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.

项目摘要 针对Aβ的人源化或全人化单抗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，甚至延缓接种疫苗的受试者的认知能力下降 作为一种预防措施。然而，即使是最有效的抗Aβ单抗的被动免疫治疗也不是 由于需要经常(每月)，作为健康受试者的一种预防措施，实用且成本效益高 给予高浓度(~800 mg静脉注射/次)这种免疫治疗药物 相当多的病人。同时，高剂量单抗经常(~30%)诱发ARIA-E和ARIA-E。 H.相比之下，AD疫苗与绝大多数疫苗相似，在使用时可能非常有效 作为预防/早期干预措施。今天，来自ACC001、CAD106、 和UB311表位疫苗临床试验，但幸运的是，关于AN-1792的全面数据已经公布。这些 数据表明，AN-1792疫苗诱导的针对淀粉样蛋白N末端的抗体在~19% 对AD患者进行免疫，不会导致ARIA-E和ARIA-H异常。重要的是后续分析 据透露，即使在疫苗接种后14年，接种疫苗的受试者也没有斑块，而且有 外周血抗Aβ抗体效价与斑块计数呈显著负相关。尽管 Aβ病理的减少，接种疫苗并没有改善认知功能，这可能是由于tau病理堆积所致。 这些数据支持我们长期以来提出的以AV-1959D作为预防性疫苗开始接种抗A-β疫苗的建议 在AD高危人群中检测抑制/减少Aβ寡聚并延缓下游病理 流程。然而，基于FDA在IND前会议上提出的道德要求，他们 建议我们在启动之前在早期AD患者中测试我们的Aβ疫苗AV-1959D 在无症状的MCI/AD风险人群中进行的预防性试验。因此，在这里，我们建议启动第一阶段 基于食品和药物管理局的首例人AβDNA疫苗AV-1959D在早期心肌梗死/AD患者中的安全性试验 批准了根据NIA合作协议(U01 AG048310)开发的IND18953。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，因为我们的方法是基于 专为人类设计的免疫原性和专有多TEP平台，旨在：(I)克服自身 通过诱导Th细胞对多TEP的反应而不是对自身Aβ表位的耐受；(Ii)减少免疫的变异性 人类白细胞抗原多样性引起的应答；(Iii)通过激活两者来增加抗-Aβ抗体的产生 幼稚和预先存在的记忆Th细胞，尤其有利于免疫衰老的老年患者。 因此，在第一阶段试验中，第一个针对A-β1-11 B细胞表位的人多TEP DNA疫苗 应该是安全的，并应该诱导相当数量的抗Aβ抗体在治疗上达到足够的滴度 早期AD受试者接种疫苗。我们未来的计划包括无症状的预防性疫苗试验 有MCI/AD风险的人只使用最具免疫原性和安全剂量的AV-1959D。

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.