Abeta DNA Vaccination for Alzheimer's Disease: Focus on Disease Prevention
Abeta DNA Vaccination for Alzheimer's Disease: Focus on Disease Prevention
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DOI：
10.2174/187152710791012080
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发表时间：
2010-04-01
影响因子：
3
通讯作者：
Cribbs, David H.
中科院分区：
文献类型：
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作者：
Cribbs, David H.
临床前和临床数据表明，开发一种安全有效的抗淀粉样蛋白- β (a β)免疫疗法治疗阿尔茨海默病（AD）将需要治疗水平的抗a β抗体，同时避免促炎佐剂和自身反应性T细胞，这可能会增加老年人群接受免疫治疗的不良事件发生率。AN1792在AD患者中的首次主动免疫临床试验因部分患者出现无菌性脑膜脑炎而停止。首个使用bapineuzumab（一种针对a β末端的人源化单克隆抗体）的被动免疫治疗试验在研究的II期部分也遇到了一些剂量依赖性的不良事件，12例血管源性水肿，这在ApoE4携带者中明显过多。建议的补救措施是用较低剂量治疗未来的患者，特别是ApoE4携带者。目前，至少有五项抗a β免疫疗法正在进行临床试验。其中三个临床试验使用人源化单克隆抗体，这种抗体价格昂贵，需要反复给药以维持患者体内抗体的治疗水平。然而，如果对被动治疗产生不良反应，抗体递送可以简单地停止，这可能提供一个解决问题的方法。因为在这一点上，我们不能轻易地确定个体在阿尔茨海默病发病的临床前或前驱阶段，被动免疫治疗是保留给那些已经有临床症状的人。不幸的是，到那时，这些人在大脑的受影响区域积累了大量的神经病理学。此外，如果在一些转基因动物模型中报道的A β病理驱动tau病理，并且一旦确定tau病理可以自我繁殖，那么抗A β免疫治疗的早期干预可能对良好的临床结果至关重要。另一方面，主动免疫有几个显著的优势，包括较低的成本和典型的免疫方案相对于被动治疗对患者的侵入性要小得多。然而，在A -抗体免疫复合物诱导的不良事件出现时，患者将不得不接受一段较长时间的免疫抑制治疗，直到抗A -抗体水平随着疫苗的作用随着时间的推移而自然下降。显然，需要改进疫苗设计，以提高抗a β免疫疗法的安全性和有效性。本综述的重点是DNA疫苗接种用于抗a β免疫治疗的优势，以及主要障碍，如免疫衰老，适当的分子佐剂的选择，通用T细胞表位，以及可能基于利用普通人群中因儿童或季节性疫苗以及各种感染而产生的现有记忆T细胞的多肽类设计。最终，我们相信进一步完善我们的阿尔茨海默病DNA表位疫苗，可能结合主要的增强方案，将有助于转化为早期阿尔茨海默病的人类临床试验，或者最好是在经验证的阿尔茨海默病生物标志物鉴定的临床前阶段个体。
Pre-clinical and clinical data suggest that the development of a safe and effective anti-amyloid-beta (A beta) immunotherapy for Alzheimer's disease (AD) will require therapeutic levels of anti-A beta antibodies, while avoiding proinflammatory adjuvants and autoreactive T cells which may increase the incidence of adverse events in the elderly population targeted to receive immunotherapy. The first active immunization clinical trial with AN1792 in AD patients was halted when a subset of patients developed aseptic meningoencephalitis. The first passive immunotherapy trial with bapineuzumab, a humanized monoclonal antibody against the end terminus of A beta also encountered some dose-dependent adverse events during the Phase II portion of the study, vasogenic edema in 12 cases, which were significantly over represented in ApoE4 carriers. The proposed remedy is to treat future patients with lower doses, particularly in the ApoE4 carriers. Currently there are at least five ongoing anti-A beta immunotherapy clinical trials. Three of the clinical trials use humanized monoclonal antibodies, which are expensive and require repeated dosing to maintain therapeutic levels of the antibodies in the patient. However, in the event of an adverse response to the passive therapy antibody delivery can simply be halted, which may provide a resolution to the problem. Because at this point we cannot readily identify individuals in the preclinical or prodromal stages of AD pathogenesis, passive immunotherapy is reserved for those that already have clinical symptoms. Unfortunately those individuals have by that point accumulated substantial neuropathology in affected regions of the brain. Moreover, if A beta pathology drives tau pathology as reported in several transgenic animal models, and once established if tau pathology can become self propagating, then early intervention with anti-A beta immunotherapy may be critical for favorable clinical outcomes. On the other hand, active immunization has several significant advantages, including lower cost and the typical immunization protocol should be much less intrusive to the patient relative to passive therapy. However in the advent of A beta antibody immune complex-induced adverse events the patients will have to receive immuno-suppressive therapy for an extended period until the anti-A beta antibody levels drop naturally as the effect of the vaccine decays over time. Obviously, improvements in vaccine design are needed to improve both the safety, as well as the efficacy of anti-A beta immunotherapy. The focus of this review is on the advantages of DNA vaccination for anti-A beta immunotherapy, and the major hurdles, such as immunosenescence, selection of appropriate molecular adjuvants, universal T cell epitopes, and possibly a polyepitope design based on utilizing existing memory T cells in the general population that were generated in response to childhood or seasonal vaccines, as well as various infections. Ultimately, we believe that the further refinement of our AD DNA epitope vaccines, possibly combined with a prime boost regime will facilitate translation to human clinical trials in either very early AD, or preferably in preclinical stage individuals identified by validated AD biomarkers.