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

抗 Tau AD 疫苗 1 期试验的 IND 临床前研究

• 批准号: 10364623
• 负责人: Michael G Agadjanyan
• 金额: $ 223.8万
• 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/10364623
• 关键词: Adjuvant; Aducanumab; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer' s disease risk; Amyloid beta-Protein; Antibodies; Antibody titer measurement; Antigens; Biomanufacturing; Brain; Cells; Chemistry; Clinical; Clinical Data; Clinical Trials; Cyclic GMP; Data; Disease; Disease Progression; Elderly; Engineering; FDA approved; Formulation; Future; Generations; Genetic Polymorphism; Goals; Human; Immune response; Immunization; Immunize; Immunotherapeutic agent; Impaired cognition; Investigational Drugs; Investigational New Drug Application; Keyhole Limpet Hemocyanin; Liposomes; MHC Class II Genes; Measures; Memory; Monkeys; Mus; Oryctolagus cuniculus; Pathogenesis; Pathologic; Pathology; Patients; Peptides; Persons; Pharmaceutical Preparations; Phase I Clinical Trials; Phase II/III Clinical Trial; Preparation; Preventive measure; Process; Publishing; Recombinant Proteins; Recombinants; Recommendation; Reporting; Research Personnel; Running; Safety; Tauopathies; Technology; Testing; Therapeutic; Therapeutic antibodies; Time; Toxicology; Translating; Vaccinated; Vaccination; Vaccine Clinical Trial; Vaccinee; Vaccines; alpha synuclein; autoreactivity; base; cross reacting material 197; design; immunogenic; immunogenicity; immunosenescence; meetings; mouse model; multidisciplinary; novel; phase I trial; pre-clinical; preclinical study; prodromal Alzheimer' s disease; prophylactic; symptomatic improvement; tau Proteins; tau aggregation; tau-1; therapeutic vaccine; vaccination protocol; vaccine formulation; vaccine platform; vaccine trial

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.

项目摘要 针对Aβ病理学的各种阿尔茨海默病（AD）活性疫苗临床试验数据表明， 这些试验没有成功，因为疫苗：（i）没有诱导治疗有效的抗A β滴度 免疫老年人的免疫衰老和（ii）抗体开始太晚，在AD 发病机制我们认为，最佳的AD疫苗配方，佐剂的选择和靶向的权利， 在疾病的正确阶段的病理分子对于成功的免疫治疗方法至关重要。 我们基于MultiTEP平台技术开发了新型、安全和免疫原性疫苗， 与目前临床试验中使用的疫苗平台相比，提供了实质性的益处。我们的MultiTEP疫苗 是专门为人类免疫而设计的，我们在各种Tg小鼠中产生的临床前数据， 兔和猴的研究表明，这些疫苗可能（i）克服MHC类抗原的高度多态性， II基因通过激活对载体特异性的幼稚和记忆Th细胞的广泛库（MultiTEP平台）;（ii） 诱导高滴度的对AD中涉及的病理分子（例如，Aβ/tau），但不与 MultiTEP平台本身;和（iii）在绝大多数的免疫系统中产生治疗有效的免疫应答。 接种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，Aβ病理在tau病理积累之前多年出现， 认知障碍的初步迹象重要的是，tau蛋白的积累而不是Aβ的积累最强烈地相关。 认知能力下降因此，我们假设，虽然抗A β疫苗接种应作为一种预防措施启动， 极早期AD（前驱期）和/或有AD风险的无症状受试者的预防措施，基于tau 免疫抑制剂可用作轻度-中度AD患者的治疗措施。因此，委员会认为， 在本提案中，我们建议对基于MultiTEP治疗性疫苗进行临床前IND研究 靶向病理性Tau（AV-1980 R）的N-末端。重要的是，我们的数据显示，AV-1980 R 在新型cGMP级AdvaxCpG佐剂（AV-1980 R/A）中配制的药物可能是安全有效的，因为它 诱导治疗性抗体，有效减少接种疫苗的Tg小鼠脑中的总Tau和磷酸化Tau 小鼠而不产生潜在有害的自身反应性细胞免疫应答。总体而言，已发布的数据 包括我们在内的不同小组的研究结果和AV-1980 R/A的初步结果为以下结论提供了有力的支持： 根据FDA指南生产工程运行（又名首次运行cGMP）重组蛋白 （ii）完成在患病小鼠模型中的安全性/毒理学研究， Tauopathy和健康兔，（iii）制造cGMP AV-1980 R/A，和（iv）获得所有必要的调节剂， 提交IND的文件。获得FDA批准的AV-1980 R/A IND将使我们能够测试第一个 在I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的时间 并为未来的2/3期临床试验制定有效的疫苗接种方案。