Departamento de Morfología y Biología Celular, Universidad de Oviedo, Oviedo, Spain.
Curr Pharm Des. 2011;17(5):508-20. doi: 10.2174/138161211795164112.
Amyloid-β (Aβ) immunotherapy has recently begun to gain considerable attention as a potentially promising therapeutic approach to reducing the levels of Aβ in the Central Nervous System (CNS) of patients with Alzheimer's Disease (AD). Despite extensive preclinical evidence showing that immunization with Aβ(1-42) peptide can prevent or reverse the development of the neuropathological hallmarks of AD, in 2002, the clinical trial of AN-1792, the first trial involving an AD vaccine, was discontinued at Phase II when a subset of patients immunized with Aβ(1-42) developed meningoencephalitis, thereby making it necessary to take a more refined and strategic approach towards developing novel Aβ immunotherapy strategies by first constructing a safe and effective vaccine. This review describes the rational basis in modern clinical trials that have been designed to overcome the many challenges and known hurdles inherent to the search for effective AD immunotherapies. The precise delimitation of the most appropriate targets for AD vaccination remains a major point of discussion and emphasizes the need to target antigens in proteins involved in the early steps of the amyloid cascade. Other obstacles that have been clearly defined include the need to avoid unwanted anti-Aβ/APP Th1 immune responses, the need to achieve adequate responses to vaccination in the elderly and the need for precise monitoring. Novel strategies have been implemented to overcome these problems including the use of N-terminal peptides as antigens, the development of DNA based epitope vaccines and vaccines based on passive immunotherapy, recruitment of patients at earlier stages with support of novel biomarkers, the use of new adjuvants, the use of foreign T cell epitopes and viral-like particles and adopting new efficacy endpoints. These strategies are currently being tested in over 10,000 patients enrolled in one of the more than 40 ongoing clinical trials, most of which are expected to report final results within two years.
淀粉样蛋白-β（Aβ）免疫疗法最近作为一种有希望降低阿尔茨海默病（AD）患者中枢神经系统（CNS）中 Aβ 水平的潜在治疗方法引起了广泛关注。尽管有大量临床前证据表明，用 Aβ（1-42）肽免疫可以预防或逆转 AD 的神经病理学特征的发展，但在 2002 年，涉及 AD 疫苗的第一个临床试验 AN-1792 的临床试验在 II 期因接种 Aβ（1-42）的患者子集发生脑膜炎而停止，因此有必要采取更精细和更具战略性的方法来开发新的 Aβ免疫疗法策略，首先构建安全有效的疫苗。
本综述描述了现代临床试验的合理基础，这些临床试验旨在克服寻找有效 AD 免疫疗法所固有的许多挑战和已知障碍。精确限定 AD 疫苗接种的最合适目标仍然是一个主要的讨论点，并强调需要针对涉及淀粉样蛋白级联早期步骤的蛋白质中的抗原进行靶向。已经明确定义的其他障碍包括需要避免不希望的抗 Aβ/APP Th1 免疫反应，需要在老年人中实现对疫苗接种的充分反应，以及需要精确监测。已经实施了新策略来克服这些问题，包括使用 N 端肽作为抗原、开发基于 DNA 的表位疫苗和基于被动免疫疗法的疫苗、在新型生物标志物的支持下招募早期患者、使用新佐剂、使用外国 T 细胞表位和病毒样颗粒以及采用新的疗效终点。
这些策略目前正在 10,000 多名患者中进行测试，这些患者参加了 40 多项正在进行的临床试验中的一项，其中大多数预计将在两年内报告最终结果。
