascicularis; Memory; Methods; Monitor; Monkeys; Monoclonal Antibodies; Mus; Onset of illness; Paper; Passive Immunotherapy; Pathologic; Pathologic Processes; Pathology; Peripheral Blood Mononuclear Cell; Phase; Preventative vaccination; Preventive; Preventive treatment; Production; Publishing; Recombinant Proteins; Reporting; Research; Risk; Safety; Site; Testing; Therapeutic; Time; TimeLine; Toxic effect; Toxicology; Vaccine Clinical Trial; Vaccines; adaptive immunity; age group; aged; autoreactive T cell; autoreactivity; base; first-in-human; immunogenic; immunogenicity; male; meetings; mouse model; multidisciplinary; multiple omics; non-demented; nonhuman primate; novel; pathogen; phase I trial; pre-clinical; prevent; programs; response; synergism; targeted treatment; tau Proteins; tau aggregation; tau-1; therapy development; treatment strategy; vaccine development; 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 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.

项目概要 免疫疗法仍然被认为是一种非常有前途的 AD 预防治疗策略 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研究 长期坚持的原则是，免疫原性 AD 疫苗至少可以延缓疾病进展 在 AD 之前疾病的早期阶段针对 Aβ 和 Tau 病理分子 表现，甚至在有 AD 风险的无症状健康人群中。近日FDA宣布 紧急加速批准 mAb Aducanumab 用于治疗早期 AD。然而，它是 使用非常昂贵的单克隆抗体作为健康受试者的预防性治疗是不切实际的，因为 需要频繁（每月）注射高浓度（每次静脉注射 700-800 毫克） 这种免疫治疗。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 U01 AG060965 的行政补充中，我们 提议测试针对 Aβ 的双重疫苗 (DUVAC) 的整体安全性和免疫原性 非人类灵长类动物中的 Tau 蛋白与人类免疫系统更相似。这些 数据将支持向 FDA 提交 IND 进行未来的临床试验，这将使我们能够 使用极具免疫原性的 Aβ 和 tau 蛋白治疗有 MCI 风险的无症状健康受试者 基于相同且极具免疫原性的 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 多态性并激活初始 Th 细胞和预先存在的 记忆 Th 细胞响应传统疫苗和/或各种感染而产生 在人的一生中，病原体不会被激活，而有害的自身反应性 T 细胞不会被激活。这些 “非自身”Th 细胞应激活 B 细胞并诱导产生具有治疗作用的有效物质 人类病理性 Aβ 和 Tau 特异性抗体，与非人类灵长类动物相似。 完成老年猴子的研究以及 AG060965 安全性/毒理学研究的数据 患病小鼠应该强烈支持我们提交的首个人类预防性双重临床试验申请（IND） 基于研究血液、脑脊液、大脑，为有 MCI 风险或更早风险的健康人接种 Aβ/tau 疫苗 生物标志物。