Bispecific Antibody-Based PET Ligands for Imaging Tauopathies

项目总结 阿尔茨海默病(AD)的特征是两种主要蛋白质--淀粉样β蛋白的错误折叠和聚集 (aβ)和tau。虽然β聚集在临床症状之前几年就发生了，但tau在大脑中的积累是 与神经元死亡更密切相关，最终导致认知功能丧失。此外，tau还 在其他痴呆中也可发现包涵体，如额颞叶痴呆和皮质基底膜变性。 因此，体内成像tau的能力将对临床诊断和评估tau-2的疗效具有重要意义。 有针对性的治疗。早期用于放射成像的候选放射性配基一直基于小的- 分子药物化合物；然而，这些放射性配体表现出很大程度的脱靶结合和 除AD外，痴呆患者无法与tau结合。另一方面，单链可变型抗体 片段(ScFv)作为治疗或诊断正电子发射断层扫描(PET)的标志物具有很大的吸引力 更强的特异性和高亲和力结合。一种β斑块成像探针源于β-Sheet结合染料 已经在临床上使用，一些这样的tau结合染料正在被评估用于癌症检测。抗体- 衍生的探针可能为检测tau损伤提供更高的特异性；然而，它们的大脑质量很差 外透性限制了它们作为PET配体的使用，用于对中枢神经系统内的目标进行成像。此前，我们有 成功地证明了抗体ScFv可以通过血脑屏障(BBB)运输 通过与转铁蛋白受体(TFR)的相互作用，以及基于双特异性抗体的PET TfR片段与A-β抗体融合形成的配体能够检测A-β聚集体 活体，野生型和野生型之间在数量和视觉上的大脑吸收都有明显的差异 转基因小鼠，与Aβ病理有很好的相关性。事实上，我们的人性化形式(BAN2401) 先前开发的单抗mAb158首次在IIb期显示出有希望的结果 作为抗Aβ治疗AD的临床试验，由于其对可溶性Aβ原纤维具有独特的选择性。因此，在 在这项提议中，我们将首次应用相同的策略来创建基于双特异性抗体的PET 用于选择性活体成像的配体。在此应用程序中，我们组建了一个团队 来自美国和瑞典的专家和我们建议在我们的经验基础上开发、评估 以及翻译PET tau探针以基于其PET来优先处理初始tau抗体配基集合 并选择两种最佳的tau抗体配体用于后续的判别 在tau动物模型中的评价。也就是说，我们将确定它们作为生物标志物的能力，以提供有意义的 在动物模型中评估目标参与度。研究团队拥有广泛的、多学科的 在化学、生物化学、药理学、神经成像、tau抗体、tau动物模型、状态- 最先进的体外和体内方法学，以及药物发现和开发。该团队还拥有专业知识 用于转译研究；例如，根据GMP指南进行研究，以获得用于临床测试的IND。

PROJECT SUMMARY Alzheimer's disease (AD) is characterized by misfolding and aggregation of two major proteins, amyloid-beta (Aβ) and tau. While Aβ aggregation occurs years before clinical symptoms, tau accumulation in the brain is more closely correlated to the neuronal death and eventually the loss of cognitive function. In addition, tau inclusions are also found in other dementias, such as frontotemporal dementias and corticobasal degeneration. Thus, the ability to in vivo image tau would be important for clinical diagnosis and to evaluate effects of tau- targeted treatments. Earlier candidate radioligands for imaging tauopathies have been based on small- molecule drug compounds; however, these radioligands have displayed large degrees of off-target binding and an inability to bind to tau in dementias other than AD. On the other hand, single-chain variable antibody fragments (scFv) are attractive as therapy or diagnostic positron emission tomography (PET) markers for their greater specificity and high-affinity binding. Aβ plaque imaging probes derived from β-sheet binding dyes are already in clinical use, and a few such tau-binding dyes are being evaluated for cancer detection. Antibody- derived probes are likely to provide greater specificity for detecting tau lesions; however, their poor brain penetrance has restricted their use as PET ligands for imaging of targets within the CNS. Previously, we have successfully demonstrated that the transport of antibody scFv across the blood-brain barrier (BBB) can be facilitated through interaction with the transferrin receptor (TfR), and that the bispecific antibody-based PET ligands generated by fusion of fragments of TfR and Aβ antibodies were capable of detecting Aβ aggregates in vivo with distinctive differences, both quantitatively and visually, in brain uptake between wild type and transgenic mice, and with a good correlation with Aβ pathology. In fact, a humanized form (BAN2401) of our previously developed monoclonal antibody mAb158 showed promising results, for the first time, in a Phase IIb clinical trial as an anti-Aβ therapy against AD due to its distinctive selectivity for soluble Aβ protofibrils. Thus, in this proposal we will apply the same strategy to create, for the first time, bispecific antibody-based PET ligands for selective in vivo imaging of tauopathies. In this application, we have assembled a team of experts from the US and Sweden and we propose to build upon our experience in the development, evaluation and translation of PET tau probes to prioritize the initial tau antibody ligand collection based on their PET imaging performance profiles and select two optimal tau antibody ligands for the subsequent discriminative evaluation in tau animal models. That is, we will determine their capability as biomarkers to provide meaningful assessments of target engagement in animal models. The research team has extensive, multi-disciplinary experience in chemistry, biochemistry, pharmacology, neuroimaging, tau antibodies, tau animal models, state- of-the-art in vitro & in vivo methodologies, and drug discovery and development. The team also has expertise for translational research; e.g. conducting studies under GMP guidelines to obtain IND for clinical testing.