IND-enabling Preclinical Studies on Anti-Tau AD Vaccine for Phase 1 Trial

项目摘要 针对Aβ病理的各种阿尔茨海默病(AD)活性疫苗临床试验的数据表明 这些试验没有成功，因为疫苗：(I)没有诱导出具有治疗效力的抗A-β滴度 免疫衰老和(Ii)AD患者启动太晚的免疫老年人的抗体 发病机制。我们建议AD疫苗的最佳配方、佐剂的选择和靶向性正确 在疾病的正确阶段，病理分子将是成功的免疫治疗方法的关键。 我们基于多TEP平台技术开发了新型、安全和免疫原性的疫苗， 与目前临床试验中使用的疫苗平台相比，提供了实质性的好处。我们的基于多TEP的疫苗 是专门为人类免疫而设计的，我们的临床前数据是在各种TG小鼠中产生的， 兔和猴子表明这些疫苗潜在地可以(I)克服MHC类的高度多态 通过激活广泛的针对载体的幼稚和记忆Th细胞(多TEP平台)来表达II基因；(Ii) 诱导高滴度的针对AD相关病理分子的抗体(例如，Aβ/tau)，但不针对 多TEP平台本身；以及(Iii)在绝大多数 接种了疫苗的受试者，没有诱导潜在有害的自身反应性Th细胞。目前，越来越多的 有证据表明，β病理在tau病理积累之前多年就出现了，在 认知障碍的第一个迹象。重要的是，tau的积累，而不是Aβ的积累，相关性最强 阿尔茨海默病患者认知功能下降。因此，我们假设，虽然抗A-β疫苗接种应该作为一种 以tau为基础的极早期AD(前驱症状)和/或有AD风险的无症状受试者的预防措施 免疫疗法(S)可作为轻中度AD患者的治疗措施。因此， 在这项建议中，我们建议开展基于多TEP的治疗性疫苗的临床前IND使能研究 靶向病理性Tau的N末端(AV-1980R)。重要的是，我们的数据显示，AV-1980R 在新型cGMP级AdvaxCpG佐剂(AV-1980R/A)中配制的可能是安全有效的，因为它 正在诱导治疗性抗体，有效降低接种甘油三酯后脑内总Tau和磷酸化Tau 不会产生潜在有害的自身反应性细胞免疫反应。总体而言，发布的数据 包括我们在内的不同小组和关于AV-1980R/A的初步结果为(I)提供了强有力的支持 按照FDA指南生产工程RUN(又名First Run cGMP)重组蛋白 足以进行安全性/毒理学研究；(Ii)完成对患病小鼠模型的安全性/毒理学研究 (3)制造cGMP AV-1980R/A；(4)获得所有必要的调节 IND提交的文件。获得FDA批准的AV-1980R/A IND将使我们能够测试第一个 一期临床试验中靶向tau N末端的活性疫苗的安全性和免疫原性 并为未来的2/3期临床试验制定有效的疫苗接种方案。

Project Summary Data from various Alzheimer’s disease (AD) active vaccine clinical trials targeting Aβ pathology suggest that these trials were unsuccessful because the vaccines: (i) did not induce therapeutically potent titers of anti-Aβ antibodies in immunized elderly people with immunosenescence and (ii) were initiated too late in AD pathogenesis. We suggest that an optimal AD vaccine formulation, adjuvant selection and targeting of the right pathological molecules at the right stage of disease will be crucial to a successful immunotherapeutic approach. We have developed novel, safe and immunogenic vaccines, based on the MultiTEP platform technology, that offer substantial benefits over vaccine platforms presently used in clinical trials. Our MultiTEP-based vaccines are specifically designed for the immunization of humans and our pre-clinical data generated in various Tg mice, rabbits, and monkeys suggest that these vaccines potentially can (i) overcome high polymorphism of MHC class II genes by activating a broad repertoire of naïve and memory Th cells specific to carrier (MultiTEP platform); (ii) induce high titers of antibodies specific to pathological molecules involved in AD (e.g., Aβ/tau), but not to the MultiTEP platform itself; and (iii) generate therapeutically potent immune responses in the vast majority of vaccinated subjects without induction of potentially harmful autoreactive Th cells. Currently, a growing body of evidence suggests that Aβ pathology emerges many years before accumulation of tau pathology and before the first signs of cognitive impairment. Importantly, the accumulation of tau rather than Aβ correlates most strongly with cognitive decline in AD. Hence, we hypothesized that while anti-Aβ vaccination should be initiated as a prophylactic measure in very early AD (prodromal) and/or in non-symptomatic subjects at risk for AD, tau-based immunotherapeutic(s) can be used as a therapeutic measure in patients with mild-moderate AD. Accordingly, in this proposal we suggest to conduct pre-clinical IND-enabling studies on MultiTEP-based therapeutic vaccine targeting N-terminus of pathological Tau (AV-1980R). Importantly, our data showed that the AV-1980R formulated in the novel cGMP grade AdvaxCpG adjuvant (AV-1980R/A) is likely to be safe and effective, since it is inducing therapeutic antibodies that efficiently reduce total and phosphorylated Tau in brains of vaccinated Tg mice without generating potentially harmful autoreactive cellular immune responses. Collectively, published data from different groups including ours and preliminary results on AV-1980R/A provide the strong support for (i) manufacturing of engineering run (aka first run cGMP) recombinant protein that is according to FDA guidance is sufficient for safety/toxicology studies; (ii) completing safety/toxicology studies in diseased mouse model of Tauopathy and healthy rabbits, (iii) manufacturing cGMP AV-1980R/A, and (iv) obtaining all necessary regulatory documents for the IND submission. Getting an FDA-cleared IND for AV-1980R/A will allow us to test for the first time the safety and immunogenicity of an active vaccine targeting the N-terminus of tau in Phase 1 clinical trials and develop an effective vaccination protocol for future Phase 2/3 clinical trials.