A Novel Antibody that Promotes Neuronal Integrity and Neurogenesis for Treating Alzheimer's Disease

一种促进神经元完整性和神经发生的新型抗体，用于治疗阿尔茨海默病

基本信息

批准号：
10600796
负责人：
Neil A Fanger
金额：
$ 44.13万
依托单位：
VIRTICI, LLC
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-30 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10600796
关键词：
Abeta synthesis Acute Alzheimer&apos s Disease American Amyloid beta-Protein Amyloid beta-Protein Precursor Animals Antibodies Apolipoproteins B Autopsy Behavior Binding Binding Proteins Biodistribution Biological Assay Bispecific Antibodies Blood Blood - brain barrier anatomy Blood Chemical Analysis Brain C-terminal Cell model Cytoprotection Data Dependovirus Deposition Development Disease Dose Drug Kinetics Engineering Enzyme-Linked Immunosorbent Assay Goals Health Hematology Hepatocyte Hippocampus (Brain)Histopathology Human Immunoglobulin Fragments Literature Longevity Medical Membrane Mus Neurofibrillary Tangles Neurons Pathologic Peptide Hydrolases Peptides Pharmaceutical Preparations Pharmacodynamics Phase Process Protein Fragment Proteins Quality Control Recombinants Senile Plaques Site Small Business Innovation Research Grant Survival Rate Testing Therapeutic Tissues Toxicology Viral Proteins Weight Work abeta accumulation alpha secretase amyloid precursor protein processing beta secretase cognitive performance cost economic cost extracellular inflammatory marker mouse model neurogenesis novel novel therapeutic intervention prevent regenerative secretase side effect subcutaneous symptom treatment vector

项目摘要

Project Summary Our goal is to develop a novel neuron-penetrating bispecific antibody that promotes neuronal integrity and neurogenesis for the treatment of AD. In the US alone, over 6 million Americans are currently living with AD, with total economic costs around $355 billion in 20211. Despite the staggering cost, only a few mildly effective AD symptom-treating drugs exist. As a result, treating and even reversing the effects of AD remains a significant unmet need. Pathologically, AD is characterized by the presence of neuritic plaques and neurofibrillary tangles in the brain. The primary component of the extracellular neuritic plaques is the β-amyloid protein (Aβ), an approximately 4 kDa fragment proteolytically derived from the larger amyloid precursor protein (APP)2. A vast amount of literature has implicated Aβ accumulation as being central to the progression of AD, and inhibiting Aβ production represents a promising strategy for treating AD. We have generated two single-chain variable domain antibody fragments (scFv), Asec and Bsec, which respectively promote α-secretase activity and block β-secretase activity toward amyloid precursor protein (APP) by binding to APP at either the α-site or the β-site3-5. Next, we generated a tandem bispecific antibody that combines the Asec and Bsec scFvs and showed that it elevates levels of sAPPα, a soluble α-secretase- associated APP fragment, and decreases levels of Aβ and sAPPβ, a soluble β-secretase-associated fragment in cell models of AD6. An ApoB tag was added to the bispecific antibody (called VTC-939), which can facilitate transfer across the blood-brain barrier (BBB)6-8 and neuronal targeting. Using recombinant human adeno- associated virus (rAAV) as a vector infective to hepatic cells, VTC-939 could be secreted into the blood and brain at high levels. When VTC-939 was tested as a therapeutic in an APP/PS1 AD mouse model, VTC-939 increased levels of sAPPα, while decreasing Aβ deposits and oligomeric Aβ levels. In addition, VTC-939 treatment increased neuronal health, substantially increased hippocampal neurogenesis and significantly increased survival rates compared with untreated mice9. These results indicate that altering APP processing to inhibit toxic amyloidogenic β-site activity while simultaneously promoting neuroprotective α-secretase processing provides increased neuronal benefits and represents a promising new therapeutic approach for treating, and potentially reversing AD. Building from this work, our objective is to develop VTC-939 as a novel neuron-penetrating antibody that restores neuronal integrity and promotes neurogenesis for the treatment of AD. The specific aims are to: 1) produce antibody constructs and establish quality control assays, 2) determine the optimal effective dose of VTC-939 to promote neuronal integrity, neurogenesis and longevity in the APP/PS1 AD mouse model, and 3) generate acute toxicology and biodistribution profiles for VTC-939 in normal healthy mice. A therapy that can safely and effectively promote neuronal integrity and neurogenesis would provide a significant advancement for a clear unmet medical need.

项目概要我们的目标是开发一种新型神经元穿透双特异性抗体，可促进神经元完整性和仅在美国，目前就有超过 600 万美国人患有 AD。到 20211 年，总经济成本约为 3550 亿美元。尽管成本惊人，但只有少数措施效果较好治疗 AD 症状的药物已经存在，因此，治疗甚至逆转 AD 的影响仍然是一个难题。重大未满足的需求。在病理学上，AD的特征是大脑中存在神经原纤维斑块和神经原纤维缠结。细胞外神经斑的主要成分是 β-淀粉样蛋白 (Aβ)，大约为 4 kDa 片段通过蛋白水解衍生自较大的淀粉样前体蛋白 (APP)2。文献表明 Aβ 积累是 AD 进展的核心，抑制 Aβ 生产代表了治疗 AD 的一种有前途的策略。我们生成了两个单链可变域抗体片段（scFv），Asec 和 Bsec，分别促进 α-分泌酶活性和阻断 β-分泌酶对淀粉样前体蛋白的活性 (APP) 通过在 α 位点或 β 位点 3-5 处结合 APP 接下来，我们生成了串联双特异性抗体。结合了 Asec 和 Bsec scFv，并表明它提高了 sAPPα（一种可溶性 α-分泌酶）的水平相关 APP 片段，并降低 Aβ 和 sAPPβ（一种可溶性 β-分泌酶相关片段）的水平在AD6的细胞模型中，双特异性抗体（称为VTC-939）中添加了ApoB标签，这可以促进使用重组人腺-转移穿过血脑屏障 (BBB)6-8 和神经靶向。相关病毒（rAAV）作为感染肝细胞的载体，VTC-939可以分泌到血液中并当 VTC-939 在 APP/PS1 AD 小鼠模型中进行治疗测试时，VTC-939 此外，VTC-939 还增加了 sAPPα 的水平，同时降低了 Aβ 沉积物和寡聚 Aβ 的水平。治疗可改善神经系统健康，显着增加海马神经发生，并显着与未治疗的小鼠相比，存活率提高9。这些结果表明，改变 APP 处理以抑制有毒的淀粉样蛋白生成 β 位点活性，同时促进神经保护性 α 分泌酶处理提供了更多的神经益处，代表了一种有前途的新治疗方法治疗并有可能逆转 AD。在这项工作的基础上，我们的目标是将 VTC-939 开发为一种新型神经元穿透抗体，恢复神经元完整性并促进神经发生以治疗 AD。具体目标是：1) 生产抗体构建体并建立质量控制测定，2) 确定最佳有效剂量 VTC-939 可促进 APP/PS1 AD 小鼠模型中的神经元完整性、神经发生和寿命，以及 3) 在正常健康小鼠中生成 VTC-939 的急性毒理学和生物分布曲线。安全有效地促进神经元完整性和神经发生将带来重大进步明确未满足的医疗需求。