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

• 批准号: 10706541
• 负责人: Neil A Fanger
• 金额: $ 28.12万
• 依托单位: VIRTICI, LLC
• 依托单位国家: 美国
• 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/10706541
• 关键词: Abeta synthesis; Acute; Alzheimer' 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; Histopathology; Human; Immunoglobulin Fragments; Literature; Longevity; Marketing; Medical; Membrane; Mus; Neurofibrillary Tangles; Neurons; Pathologic; Penetration; 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; Weight; Work; abeta accumulation; abeta oligomer; alpha secretase; amyloid precursor protein processing; beta secretase; cognitive performance; cost; economic cost; extracellular; inflammatory marker; mouse model; neurogenesis; neuroprotection; novel; novel therapeutic intervention; prevent; regenerative; secretase; side effect; subcutaneous; symptom treatment; vector

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.

项目摘要 我们的目标是开发一种新型的神经元化双特异性抗体，该抗体促进神经元完整性和 用于治疗AD的神经发生。仅在美国，超过600万美国人目前都在广告中生活， 20211年总经济成本约为3550亿美元。尽管成本惊人，但只有少量有效 存在广告症状治疗的药物。结果，治疗甚至逆转广告的影响仍然是 大量未满足的需求。 从病理上讲，AD的特征是大脑中存在神经质斑块和神经原纤维缠结。 细胞外神经质斑块的主要成分是β-淀粉样蛋白（Aβ），约4 KDA片段蛋白水解源自较大的淀粉样前体蛋白（APP）2。广泛的 文献已经实施了Aβ的积累是AD进展的核心，并抑制Aβ 生产代表了治疗广告的承诺策略。 我们已经生成了两个单链变量域抗体片段（SCFV），ASEC和BSEC，它们 分别促进α-分泌酶活性和阻断β-分泌酶的活性对淀粉样前体蛋白 （APP）通过在α地点或β-Site3-5处与APP结合。接下来，我们产生了双特异性抗体 结合了ASEC和BSEC SCFV，并表明它可以提高SAPPα的水平，这是一种可溶的α-分泌酶 - 关联的应用APP片段，并降低Aβ和SAPPβ的水平，可溶性β-分泌酶相关的片段 在AD6的细胞模型中。将APOB标签添加到双特异性抗体（称为VTC-939）中，可以促进 在血脑屏障（BBB）6-8和神经元靶向上转移。使用重组人类腺 相关病毒（RAAV）作为肝细胞的载体感染性，VTC-939可以分泌到血液中， 大脑高水平。当VTC-939在应用程序/PS1 AD鼠标模型中作为治疗性测试时，VTC-939 SAPPα水平升高，同时降低Aβ沉积物和低聚Aβ水平。另外，VTC-939 治疗增加了神经元健康，大大增加了海马神经发生，并显着增加 与未处理的小鼠相比，生存率提高。这些结果表明将应用程序处理更改为 抑制有毒的淀粉样蛋白生成β地点活性，同时促进神经保护酶 处理提供了增加的神经元益处，并代表了一种有希望的新治疗方法 治疗并有可能逆转广告。 通过这项工作建立，我们的目标是将VTC-939作为一种新型的神经元渗透抗体开发 恢复神经元完整性并促进神经发生以治疗AD。具体目的是：1） 产生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在APP/PS1 AD小鼠模型中促进神经元完整性，神经发生和寿命，3） 在正常健康小鼠中为VTC-939产生急性毒理学和生物分布谱。可以 安全有效地促进神经元完整性和神经发生将提供显着的进步 对于明确的未满足的医疗需求。