Amyloid-Beta Oligomer Selective Immunotherapy for Prodromal or Mild

2015年，美国估计有530万人患有阿尔茨海默病， 也是第六大死亡原因，缺乏预防或改变其进展的治疗方法。最新进展 在理解疾病的潜在分子机制中，增强可溶性淀粉样蛋白β的作用， （Aβ）寡聚体作为主要的神经毒素导致急性认知缺陷和进行性认知障碍， 阿尔茨海默病的神经退化然而，目前临床开发中的Aβ免疫疗法 主要靶向Aβ单体或纤维状Aβ物质;无一对可溶性Aβ寡聚体具有选择性。虽然 solanezumab和aducanumab在前驱和/或轻度 阿尔茨海默病患者的治疗益处仍有待证实，且总体上结果为Aβ 临床试验中的免疫疗法令人失望，并表明它们靶向了错误的Aβ种类。 此外，所有结合纤维状Aβ的IgG 1框架中的Aβ免疫疗法均显示ARIA-E不利作用。 临床试验的效果。我们提出了一种针对可溶性Aβ寡聚体的Aβ免疫疗法， 预期比目前正在开发的Aβ免疫疗法显示出上级疗效和更好的安全性。 ACU 193是一种专有的、亲和力成熟的人源化IgG 2单克隆抗体， 可溶性Aβ寡聚体与单体和纤维状Aβ相比，显示出有效的体外和体内疗效。 ACU 193已经在阿尔茨海默病小鼠模型中证明了体内生物化学和行为功效， 穿过血脑屏障，并与脑中的可溶性Aβ寡聚体形成复合物。ACU 193具有 在四种动物种属中具有优异的药代动力学、生物分布和脑渗透特性。 在恒河猴中进行的探索性毒性研究和体外蛋白结合研究显示， ACU 193的配置文件。高产、稳定的细胞系适用于生产ACU 193。ACU 193是一种高度 有前途的IND追踪Aβ免疫疗法，预计可提供急性认知益处， 进展，并且在阿尔茨海默病患者中安全且耐受良好。 本申请的目的是完成临床前化学、生产和控制研究， 毒理学和药代动力学研究，向FDA提交IND档案，然后首先在人体中进行 ACU 193的临床安全性试验ACU 193的人体试验将代表对以下假设的首次检验， 可溶性Aβ寡聚体是阿尔茨海默病的主要分子原因，其结果可能 极大地扩展了对阿尔茨海默病病理生理学的理解。拟定临床 ACU 193的试验包括1a/1b和/2a期安全性、耐受性、药代动力学 ACU 193在前驱期或轻度阿尔茨海默病患者中的药效学和认知作用。

In 2015 in the United States 5.3 million people were estimated to suffer from Alzheimer’s disease, which is also the 6th leading cause of death and lacks treatments to prevent or alter its progression. Recent advances in understanding of the underlying molecular mechanisms of the disease reinforce the role of soluble amyloid-beta (Aβ) oligomers as primary neurotoxins responsible for the acute cognitive deficits and progressive neurodegeneration of Alzheimer’s disease. However, current Aβ immunotherapies in clinical development primarily target Aβ monomers or fibrillic Aβ species; none have selectivity for soluble Aβ oligomers. Although solanezumab and aducanumab have shown some evidence of therapeutic benefit in prodromal and/or mild Alzheimer’s disease patients, therapeutic benefit remains to be confirmed, and on the whole results for Aβ immunotherapies in clinical testing have been disappointing, and indicate they target the wrong Aβ species. Moreover, all Aβ immunotherapies in an IgG1 framework that bind fibrillic Aβ have displayed ARIA-E adverse effects in clinical trials. We propose an Aβ immunotherapy targeting soluble Aβ oligomers that would be expected to display superior efficacy and better safety than Aβ immunotherapies currently in development. ACU193 is a proprietary, affinity matured, humanized, IgG2 monoclonal antibody that has high selectivity for soluble Aβ oligomers versus monomeric and fibrillic Aβ, and shows potent in vitro and in vivo efficacy. ACU193 has demonstrated in vivo biochemical and behavioral efficacy in Alzheimer’s disease mouse models, crosses the blood-brain barrier, and forms complexes with soluble Aβ oligomers in the brain. ACU193 has excellent pharmacokinetics, biodistribution and brain penetration properties in four animal species. Exploratory toxicity studies in rhesus monkeys and in vitro protein binding studies reveal an excellent safety profile for ACU193. A high producing, stable cell line is suitable for production of ACU193. ACU193 is a highly promising IND-track Aβ immunotherapy that is expected to provide acute cognitive benefits, slow disease progression, and be safe and well tolerated in Alzheimer’s disease patients. The aims of this application are to complete pre-clinical chemistry, manufacturing and control studies, toxicology and pharmacokinetic studies, submit an IND dossier to the FDA, and then conduct first in human clinical safety trials for ACU193. Human trials of ACU193 will represent the first test of the hypothesis that soluble Aβ oligomers are the primary molecular cause of Alzheimer’s disease, the results of which may dramatically expand understanding of the pathophysiology of Alzheimer’s disease. The proposed clinical testing of ACU193 consists of Phase 1a/1b and /2a studies of the safety, tolerability, pharmacokinetics, pharmacodynamics and cognitive effects of ACU193 in patients with prodromal or mild Alzheimer disease.