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: 10615185
• 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 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10615185
• 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; Amyloid beta-Protein; Anemia; Antibodies; Binding; Biologic Development; Biological; Biological Models; Biological Products; Blood - brain barrier anatomy; Blood Vessels; Brain; Central Nervous System; 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; Literature; Mediating; Memory impairment; Mus; NOR Mouse; 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; Therapeutic; Therapeutic Effect; Therapeutic Index; Therapeutic Intervention; Time; Tissues; Toxic effect; Transgenic Mice; Tumor Necrosis Factor Receptor; White Blood Cell Count procedure; 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; neural; neuron loss; neuropathology; pre-clinical; receptor; response; side effect; 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.

项目总结/摘要 阿尔茨海默病（AD）临床试验主要以抗A β和抗tau蛋白为中心，然而， 单靶点治疗方法迄今尚未成功。AD可以被阻止的想法，或者 由于针对单一病理事件而延迟，需要修改和多层次的治疗方法， 需要AD。有限的多层次方法已经过AD测试，但失败的主要原因是 治疗时间不合适，副作用和缺乏大脑渗透。一种有前途的多层次治疗方法 方法是靶向TNF-α，其在AD病理学的多个阶段中起核心作用。现有生物 因此，TNF-α抑制剂（TNFIs）是治疗AD的潜在药物，但不能穿过血脑屏障 （BBB）。至今还没有研究开发出用于AD的BBB穿透性生物TNFI，本申请旨在 填补这一空白，并专注于开发治疗AD的BBB渗透性生物TNFI。模型生物 本申请中的TNFI是依那西普，其是一种II型TNF-α诱饵受体（TNFR）-Fc融合蛋白。 我们已经将TNFR与针对小鼠转铁蛋白受体的嵌合抗体（cTfRMAb）融合，其中TNFR与抗小鼠转铁蛋白受体的嵌合抗体（cTfRMAb）融合。 cTfRMAb结构域作为一种分子特洛伊木马，将TNFR非侵入性地通过 经血管途径。我们最近发现这种穿透血脑屏障的cTfRMAb-TNFR融合蛋白导致 在AD小鼠中比依那西普（非BBB穿透性TNFI）具有更好的治疗指数，强调了需要 用于向大脑输送生物TNFI我们的中心假设是全身给予cTfRMAb- TNFR调节外周和神经TNF-α，干预AD病理学的多个水平， 从而治疗AD。在所提出的研究中，我们将利用两种不同的AD小鼠（APPswe，PSEN 1dE 9 双转基因小鼠和3xTg三转基因小鼠），年龄为4个月和12个月，以模拟早期和晚期AD，并治疗 全身性给予溶媒、cTfRMAb-TNFR、依那西普或cTfRMAb，每周3天，持续12周。以下 将提出具体目标：目标1：优化BBB的剂量-反应和治疗时间窗- 渗透性生物TNFI。对神经病理学标志（Aβ和tau）和临床标志的影响 将使用三种剂量（lmg/kg、3 mg/kg和6 mg/kg）研究（认知缺陷）。目标2：描述 BBB穿透性生物TNFI的治疗作用涉及的机制。的效果 将确定炎症、BBB功能、氧化应激和突触/神经元损失的标志物。目标3： 评估与长期服用BBB渗透生物TNFI相关的不良反应。两 将研究与cTfRMAb和TNF-α抑制相关的不良反应。这些研究将有助于优化 导致高疗效与毒性比的最低剂量，概述了TNF-α的治疗时间窗 抑制，确定涉及cTfRMAb-TNFR的治疗作用的机制，这可能使 确定新靶点，并将提供必要的临床前结果， 用于人类AD的cTfRMAb-TNFR的开发。