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: 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
• 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' 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

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穿透性双特异性抗体，它能促进神经元的完整性和 阿尔茨海默病的神经发生治疗。仅在美国，目前就有超过600万美国人患有AD， 20211年度的总经济成本约为3,550亿美元。尽管成本惊人，但只有少数几种药物略有效果 有治疗症状的药物存在。因此，治疗甚至逆转阿尔茨海默病的影响仍然是一个 重大的未得到满足的需求。 病理上，阿尔茨海默病的特点是脑内出现神经炎性斑块和神经原纤维缠结。 细胞外神经炎斑块的主要成分是β-淀粉样蛋白(Aβ)，约为4 KDA片段蛋白水解性来源于较大的淀粉样前体蛋白(APP)2。 文献表明，β积聚是AD进展的中心，并抑制Aβ 生产是治疗阿尔茨海默病的一种有前途的策略。 我们已经产生了两个单链可变区抗体片段(ScFv)，ASEC和BSEC，它们 对淀粉样前体蛋白分别促进α分泌酶活性和阻断β分泌酶活性 (APP)通过在α站点或β站点3-5绑定到APP。接下来，我们产生了一种串联的双特异性抗体 这结合了ASEC和BSEC单链抗体，并表明它提高了sAPPα的水平，这是一种可溶性α分泌酶- 相关的APP片段，并降低Aβ和sAPPβ的水平，这是一种可溶性β分泌酶相关片段 在AD6的细胞模型中。ApoB标签被添加到双特异性抗体(称为VTC-939)中，这可以促进 跨越血脑屏障(BBB)6-8的转移和神经元靶向。使用重组人腺病毒- 相关病毒(RAAV)作为感染肝细胞的载体，VTC-939可分泌到血液中并 大脑处于高水平。当在APP/PS1 AD小鼠模型上测试VTC-939作为治疗剂时，VTC-939 SAPPα水平升高，而Aβ沉积和寡聚体Aβ水平下降。此外，职训局-939 治疗改善了神经元的健康，显著增加了海马神经发生和显著 与未经治疗的小鼠相比，存活率提高了9。这些结果表明，将应用程序处理更改为 抑制毒性淀粉样变性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元益处，并代表了一种有前途的新的治疗方法 治疗，并有可能逆转阿尔茨海默病。 在这项工作的基础上，我们的目标是开发VTC-939作为一种新型的神经元穿透抗体， 恢复神经元的完整性，促进神经再生，用于AD的治疗。具体目标是：1) 制备抗体载体并建立质量控制分析方法，2)确定最佳有效剂量 VTC-939用于促进APP/PS1 AD小鼠模型中神经元的完整性、神经发生和寿命，以及3) 产生VTC-939在正常健康小鼠中的急性毒理学和生物分布概况。一种可以 安全和有效地促进神经元的完整性和神经发生将提供一个重大的进步 为了一个明显的未得到满足的医疗需求。