A Brain Penetrating Bi-functional Transferrin Receptor Antibody-TNF-alpha Decoy Receptor Fusion Protein for Alzheimer's Disease

用于治疗阿尔茨海默病的脑穿透双功能转铁蛋白受体抗体-TNF-α诱饵受体融合蛋白

• 批准号: 10397273
• 负责人: Rachita Sumbria
• 金额: $ 37.77万
• 依托单位: CHAPMAN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10397273
• 关键词: 3xTg-AD mouse; Address; Advanced Development; Adverse effects; Affinity; Age; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease test; Alzheimer' s disease therapeutic; Amyloid beta-Protein; Anemia; Antibodies; Binding; Biologic Development; Biological; Biological Models; Blood - brain barrier anatomy; Brain; Central Nervous System Diseases; Chemistry; Chimeric Proteins; Chronic; Clinical; Clinical Trials; Cognitive deficits; Complete Blood Count; Data; Development; Dose; Endothelium; Engineering; Etanercept; Event; Extracellular Domain; Face; Fc Receptor; Goals; Histology; Human; Ibuprofen; Impaired cognition; Inflammation; Leukocytes; Literature; Mediating; Memory impairment; Mus; NOR Mouse; Neuraxis; Oxidative Stress; Parkinson Disease; Pathologic; Pathologic Processes; Penetration; Peripheral; Pharmaceutical Preparations; Play; Primates; Reporting; Research Support; Role; Route; Serum; Stroke; Synapses; TFRC gene; TNF gene; TNFR-Fc fusion protein; Therapeutic; Therapeutic Effect; Therapeutic Index; Therapeutic Intervention; Time; Tissues; Toxic effect; Transgenic Mice; Treatment Side Effects; Tumor Necrosis Factor Receptor; Work; blood-brain barrier disruption; blood-brain barrier function; blood-brain barrier penetration; cerebral microbleeds; chimeric antibody; clinical phenotype; drug development; improved; inflammatory marker; molecular trojan horse; mouse model; neuron loss; pre-clinical; receptor; relating to nervous system; response; targeted treatment; tau Proteins; transcytosis; tumor necrosis factor-alpha inhibitor; β-amyloid burden

PROJECT SUMMARY / ABSTRACT Alzheimers disease (AD) clinical trials have primarily been anti-Aβ and anti-tau centric, however this single-target therapeutic approach has not been successful so far. The idea that AD can be stopped, or delayed by targeting a single pathological event, needs revision and a multi-level therapeutic approach is needed for AD. Limited multi-level approaches have been tested for AD but have failed primarily due to inappropriate time of treatment, side-effects and lack of brain penetration. A promising multi-level therapeutic approach is to target TNF-α which plays a central role at multiple stages of AD pathology. Existing biologic TNF-α inhibitors (TNFIs) are thus a potential treatment for AD, however, do not cross the blood-brain barrier (BBB). No study still date has developed a BBB-penetrating biologic TNFI for AD and this application aims to fill this gap, and focuses on the development of a BBB-penetrating biologic TNFI for AD. The model biologic TNFI in the current application is etanercept, which is a type-II TNF-α decoy receptor (TNFR)-Fc fusion protein. We have fused TNFR to a chimeric antibody against the mouse transferrin receptor (cTfRMAb), wherein the cTfRMAb domain acts as a molecular Trojan horse to ferry the TNFR into the brain non-invasively via the transvascular route. We have recently shown that this BBB-penetrating cTfRMAb-TNFR fusion protein results in better therapeutic indices than etanercept (non-BBB-penetrating TNFI) in AD mice, underscoring the need for brain delivery of the biologic TNFI. Our central hypothesis is that systemic administration of cTfRMAb- TNFR, which modulates both peripheral and neural TNF-α, intervenes at multiple levels of AD pathology and is thus therapeutic in AD. In the proposed studies, we will utilize two different AD mice (APPswe, PSEN1dE9 double and 3xTg triple transgenic mice), ages 4- and 12-months to mimic early- and late-stage AD, and treat with vehicle, cTfRMAb-TNFR, etanercept or cTfRMAb systemically 3 days/week for 12-weeks. The following specific aims will be addressed: Aim 1: Optimize dose-response and therapeutic time-window of the BBB- penetrating biologic TNFI. The effect on neuropathological hallmarks (Aβ and tau), and clinical hallmark (cognitive deficit) will be studied using three doses (1mg/kg, 3mg/kg and 6 mg/kg). Aim 2: Characterize the mechanisms involved in the therapeutic effects of the BBB-penetrating biologic TNFI. The effects on markers of inflammation, BBB function, oxidative stress and synaptic/neuronal loss will be determined. Aim 3: Evaluate the adverse effects associated with chronic dosing of the BBB-penetrating biologic TNFI. Both cTfRMAb- and TNF-α inhibition-relevant adverse-effects will be studied. These studies will help optimize the lowest dose that results in a high efficacy to toxicity ratio, outline the therapeutic time-window for TNF-α inhibition, identify mechanisms involved in the therapeutic effects of cTfRMAb-TNFR which may enable the identification of new targets, and will provide the necessary pre-clinical results that will advance the development of cTfRMAb-TNFR for AD in humans.

