Immunogenicity, efficacy, safety, and mechanism of action of epitope vaccine (Lu AF20513) for Alzheimer's disease: prelude to a clinical trial.
Immunogenicity, efficacy, safety, and mechanism of action of epitope vaccine (Lu AF20513) for Alzheimer's disease: prelude to a clinical trial.
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DOI：
10.1523/jneurosci.4672-12.2013
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发表时间：
2013-03-13
期刊：
影响因子：
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通讯作者：
Agadjanyan MG
中科院分区：
文献类型：
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作者：
Davtyan H;Ghochikyan A;Petrushina I;Hovakimyan A;Davtyan A;Poghosyan A;Marleau AM;Movsesyan N;Kiyatkin A;Rasool S;Larsen AK;Madsen PJ;Wegener KM;Ditlevsen DK;Cribbs DH;Pedersen LO;Agadjanyan MG
阿尔茨海默病（AD）过程被理解为涉及淀粉样蛋白斑块和tau缠结在脑中的积累。然而，迄今为止，针对主要罪魁祸首神经毒性Aβ肽的尝试被证明无法改善认知功能。最近被动给予抗A β抗体的临床试验未能减缓轻中度AD患者的认知功能下降，但表明免疫治疗方法可能对轻度AD患者有效。在AD小鼠模型（Tg 2576）中，我们测试了临床级Lu AF 20513疫苗的免疫原性（细胞和体液免疫应答）和功效（AD样病理学）。Lu AF 20513诱导了强有力的“非自身”T细胞应答和抗A β抗体的产生，其减少了Tg 2576小鼠脑中的AD样病理学，而不诱导小胶质细胞活化和增强星形细胞增多或CAA。重要的是，用Lu AF 20513的单次免疫在具有预先存在的记忆Th细胞的小鼠中诱导强的体液免疫。此外，Lu AF 20513在豚鼠和猴子中诱导强烈的体液应答。总的来说，这些数据表明Lu AF 20513转化为临床环境，目的是（i）在患有轻度AD的患者中诱导治疗有效的抗A β抗体应答，特别是如果他们具有在用常规破伤风类毒素疫苗免疫后产生的记忆Th细胞;（ii）排除可能的病理性自身反应性T细胞应答。
Alzheimer’s disease (AD) process is understood to involve the accumulation of amyloid plaques and tau tangles in the brain. However, attempts at targeting the main culprits, neurotoxic Aβ peptides, have thus far proven unsuccessful for improving cognitive function. Recent clinical trials with passively administrated anti-Aβ antibodies failed to slow cognitive decline in mild-moderate AD patients, but suggest that an immunotherapeutic approach could be effective in patients with mild AD. In an AD mouse model (Tg2576) we tested the immunogenicity (cellular and humoral immune responses) and efficacy (AD-like pathology) of clinical grade Lu AF20513 vaccine. Lu AF20513 induces robust “non-self” T cell responses and production of anti-Aβ antibodies that reduce AD-like pathology in the brains of Tg2576 mice without inducing microglial activation and enhancing astrocytosis or CAA. Importantly, a single immunization with Lu AF20513 induces strong humoral immunity in mice with pre-existing memory Th cells. In addition, Lu AF20513 induces strong humoral responses in guinea pigs and monkeys. Collectively, these data suggest translation of Lu AF20513 to clinical setting with aims to (i) induce therapeutically potent anti-Aβ antibody responses in patients with mild AD, particularly if they have memory Th cells generated after immunizations with conventional Tetanus Toxoid vaccine; (ii) exclude likely pathological autoreactive T cell responses.