Safety/Tolerability/Immunogenicity of first-in-human Aβ DNA vaccine, AV-1959D Phase 1 trials in early-stage AD subjects: based on IND18953 cleared by FDA.

首个人类 Aβ DNA 疫苗的安全性/耐受性/免疫原性，AV-1959D 在早期 AD 受试者中的 1 期试验：基于 FDA 批准的 IND18953。

• 批准号: 10571883
• 负责人: Michael G Agadjanyan
• 金额: $ 240.86万
• 依托单位: INSTITUTE FOR MOLECULAR MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-15 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10571883
• 关键词: AN-1792; Aducanumab; Adverse event; Alzheimer disease prevention; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Amyloid; Amyloid beta-Protein; Antibodies; Antibody Formation; Antibody titer measurement; Attenuated; B-Lymphocyte Epitopes; B-Lymphocytes; Binding; Biological Markers; Blood; Brain; Clinical; Clinical Data; Clinical Trials; Collecting Cell; Control Groups; DNA Vaccines; Data; Detection; Disease; Dose; Double-Blind Method; Early Intervention; Elderly; Enzyme-Linked Immunosorbent Assay; Epitopes; Ethics; Future; Genetic Polymorphism; Goals; Helper-Inducer T-Lymphocyte; Hepatitis B; Human; Immune response; Immunize; Immunotherapeutic agent; Immunotherapy; Impaired cognition; Inflammation; Influenza; Injections; Interferon Type II; Laboratories; MHC Class II Genes; Measures; Memory; Methods; Monkeys; Monoclonal Antibodies; Nucleic Acids; Oryctolagus cuniculus; PADRE 45; Participant; Passive Immunotherapy; Pathologic; Pathologic Processes; Pathology; Patients; Peptides; Peripheral Blood Mononuclear Cell; Persons; Phase; Physical Examination; Placebo Control; Placebos; Populations at Risk; Positron-Emission Tomography; Preparation; Preventive; Preventive measure; Preventive treatment; Preventive vaccine; Publishing; Randomized; Recommendation; Reporting; Risk; Safety; Self Tolerance; Senile Plaques; Serum; Target Populations; Test Result; Testing; Tetanus Toxin; Therapeutic; Time; U-Series Cooperative Agreements; Vaccinated; Vaccination; Vaccine Clinical Trial; Vaccinee; Vaccines; abeta oligomer; active method; autoreactivity; cognitive function; cost; cost effective; design; enzyme linked immunospot assay; first-in-human; follow-up; human monoclonal antibodies; immunogenic; immunogenicity; immunosenescence; intravenous injection; manufacture; mouse model; multidisciplinary; non-demented; novel marker; older patient; patient population; peptide B; peripheral blood; phase 1 study; phase I trial; pre-Investigational New Drug meeting; prevent; primary outcome; programs; prophylactic; response; retinal S antigen peptide M; safety testing; secondary outcome; synthetic peptide; tau Proteins; tau aggregation; treatment arm; vaccine evaluation; vaccine strategy; vaccine trial

Project Summary Recent data from clinical trials with humanized or fully human mAbs targeting Aβ suggest that immunotherapy could clear/reduce brain amyloid plaques and even slow cognitive decline in vaccinated subjects when initiated as a preventive measure. However, passive immunotherapy with even the most effective anti-Aβ mAb is not practical and cost-effective as a preventive measure in healthy subjects due to the need for frequent (monthly) administrations of high concentrations (~800mg IV injections/each time) of this immunotherapeutic in a substantial patient population. At the same time, high doses of mAb frequently (~30%) induce ARIA-E and ARIA- H. In contrast, AD vaccine, similar to the vast majority of vaccines in general, could be very effective when used as a preventive/early intervention measure. Today, only limited results are available from ACC001, CAD106, and UB311 epitope vaccine clinical trials, but fortunately, comprehensive data on AN-1792 are published. These data demonstrated that the AN-1792 vaccine has induced antibodies specific to N-terminus of amyloid in ~19% immunized AD patients without causing ARIA-E and ARIA-H abnormalities. Importantly the follow-up analysis revealed that even after 14 years post-vaccination, the vaccinated subjects were plaque-free, and there was a significant inverse correlation between peripheral blood anti-Aβ antibody titers and the plaque counts. Despite the reduction of Aβ pathology, vaccination did not improve cognitive functions likely due to tau pathology buildup. These data support our long-standing proposal of starting anti-Aβ vaccination with AV-1959D as a prophylactic measure in subjects at risk for AD to inhibit/reduce oligomerization of Aβ and delay downstream pathological processes. However, based on an ethical imperative raised by the FDA during our pre-IND meeting, they recommended us to test our Aβ vaccine AV-1959D in participants with early-stage AD patients prior to initiating the preventive trials in asymptomatic people at risk of MCI/AD. Therefore, here we propose to initiate a Phase 1 safety trial with the first-in-human Aβ DNA vaccine, AV-1959D in early-stage MCI/AD patients based on FDA cleared IND18953 developed under an NIA cooperative agreement (U01 AG048310). Importantly, our vaccine strategy differs from all previous or current vaccines tested in clinical trials, as our approach is based on the very immunogenic and proprietary MultiTEP platform designed for human use and aimed to (i) overcome self- tolerance by inducing Th cell responses to MultiTEP, but not to self-Aβ epitopes; (ii) diminish variability of immune responses due to HLA diversity in humans; (iii) augment anti-Aβ antibody production through activation of both naïve and pre-existing memory Th cells, especially beneficial for elderly patients with immunosenescence. Therefore, in Phase 1 trials, the first-in-human MultiTEP-based DNA vaccine targeting Aβ1-11 B cell epitope should be safe and should induce therapeutically sufficient titers of anti-Aβ antibodies in an appreciable number of vaccinated early stage AD subjects. Our future program includes preventive vaccine trial in asymptomatic people at risk of MCI/AD using only the most immunogenic and safe dose of AV-1959D.