项目概要/摘要 阿尔茨海默病 (AD) 临床试验主要以抗 Aβ 和抗 tau 蛋白为中心，然而， 迄今为止，单靶点治疗方法尚未成功，或者说AD可以被阻止。 由于针对单一病理事件而延迟，需要修正和多层次的治疗方法 AD 所需的有限多级方法已针对 AD 进行了测试，但主要由于以下原因而失败。 治疗时间不当、副作用和缺乏大脑渗透性是一种有前途的多层次治疗方法。 方法是针对 TNF-α，它在现有 AD 病理学的多个阶段发挥着核心作用。 因此，TNF-α 抑制剂 (TNFIs) 是 AD 的潜在治疗方法，但不能穿过血脑屏障 (BBB) 目前尚无研究开发出用于 AD 的 BBB 穿透性生物 TNFI，本申请旨在 填补这一空白，并专注于开发用于 AD 的 BBB 穿透生物 TNFI 模型生物制剂。 目前应用的TNFI是依那西普，它是一种II型TNF-α诱饵受体（TNFR）-Fc融合蛋白。 我们将 TNFR 与针对小鼠转铁蛋白受体 (cTfRMAb) 的嵌合抗体融合， cTfRMAb 结构域充当分子特洛伊木马，通过非侵入性地将 TNFR 运送到大脑中 我们最近证明了这种 BBB 穿透性 cTfRMAb-TNFR 融合蛋白的结果。 在 AD 小鼠中，其治疗指数优于依那西普（非 BBB 穿透性 TNFI），强调了这一需求 我们的中心假设是全身施用 cTfRMAb-。 TNFR 可调节外周和神经 TNF-α，在 AD 病理学的多个层面进行干预，并且 因此，在拟议的研究中，我们将利用两种不同的 AD 小鼠（APPswe、PSEN1dE9）。 双和 3xTg 三重转基因小鼠），年龄为 4 个月和 12 个月，以模拟早期和晚期 AD，并治疗 每周 3 天，使用载体、cTfRMAb-TNFR、依那西普或 cTfRMAb 进行全身治疗，持续 12 周。 将解决具体目标： 目标 1：优化 BBB 的剂量反应和治疗时间窗口 穿透性生物 TNFI 对神经病理学标志（Aβ 和 tau）和临床标志的影响。 （认知缺陷）将使用三种剂量（1mg/kg、3mg/kg 和 6mg/kg）进行研究：目标 2：表征 参与 BBB 穿透性生物 TNFI 治疗作用的机制。 将确定炎症、血脑屏障功能、氧化应激和突触/神经元损失的标志物。目标 3： 评估与 BBB 穿透性生物 TNFI 长期给药相关的不良反应。 将研究 cTfRMAb 和 TNF-α 抑制相关的副作用，这些研究将有助于优化。 产生高疗效/毒性比的最低剂量，概述 TNF-α 的治疗时间窗口 抑制，确定涉及 cTfRMAb-TNFR 治疗效果的机制，这可能使 确定新目标，并将提供必要的临床前结果，以推进 开发用于人类 AD 的 cTfRMAb-TNFR。