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.

项目摘要 /摘要 阿尔茨海默氏病（AD）临床试验主要是抗Aβ和抗TAU，但是这是 到目前为止，单目标热方法还没有成功。可以停止广告的想法，或者 通过针对单个病理事件的延迟，需要修订和多级热方法是 广告所需的。有限的多层次方法已经测试了AD的测试，但主要是由于 不适当的治疗时间，副作用和缺乏脑穿透。有希望的多层次疗法 方法是靶向TNF-α，在AD病理的多个阶段起着核心作用。现有的生物学 因此，TNF-α抑制剂（TNFI）是AD的潜在治疗方法，但是，请勿越过血脑屏障 （BBB）。没有研究日期仍开发了用于AD的BBB渗透生物学TNFI，该应用程序旨在 填补这一空白，并着重于用于AD的BBB渗透生物TNFI的开发。模型生物学 当前应用中的TNFI是Etanercept，它是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）的嵌合抗体融合在一起，其中 CTFRMAB结构域充当分子特洛伊木马，可以通过侵入性地将TNFR运送到大脑 血管内途径。我们最近表明，这种BBB渗透CTFRMAB-TNFR融合蛋白结果 在AD小鼠中，在更好的治疗指标（非BBB穿透TNFI）中，强调了需求 用于生物TNFI的大脑递送。我们的核心假设是系统给予CTFRMAB- 调节外围和神经TNF-α的TNFR介入多个级别的AD病理学，IS 因此在AD中的理论。在拟议的研究中，我们将利用两只不同的AD小鼠（Appswe，PSEN1DE9 双重和3xtg三重转基因小鼠），年龄为4个月和12个月的早期和晚期AD，并治疗 使用车辆，CTFRMAB-TNFR，Etanercept或CTFRMAB全身为12周/周3天。下列 将解决具体目的：目标1：优化BBB-的剂量反应和治疗时间窗口 穿透生物学TNFI。对神经病理学标志（Aβ和TAU）以及临床标志的影响 （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：特征 BBB渗透生物学TNFI的治疗作用涉及的机制。影响 将确定炎症，BBB功能，氧化应激和突触/神经元丧失的标记。目标3： 评估与BBB渗透生物学TNFI的慢性剂量相关的不良反应。两个都 将研究CTFRMAB-和TNF-α抑制作用广告效应。这些研究将有助于优化 最低剂量导致毒性比高效率，概述了TNF-α的治疗时间窗口 抑制，确定CTFRMAB-TNFR治疗作用涉及的机制，这可能使 识别新目标，并将提供必要的临床前结果，以推动 为人类广告的CTFRMAB-TNFR开发。