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 零星的，晚期的阿尔茨海默氏病（负载）是依赖衰老的最常见形式 神经退行性疾病。负载与细胞外淀粉样蛋白的沉积有关 由Aβ肽和磷酸形成的斑块和神经元内神经原纤维缠结（NFT） tau分别在中枢神经系统（CNS）中。尽管有强烈共识 Aβ和TAU的有毒形式会导致认知障碍，努力停止或反向认知 靶向Aβ，斑块和缠结的负载患者的下降一直无效，并且 强调对不基于负载相关的治疗方法的未满足的需求 解剖病。 几个数据暗示神经炎症，小胶质细胞功能障碍和超生理TNFα 负载发病机理的活性。这些包括D'Adamio博士产生的新证据， Nanonewron LLC的联合创始人，表明超生理TNF-α增加 兴奋/抑制平衡并损害长期增强（LTP），这是一种突触的形式 代表学习和记忆的细胞模型的可塑性。这些变化很早就发生 并且独立于Aβ水平和脑病理学的变化。重要的是，重置TNFα 使用低剂量的抗RAT-TNF-α中和抗体在物理水平上的活性 将这些变化归一化。 FDA批准的生物学TNFα–的脊柱周围和鞘内给药的证据 特定的抑制剂（TNFI）改善了负载患者的认知进一步强调 靶向负载型超生理TNFα的治疗潜力。不幸的是，FDA- 批准的生物TNFI的血脑屏障（BBB）渗透有限，因为很大 尺寸。 为了克服这一BBB渗透障碍，nanonewron LLC提案A期ISTTR 项目以中和TNF-α活性（TNFI- NABS），目的是防止，逮捕或逆转负载。鉴于小尺寸和 与传统抗体相比，结构纳米体可以渗透CNS速度要快得多。 此外，可以通过将纳米机靶向转铁蛋白来提高BBB渗透率 微血管内皮细胞表面的受体有利于跨经细胞增多症和/或通过 增加等电点。那，纳米旋龙还开发了单价tfr-nabs 这将用于将TNFI-NABS有效地驶入中枢神经系统。这项研究的结果将 作为Nanonewron努力发展TNFI-NABS疾病的努力的垫脚石 负载的治疗候选者。