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Bispecific Antibody-Based PET Ligands for Imaging Tauopathies

用于 Tau蛋白病成像的双特异性抗体 PET 配体

基本信息

批准号：
10086539
负责人：
YU-SHIN DING
金额：
$ 39.6万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-01 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10086539
关键词：
Abeta clearance Affinity Alzheimer&apos s Disease Alzheimer&apos s disease therapeutic Amyloid beta-Protein Animal Model Antibodies Antibody Specificity Antibody Therapy Antigens Binding Biochemistry Biological Assay Biological Markers Bispecific Antibodies Blood - brain barrier anatomy Brain Cancer Detection Chemistry Clinical Clinical Trials Collection Dementia Detection Development Diagnostic Drug Compounding Drug Targeting Dyes Enzyme-Linked Immunosorbent Assay Evaluation Failure Fc Receptor Frontotemporal Dementia Generations Goals Guidelines I125 isotope Image Imaging ligands Immunoglobulin Fragments Immunotherapy Impaired cognition In Vitro Lesion Ligands Methodology Methods Monoclonal Antibodies Pathologic Pathology Penetrance Penetration Performance Pharmaceutical Preparations Pharmacology Phase Positron-Emission Tomography Proteins Protocols documentation Publishing Radiolabeled Recombinants Research Senile Plaques Specificity Sweden Symptoms TFRC gene Tauopathies Therapeutic Time Transgenic Animals Transgenic Mice Translational Research Translations Wild Type Mouse Work abeta accumulation abeta deposition base beta amyloid pathology beta pleated sheet clinical Diagnosis cognitive function corticobasal degeneration cost drug development drug discovery experience imaging probe in vivo in vivo imaging mouse model multidisciplinary neuroimaging neuron loss protein expression radioligand radiotracer research and development research clinical testing small molecule targeted imaging tau Proteins tau aggregation tau-1 uptake

项目摘要

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.

项目概要阿尔茨海默氏病 (AD) 的特点是两种主要蛋白质（β-淀粉样蛋白）的错误折叠和聚集 (Aβ) 和 tau。虽然 Aβ 聚集发生在临床症状出现前数年，但 tau 蛋白在大脑中的聚集却是与神经元死亡和最终认知功能丧失密切相关。此外，τ 包涵体也存在于其他痴呆症中，例如额颞叶痴呆和皮质基底节变性。因此，体内 tau 成像的能力对于临床诊断和评估 tau 的影响非常重要。有针对性的治疗。早期用于 tau蛋白病成像的候选放射性配体是基于小分子药物化合物；然而，这些放射性配体表现出很大程度的脱靶结合和除 AD 之外的痴呆症患者无法与 tau 蛋白结合。另一方面，单链可变抗体片段（scFv）作为治疗或诊断正电子发射断层扫描（PET）标记物很有吸引力更高的特异性和高亲和力结合。源自 β-片层结合染料的 Aβ 斑块成像探针是已经投入临床使用，并且一些此类 tau 结合染料正在评估用于癌症检测。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，他们可怜的大脑外显率限制了它们作为 PET 配体在中枢神经系统内靶标成像中的应用。此前，我们有成功证明抗体 scFv 可以穿过血脑屏障 (BBB) 通过与转铁蛋白受体 (TfR) 的相互作用促进，并且基于双特异性抗体的 PET TfR 和 Aβ 抗体片段融合产生的配体能够检测 Aβ 聚集体体内野生型和野生型之间的大脑摄取在数量和视觉上都存在明显差异转基因小鼠，与Aβ病理学具有良好的相关性。事实上，我们的人性化形式（BAN2401）先前开发的单克隆抗体 mAb158 在 IIb 期试验中首次显示出有希望的结果由于其对可溶性 Aβ 原纤维的独特选择性，作为抗 AD 疗法进行了临床试验。因此，在根据该提案，我们将应用相同的策略来首次创建基于双特异性抗体的 PET 用于tau蛋白病选择性体内成像的配体。在这个应用程序中，我们组建了一个团队来自美国和瑞典的专家，我们建议借鉴我们在开发、评估方面的经验 PET tau 探针的翻译，以根据 PET 优先收集初始 tau 抗体配体成像性能概况并选择两个最佳 tau 抗体配体进行后续判别 tau 动物模型的评估。也就是说，我们将确定它们作为生物标志物的能力，以提供有意义的信息动物模型中目标参与度的评估。研究团队拥有广泛的、跨学科的具有化学、生物化学、药理学、神经影像学、tau 抗体、tau 动物模型、状态方面的经验最先进的体外和体内方法以及药物发现和开发。团队也有专业知识用于转化研究；例如根据 GMP 指南进行研究以获得 IND 进行临床测试。