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