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：
9809715
负责人：
YU-SHIN DING
金额：
$ 25.63万
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 2021-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9809715
关键词：
Abeta clearance Affinity Alzheimer&apos s Disease 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.

项目摘要阿尔茨海默氏病（AD）的特征是两种主要蛋白质淀粉样蛋白折叠和聚集（Aβ）和tau。尽管Aβ聚集发生在临床症状之前的几年与神经元死亡，有时是认知功能的丧失更加紧密相关。另外，tau 在其他痴呆症中也发现了夹杂物，例如额颞痴呆和皮质性肥胖变性。这是，体内图像tau的能力对于临床诊断和评估tau的影响很重要有针对性的治疗。较早的用于成像tauopathies的候选放射性体系是基于小的分子药物化合物；但是，这些放射性配体显示了大量的脱靶结合和 AD以外的其他痴呆症中无法与Tau结合。另一方面，单链变量抗体片段（SCFV）作为治疗或诊断正电子发射断层扫描（PET）标记具有吸引力更特异性和高亲和力结合。源自β-折叠结合染料的Aβ斑块成像探针是已经在临床上使用了，并且正在评估一些这样的tau结合染料以进行癌症检测。抗体- 衍生的问题可能会为检测tau病变提供更大的特异性。但是，他们的大脑可怜渗透率限制了它们作为宠物配体的使用，以成像中枢神经系统内的靶标。以前，我们有成功证明抗体SCFV跨血脑屏障（BBB）的运输可能是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PET TFR片段和Aβ抗体融合产生的配体能够检测到Aβ聚集体在野生类型和转基因小鼠，与Aβ病理有良好的相关性。实际上，我们的人性化形式（BAN2401）先前开发的单克隆抗体MAB158在IIB期首次显示出希望的结果临床试验是针对AD的抗Aβ疗法，因为其对固体Aβ原纤维的独特选择性。那，在该建议我们将采用相同的策略来首次创建基于双特异性抗体的宠物配体进行选择性化合物的体内成像。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，我们建议以我们在开发和评估方面的经验为基础并翻译PET TAU问题以根据其PET优先考虑最初的Tau抗体配体系列成像性能曲线并选择两种最佳tau抗体配体以进行后续歧视 Tau动物模型的评估。也就是说，我们将确定他们作为生物标志物提供有意义的生物标志物的能力评估动物模型中的目标参与。研究团队拥有广泛的多学科化学，生物化学，药理学，神经影像学，tau抗体，tau动物模型，状态 - 体外和体内方法的艺术以及药物发现与发育。该团队也有专业知识用于翻译研究；例如根据GMP指南进行研究以获取用于临床测试的IND。