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: 10893118
• 负责人: Neil A Fanger
• 金额: $ 25.74万
• 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/10893118
• 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。