项目概要 针对 Aβ 的人源化或全人单克隆抗体的临床试验的最新数据表明，免疫疗法 可以清除/减少大脑淀粉样斑块，甚至可以减缓空白受试者的认知能力下降 然而，即使是最有效的抗 Aβ 单克隆抗体的被动免疫疗法也不能作为预防措施。 由于需要频繁（每月），作为健康受试者的预防措施实用且具有成本效益 高浓度（约 800 毫克静脉注射/每次）的免疫治疗药物的给药 同时，高剂量的 mAb 经常（约 30%）诱导 ARIA-E 和 ARIA-。 H. 相反，AD 疫苗与绝大多数一般疫苗类似，使用时可能非常有效 作为预防/早期干预措施，ACC001、CAD106 只能提供有限的结果。 和UB311表位疫苗临床试验，但幸运的是，AN-1792的综合数据已发表。 数据表明，AN-1792 疫苗已诱导约 19% 的人产生针对淀粉样蛋白 N 末端的特异性抗体 免疫AD患者不会引起ARIA-E和ARIA-H异常，重要的是后续分析。 研究表明，即使在接种疫苗 14 年后，接种疫苗的受试者也没有出现噬菌斑，并且存在 外周血抗Aβ抗体滴度与斑块计数呈显着负相关。 尽管 Aβ 病理学减少，但疫苗接种并没有改善认知功能，这可能是由于 tau 病理学积累所致。 这些数据支持我们长期以来的建议，即开始使用 AV-1959D 进行抗 Aβ 疫苗接种作为预防措施 对有 AD 风险的受试者进行测量，以抑制/减少 Aβ 寡聚化并延迟下游病理学 然而，根据 FDA 在我们的 IND 前会议上提出的道德要求，他们。 建议我们在开始之前在患有早期 AD 患者的参与者中测试我们的 Aβ 疫苗 AV-1959D 因此，我们建议启动第一阶段。 基于 FDA 的首个人类 Aβ DNA 疫苗 AV-1959D 在早期 MCI/AD 患者中的安全性试验 批准了根据 NIA 合作协议开发的 IND18953（U01 AG048310）。重要的是，我们的疫苗。 策略不同于所有以前或当前在临床试验中测试的疫苗，因为我们的方法基于非常 免疫原性和专有的 MultiTEP 平台专为人类使用而设计，旨在 (i) 克服自我 通过诱导 Th 细胞对 MultiTEP 而非自身 Aβ 表位的反应来增强耐受性；(ii) 减少免疫的变异性； 由于人类 HLA 多样性而产生的反应；(iii) 通过激活两者来增强抗 Aβ 抗体的产生 幼稚和预先存在的记忆 Th 细胞，对于患有免疫衰老的老年患者尤其有益。 因此，在第一阶段试验中，第一个基于 MultiTEP 的人类 DNA 疫苗针对 Aβ1-11 B 细胞表位 应该是安全的，并且应该诱导可观数量的、具有治疗意义的足够滴度的抗 Aβ 抗体 我们未来的计划包括对无症状患者进行预防性疫苗试验。 有 MCI/AD 风险的人仅使用最具免疫原性和安全剂量的 AV-1959D。