Development of a non-fibrillic amyloid-beta oligomer selective positron emission tomography imaging diagnostic for Alzheimer.

据估计，2015年美国有530万人患有阿尔茨海默病(AD)， 有高达50%的人没有得到诊断(阿尔茨海默氏症协会，2015年)。提出了AD的三个阶段 (美国国家老龄化研究所和阿尔茨海默病协会，2011年)：临床前AD，轻度认知障碍 (MCI)由AD引起，以及由AD引起的痴呆症。临床前阶段被建议在20年前或更长时间开始。 症状出现。今天，许多研究人员认为减缓或阻止阿尔茨海默病的治疗将是最有效的 如果在临床前或MIC阶段给药。然而，需要新的生物标记物测试来确定 处于这些早期阶段的个体。这些生物标记物测试对于监测治疗效果也是必不可少的。 目前AD的生物标志物测试是基于总淀粉样β蛋白(Aβ)水平，主要是单体，在 脑脊液中tau和磷酸化tau的水平，或纤维淀粉样斑块的水平 在大脑里。然而，许多研究人员现在认为非纤维Aβ齐聚物(Aβo)与 单体或FiBric Aβ，作为主要的Aβ毒素，导致急性认知障碍和慢性 AD的神经元变性(tau异常、突触丢失、氧化损伤等)。一种非侵入性 检测和定量Aβo的方法可为早期AD患者的识别提供有价值的生物标志物 并用于监测治疗的效果。初步研究表明，Aβo选择性抗体-正电子 发射断层扫描探针可实现体内Aβo的检测和定量。 ACU193是一种专有的、亲和力成熟的、人源化的、具有高选择性的单抗 对于Aβo和单体和Fiillic A。在AD小鼠模型中，ACU193跨越血脑屏障并 在大脑中与Ao形成复合体。ACU193具有良好的药代动力学、生物分布和脑功能 四种动物的渗透率。蛋白质结合研究显示Aβ具有极好的选择性。 对猴子的毒性研究显示，ACU193具有极好的安全性。因此，ACU193是一个理想的候选者 为了测试Aβo抗体正电子发射体层析探针在体内检测和定量Aβo的潜在效用。 这一阶段STTR应用的目标是制备和优化ACU193-PET探针和 证明它在体外提供了一种灵敏和选择性的来自转基因AD小鼠的βo依赖信号 模型组织和人AD模型脑组织。潜在的假设是，一个敏感且高度A的βo 用64Cu标记的ACU193可以制作选择性的PET探针。如果体外灵敏度和选择性是 完成后，第一阶段研究还将评估该探针在转基因AD小鼠体内的敏感性 模式。这一计划的全面成功将为检测和量化提供一种非侵入性方法 体内的βo，并支持将其开发为AD诊断工具，用于监测疾病进展和 作为一种研究工具，能够更好地了解阿尔茨海默病的病因。

In the United States in 2015 an estimated 5.3 million people suffered from Alzheimer’s disease (AD), with as many as 50% being undiagnosed (Alzheimer’s Association 2015). Three stages of AD are proposed (National Institute on Aging and the Alzheimer’s Association 2011): preclinical AD, mild cognitive impairment (MCI) due to AD, and dementia due to AD. The preclinical stage is proposed to begin 20 or more years before symptoms appear. Today, many researchers believe that treatments to slow or stop AD will be most effective if administered during the preclinical or MIC stages. However, new biomarker tests are needed to identify individuals at these early stages. These biomarker tests will also be essential for monitoring treatment effects. Current biomarker tests for AD are based on the levels of total amyloid beta (Aβ), mainly monomer, in cerebrospinal fluid (CSF), levels of tau and phosphorylated tau in CSF, or the levels of fibrillic amyloid plaques in the brain. However, many researchers now regard non-fibrillic Aβ oligomers (Aβo), in contrast to monomeric or fibrillic Aβ, as the primary Aβ toxins that cause acute cognitive deficits and induce the chronic neuronal degeneration of AD (tau abnormalities, synapse loss, oxidative damage, etc.). A non-invasive method to detect and quantify Aβo could provide a valuable biomarker test to identify early stage AD patients and for monitoring the effect of therapies. Preliminary studies suggest that an Aβo selective antibody-positron emission tomography (PET) probe may enable the in vivo detection and quantification of Aβo. ACU193 is a proprietary, affinity matured, humanized, monoclonal antibody exhibiting high selectivity for Aβo versus monomeric and fibrillic A. In AD mouse models, ACU193 crosses the blood-brain barrier and forms complexes with Ao in the brain. ACU193 exhibits excellent pharmacokinetics, biodistribution and brain penetration in four animal species. Protein binding studies show excellent selectivity for Aβo. Exploratory toxicity studies in monkeys reveal an excellent safety profile for ACU193. Thus, ACU193 is an ideal candidate for testing the potential utility of an Aβo antibody PET probe for the in vivo detection and quantification of Aβo. The objective of this Phase 1 STTR application is to prepare and optimize an ACU193-PET probe and demonstrate that it provides a sensitive and selective in vitro Aβo-dependent signal from transgenic AD mouse model tissues and human AD brain tissues. The underlying hypothesis is that a sensitive and highly Aβo selective PET probe can be made using ACU193 labeled with 64Cu. If in vitro sensitivity and selectivity are achieved, the Phase 1 study will also evaluate the sensitivity of the probe in vivo in a transgenic AD mouse mode. Overall success in this program would provide a non-invasive method for detecting and quantifying Aβo in vivo, and support its development as an AD diagnostic tool for monitoring disease progression and the effects of treatment and as a research tool that would enable a better understanding of the etiology of AD.