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.

项目概要 来自各种针对 Aβ 病理学的阿尔茨海默病 (AD) 活性疫苗临床试验的数据表明， 这些试验不成功，因为疫苗：(i) 没有诱导有效的抗 Aβ 滴度 患有免疫衰老的免疫老年人体内存在抗体，并且 (ii) 在 AD 中启动得太晚 发病。我们建议最佳的 AD 疫苗配方、佐剂选择和正确的靶向 疾病正确阶段的病理分子对于免疫治疗方法的成功至关重要。 我们基于 MultiTEP 平台技术开发了新型、安全且具有免疫原性的疫苗， 与目前临床试验中使用的疫苗平台相比，具有显着的优势。我们基于 MultiTEP 的疫苗 专为人类免疫而设计，我们在各种 Tg 小鼠中生成的临床前数据， 兔子和猴子表明这些疫苗有可能 (i) 克服 MHC 类别的高度多态性 II 基因，通过激活载体特异性的大量幼稚和记忆 Th 细胞（MultiTEP 平台）； (二) 诱导产生针对 AD 相关病理分子（例如 Aβ/tau）的高滴度抗体，但不针对 AD 相关病理分子 MultiTEP 平台本身； (iii) 在绝大多数情况下产生具有治疗作用的免疫反应 接种疫苗的受试者不会诱导潜在有害的自身反应性 Th 细胞。目前，越来越多的机构 有证据表明，Aβ 病理学在 tau 病理学积累之前和在 认知障碍的最初迹象。重要的是，tau 蛋白而非 Aβ 的积累相关性最强 AD 中认知能力下降。因此，我们假设，虽然抗 Aβ 疫苗接种应该作为 非常早期 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 免疫治疗可用作轻中度 AD 患者的治疗措施。因此， 在此提案中，我们建议对基于 MultiTEP 的治疗性疫苗进行临床前 IND 研究 靶向病理性 Tau 的 N 末端 (AV-1980R)。重要的是，我们的数据表明 AV-1980R 采用新型 cGMP 级 AdvaxCpG 佐剂 (AV-1980R/A) 配制的佐剂可能是安全有效的，因为它 正在诱导治疗性抗体，有效减少接种 Tg 的大脑中总 Tau 和磷酸化 Tau 小鼠不会产生潜在有害的自身反应性细胞免疫反应。综合公布的数据 来自包括我们在内的不同小组以及 AV-1980R/A 的初步结果为 (i) 提供了强有力的支持 根据 FDA 指导生产工程运行（又称首次运行 cGMP）重组蛋白 足以进行安全/毒理学研究； (ii) 完成患病小鼠模型的安全性/毒理学研究 Tau 病和健康兔子，(iii) 生产 cGMP AV-1980R/A，以及 (iv) 获得所有必要的监管 IND 提交文件。获得 FDA 批准的 AV-1980R/A IND 将使我们能够进行首次测试 测试针对 tau N 末端的活性疫苗在 1 期临床试验中的安全性和免疫原性 并为未来2/3期临床试验制定有效的疫苗接种方案。