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.

项目概要 散发性迟发性阿尔茨海默病 (LOAD) 是最常见的衰老依赖性疾病 神经退行性疾病。 LOAD 与细胞外淀粉样蛋白的沉积有关 斑块和神经元内神经原纤维缠结 (NFT)，由 Aβ 肽和磷酸盐形成 tau 蛋白分别存在于中枢神经系统 (CNS) 中。尽管有强烈的共识认为 有毒形式的 Aβ 和 tau 蛋白会导致认知障碍、停止或逆转认知能力 针对 Aβ、斑块和缠结的 LOAD 患者的下降是无效的，并且 强调对不基于负荷相关的治疗方法的未满足的需求 解剖病理学。 多项数据表明神经炎症、小胶质细胞功能障碍和超生理 TNFα LOAD 发病机制中的活性。其中包括达达米奥博士提出的新证据， NanoNewron LLC 联合创始人，表明超生理性 TNF-α 增加 兴奋/抑制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。这些变化发生得很早 并且与 Aβ 水平和大脑病理学的变化无关。重要的是，重置 TNFα 使用低剂量的抗大鼠 TNF-α 中和抗体在生理水平上的活性 使这些改变正常化。 FDA 批准的生物 TNFα 的脊髓周围和鞘内给药的证据 – 特异性抑制剂（TNFI）改善 LOAD 患者的认知能力进一步强调 在 LOAD 中靶向超生理性 TNFα 的治疗潜力。不幸的是，FDA—— 已批准的生物 TNFIs 的血脑屏障 (BBB) 渗透性有限，因为 尺寸。 为了克服 BBB 渗透障碍，NanoNewron LLC 提出了第一阶段 STTR 项目旨在表征中和 TNF-α 活性的抗 TNF-α 骆驼纳米抗体（TNFI- Nabs），目的是防止、阻止或逆转 LOAD。鉴于尺寸小且 结构，纳米抗体可以比传统抗体更快地穿透中枢神经系统。 此外，通过将纳米抗体靶向转铁蛋白，可以增加 BBB 通透性 微血管内皮细胞表面的受体，有利于转胞吞作用，和/或通过 提高等电点。因此，NanoNewron还开发了单价TfR-Nabs 将用于将 TNFI-Nab 有效地运送到 CNS 中。这项研究的结果将 作为 NanoNewron 开发 TNFI-Nabs 疾病修饰努力的垫脚石 LOAD 的治疗候选者。