Discovery of therapeutic nanobodies targeting brain TNF-α for the treatment of Alzheimer Disease

发现针对大脑 TNF-α 的治疗性纳米抗体用于治疗阿尔茨海默病

• 批准号: 10697218
• 负责人: LUCIANO D'ADAMIO
• 金额: $ 49.98万
• 依托单位: NANONEWRON LLC
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2024-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10697218
• 关键词: 3-Dimensional; Address; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer' s disease risk; Alzheimer' s disease therapy; American; Amyloid beta-Protein; Anatomy; Animal Model; Antibodies; Area; Astrocytes; Binding; Biological; Biological Assay; Biological Response Modifier Therapy; Blood; Blood - brain barrier anatomy; Blood Tests; Brain; Brain Pathology; Cell membrane; Cell model; Cells; Central Nervous System; Clinical Trials; Coculture Techniques; Cognition; Consensus; Data; Dementia; Deposition; Disease; Dose; Equilibrium; Equus caballus; FDA approved; Functional disorder; Funding; Genetic Polymorphism; Goals; Human; Immune; Immune response; Impaired cognition; Impairment; Iron; Isoelectric Point; Late Onset Alzheimer Disease; Lead; Learning; Long-Term Potentiation; Mediating; Medical; Memory; Microglia; Modeling; Mutagenesis; Neurodegenerative Disorders; Neurofibrillary Tangles; Outcome; Outcome Measure; Pathogenesis; Pathogenicity; Pathology; Penetrance; Penetration; Peptides; Pharmaceutical Preparations; Phase; Physiological; Population; Production; Rattus; Receptors, Tumor Necrosis Factor, Type II; Rodent; Role; Running; Selection Criteria; Senile Plaques; Serum; Small Business Technology Transfer Research; Spinal; Stress; Structure; Surface; Synaptic Transmission; Synaptic plasticity; TFRC gene; TNF gene; TNFRSF1A gene; TNFRSF1B gene; Testing; Therapeutic; Therapeutic Agents; Toxic effect; Treatment Efficacy; Vascular Endothelial Cell; Vertebral column; blood-brain barrier penetration; blood-brain barrier permeabilization; brain endothelial cell; cytotoxicity; de-immunization; drug development; extracellular; functional improvement; immunogenicity; improved; in silico; in vivo; in vivo evaluation; inhibitor; lead candidate; nanobodies; neuroinflammation; neutralizing antibody; preclinical evaluation; prevent; tau Proteins; therapeutic candidate; therapeutic target; transcytosis; transmission process; tumor necrosis factor-alpha inhibitor; uptake

Project Summary Sporadic, late onset Alzheimer disease (LOAD) is the most common form of aging-dependent neurodegenerative disorder. LOAD is associated with deposition of extracellular amyloid plaques and intra-neuronal neurofibrillary tangles (NFT), formed by Aβ peptides and phosphor- tau, respectively, in the central nervous system (CNS). Although there is strong consensus that toxic forms of Aβ and tau cause cognitive impairments, efforts to halt or reverse cognitive decline in LOAD patients targeting Aβ, plaques and tangles have been ineffective and emphasize an unmet need for therapeutic approaches that are not based on LOAD-associated anatomical pathologies. Several data implicate neuroinflammation, microglia dysfunction and supraphysiological TNFα activity in LOAD pathogenesis. These include new evidence generated by Dr. D’Adamio, the cofounder of NanoNewron LLC, indicating that supraphysiological TNF-α increases excitatory/inhibitory balance and impairs Long-Term Potentiation (LTP), a form of synaptic plasticity that represents a cellular model for learning and memory. These changes occur early and are independent of changes in Aβ levels and brain pathology. Importantly, resetting TNFα activity at physiological levels using low doses of anti-rat-TNF-α neutralizing antibody normalizes these alterations. The evidence that peri-spinal and intrathecal administration of FDA-approved biologic TNFα– specific inhibitors (TNFI) improved cognition in LOAD patients further emphasizes the therapeutic potential of targeting supraphysiological TNFα in LOAD. Unfortunately, FDA- approved biologic TNFIs have limited blood-brain barrier (BBB) penetration because of the large size. To overcome this BBB-penetrance obstacle, NanoNewron LLC proposes a Phase I STTR project to characterize anti-TNF-α camelid nanobodies that neutralize TNF-α activity (TNFI- Nabs), with the goal of preventing, arresting or reversing LOAD. Given the small size and structure, nanobodies can penetrate the CNS much more rapidly than conventional antibodies. Moreover, BBB permeability can be increased by targeting the nanobody to the transferrin receptors on the surface of microvascular endothelial cells, favoring transcytosis, and/or by increasing the isoelectric point. Thus, NanoNewron has also developed monovalent TfR-Nabs that will be used to shuttle TNFI-Nabs efficiently into the CNS. The results of this study will serve as a stepping-stone for NanoNewron’s efforts to develop TNFI-Nabs disease modifying therapeutic candidates for LOAD.

项目摘要 散发性迟发性阿尔茨海默病（LOAD）是最常见的年龄依赖性阿尔茨海默病。 神经退行性疾病LOAD与细胞外淀粉样蛋白沉积有关 斑块和神经元内神经元缠结（NFT），由Aβ肽和磷- tau，分别在中枢神经系统（CNS）。尽管有强烈的共识， Aβ和tau蛋白的毒性形式会导致认知障碍， 针对Aβ、斑块和缠结的LOAD患者的下降一直无效， 强调未满足的治疗方法需求，这些方法不是基于与LOAD相关的 解剖病理学 一些数据暗示神经炎症，小胶质细胞功能障碍和超生理TNFα 在LOAD发病机制中的活性。其中包括D 'Adamio博士提出的新证据， NanoNewron LLC的共同创始人，表明超生理TNF-α增加 兴奋性/抑制性平衡并损害长时程增强（LTP），一种突触形式 可塑性，代表了学习和记忆的细胞模型。这些变化发生得早 并且与Aβ水平和脑病理学的变化无关。重要的是，重置TNFα 使用低剂量抗大鼠TNF-α中和抗体在生理水平下的活性 使这些变化正常化。 有证据表明，脊髓周围和鞘内注射FDA批准的生物TNFα- 特异性抑制剂（TNFI）改善LOAD患者的认知进一步强调了 在LOAD中靶向超生理学TNFα的治疗潜力。很不幸，食品和药物管理局- 批准的生物TNFI具有有限的血脑屏障（BBB）渗透，因为大的 尺寸 为了克服这一BBB-恍惚障碍，NanoNewron LLC提出了第一阶段STTR 一项旨在表征中和TNF-α活性的抗TNF-α骆驼纳米抗体（TNFI-1）的项目。 Nabs），目的是防止、阻止或逆转LOAD。由于体积小， 由于纳米抗体的结构，纳米抗体可以比常规抗体更快地穿透CNS。 此外，可以通过将纳米抗体靶向转铁蛋白来增加BBB渗透性 微血管内皮细胞表面上的受体，有利于转胞吞作用，和/或通过 增加等电点。因此，NanoNewron还开发了单价的TfR-Nabs 其将用于将TNFI-Nab有效地穿梭到CNS中。这项研究的结果将 作为NanoNewron努力开发TNFI-Nabs疾病修饰的垫脚石， 用于负载的治疗候选物。