Developing novel immunogens for a safe and effective Alzheimer's disease vaccine.
Developing novel immunogens for a safe and effective Alzheimer's disease vaccine.
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DOI：
10.1016/s0079-6123(09)17506-4
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发表时间：
2009
影响因子：
--
通讯作者：
Lemere, Cynthia A.
中科院分区：
文献类型：
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作者：
Lemere, Cynthia A.
关键词：
阿尔茨海默病（AD）是神经变性的最普遍形式;然而，预防或治疗AD的疗法是不足的。β-淀粉样蛋白（Aβ）在皮质老年斑中积累，这是AD的关键神经病理学标志之一，并且在少数携带某些基因突变的家族中的早发性AD患者的脑中升高，进一步暗示其在这种毁灭性神经系统疾病中的作用。此外，可溶性Aβ寡聚体已被证明对神经元功能有害。目前正在开发旨在降低脑Aβ水平的治疗策略。一种策略是用Aβ肽免疫AD患者，使他们产生与Aβ蛋白结合并增强其清除的抗体。截至1999年，Aβ免疫治疗（通过Aβ肽主动免疫或通过Aβ特异性抗体被动转移）已显示可降低脑Aβ水平，改善AD小鼠模型的认知缺陷，并降低非人灵长类动物的斑块负荷。然而，一项使用全长人Aβ1-42肽和强Th 1偏向性佐剂QS-21的主动免疫II期临床试验于2002年提前结束，因为入组研究的约6%的AD患者发生脑膜脑炎。可能是T细胞将人全长Aβ肽识别为自身蛋白，在这些患者中诱导了不良自身免疫反应。虽然只有约20%的免疫患者产生抗A β滴度，但应答者显示认知能力下降总体减缓。在几名免疫患者的脑组织中观察到没有Aβ斑块的局灶性皮质区域，这些患者后来进行了尸检。为了避免有害的免疫应答，正在研究通过每月静脉注射人源化Aβ单克隆抗体对AD患者进行被动Aβ免疫治疗。然而，一种安全有效的活性Aβ疫苗将更具成本效益，更容易为更大的AD人群提供。我们开发了几种新型短Aβ免疫原，它们靶向含有强B细胞表位的Aβ N端，同时避免含有T细胞表位的Aβ中部区域和C端。这些免疫原包括树枝状聚合物Aβ1-15（赖氨酸抗原树上的16个Aβ1-15拷贝）、2xAβ1-15（两个赖氨酸连接的Aβ1-15肽的串联重复序列）和2xAβ1-15（添加三个氨基酸的RGD基序）（R-2xAβ1-15）。在AD转基因小鼠模型中，用我们的短Aβ片段免疫原和粘膜佐剂突变型大肠杆菌不耐热肠毒素LT（R192 G）鼻内免疫导致脑Aβ水平降低、斑块沉积和神经胶质增生，以及血浆Aβ水平升高和认知改善。在非人类灵长类动物中进行的临床前试验以及使用类似Aβ免疫原的人类临床试验目前正在进行中。Aβ免疫疗法看起来很有前途，但必须使其在老年人中产生抗体滴度方面更安全，更有效。人们希望这些新型免疫原能在广泛人群中增强Aβ抗体的产生，并避免早期临床试验中出现的不良事件。
Alzheimer’s disease (AD) is the most prevalent form of neurodegeneration; however, therapies to prevent or treat AD are inadequate. Amyloid-beta (Aβ) protein accrues in cortical senile plaques, one of the key neuropathological hallmarks of AD, and is elevated in brains of early onset AD patients in a small number of families that bear certain genetic mutations, further implicating its role in this devastating neurological disease. In addition, soluble Aβ oligomers have been shown to be detrimental to neuronal function. Therapeutic strategies aimed at lowering cerebral Aβ levels are currently under development. One strategy is to immunize AD patients with Aβ peptides so that they will generate antibodies that bind to Aβ protein and enhance its clearance. As of 1999, Aβ immunotherapy, either through active immunization with Aβ peptides or through passive transfer of Aβ-specific antibodies, has been shown to reduce cerebral Aβ levels and improve cognitive deficits in AD mouse models and lower plaque load in nonhuman primates. However, a Phase II clinical trial of active immunization using full-length human Aβ1-42 peptide and a strong Th1-biased adjuvant, QS-21, ended prematurely in 2002 because of the onset of meningoencephalitis in ~6% of the AD patients enrolled in the study. It is possible that T cell recognition of the human full-length Aβ peptide as a self-protein may have induced an adverse autoimmune response in these patients. Although only ~20% of immunized patients generated anti-Aβ titers, responders showed some general slowing of cognitive decline. Focal cortical regions devoid of Aβ plaques were observed in brain tissues of several immunized patients who have since come to autopsy. In order to avoid a deleterious immune response, passive Aβ immunotherapy is under investigation by administering monthly intravenous injections of humanized Aβ monoclonal antibodies to AD patients. However, a safe and effective active Aβ vaccine would be more cost-effective and more readily available to a larger AD population. We have developed several novel short Aβ immunogens that target the Aβ N-terminus containing a strong B cell epitope while avoiding the Aβ mid-region and C-terminus containing T cell epitopes. These immunogens include dendrimeric Aβ1-15 (16 copies of Aβ1-15 on a lysine antigen tree), 2xAβ1-15 (a tandem repeat of two lysine-linked Aβ1-15 peptides), and 2xAβ1-15 with the addition of a three amino acid RGD motif (R-2xAβ1-15). Intranasal immunization with our short Aβ fragment immunogens and a mucosal adjuvant, mutant Escherichia coli heat-labile enterotoxin LT(R192G), resulted in reduced cerebral Aβ levels, plaque deposition, and gliosis, as well as increased plasma Aβ levels and improved cognition in a transgenic mouse model of AD. Preclinical trials in nonhuman primates, and human clinical trials using similar Aβ immunogens, are now underway. Aβ immunotherapy looks promising but must be made safer and more effective at generating antibody titers in the elderly. It is hoped that these novel immunogens will enhance Aβ antibody generation across a broad population and avoid the adverse events seen in the earlier clinical trial.