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氏症，即 也是第六大死因，缺乏预防或改变其进展的治疗。最新进展 在理解疾病的潜在分子机制方面加强了可溶性淀粉样β蛋白的作用 (aβ)寡聚体是导致急性认知障碍和进行性认知障碍的主要神经毒素 阿尔茨海默病的神经退行性变。然而，目前A-β免疫疗法在临床上的发展 主要针对Aβ单体或纤维Aβ物种；没有一种对可溶性Aβ齐聚物具有选择性。虽然 Solanezumab和aducanumab已经显示出对前驱症状和/或轻度的治疗效果的一些证据。 阿尔茨海默病患者的治疗效益有待确认，总体结果为Aβ 临床测试中的免疫疗法一直令人失望，表明它们针对的是错误的Aβ物种。 此外，所有在免疫球蛋白1框架内与纤维蛋白Aβ结合的Aβ免疫疗法都显示出ARIA-E不良反应 临床试验中的效果。我们提出了一种针对可溶性Aβ寡聚体的Aβ免疫疗法，该疗法将 预计将显示出比目前正在开发的Aβ免疫疗法更好的疗效和更好的安全性。 ACU193是一种专有的、亲和力成熟的人源化IgG2单抗，对 可溶性Aβ寡聚体与单体和纤维Aβ相比，在体外和体内显示出强大的疗效。 ACU193已经在阿尔茨海默病小鼠模型中展示了体内生化和行为效果， 穿过血脑屏障，与脑内可溶性A-β寡聚体形成复合体。ACU193有 在四种动物体内具有良好的药代动力学、生物分布和脑渗透特性。 对恒河猴的探索性毒性研究和体外蛋白质结合研究显示了极好的安全性 ACU193的配置文件。一个高产、稳定的细胞系适合ACU193的生产。ACU193是一种高度 有望提供急性认知益处、延缓疾病的Ind-Track Aβ免疫疗法 在阿尔茨海默病患者中，该药的安全性和耐受性良好。 该应用程序的目标是完成临床前化学、制造和对照研究， 毒理学和药代动力学研究，向FDA提交IND档案，然后首先在人类身上进行 ACU193的临床安全性试验。ACU193的人体试验将是对这一假设的第一次检验 可溶性Aβ寡聚体是阿尔茨海默病的主要分子病因，其结果可能是 极大地扩展了对阿尔茨海默病的病理生理学的理解。建议的临床 ACU193的测试包括1a/1b和/2a阶段的安全性、耐受性、药代动力学、 ACU193在先兆或轻度阿尔茨海默病患者中的药效学和认知效应。

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.