DRα1-MOG: A Novel Immunomodulatory Therapeutic for Stroke

DRα1-MOG：一种新型中风免疫调节疗法

• 批准号: 9409245
• 负责人: Nabil J Alkayed
• 金额: $ 29.92万
• 依托单位: VIROGENOMICS BIODEVELOPMENT, INC.
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9409245
• 关键词: Affect; Age; Age-Months; Aging; Agonist; Alleles; Alpha Cell; Behavioral; Binding; Biological; Blood; Brain; Brain Injuries; Caring; Cell physiology; Cells; Clinical; Clinical Trials Design; Cognitive deficits; Coupled; Diagnosis; Dose; Encephalitis; Female; HLA-DR2 Antigen; Hemorrhage; Histocompatibility Testing; Human; ITGAM gene; Immune; Immune response; Immunity; Immunomodulators; Immunosuppression; Immunosuppressive Agents; Infarction; Infection; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Injection of therapeutic agent; Ischemia; Ischemic Brain Injury; Ischemic Stroke; Ligands; Link; MHC Class II Genes; Measures; Mechanics; Medical; Middle Cerebral Artery Occlusion; Migration Inhibitory Factor; Modeling; Mus; Myelin; Neurologic Deficit; Outcome; Patients; Peptide Receptor; Peptide/MHC Complex; Peptides; Peripheral; Pharmaceutical Preparations; Phase; Recombinant Proteins; Recombinants; Signal Transduction; Small Business Technology Transfer Research; Stroke; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; Therapeutic; Therapeutic Agents; Thromboembolism; Thrombosis; Time; Weight; Wild Type Mouse; age effect; aged; autoreactive T cell; brain tissue; cell type; clinically relevant; design; immunoregulation; improved; improved functioning; male; migration; motor deficit; neuroprotection; novel; novel therapeutics; oligodendrocyte-myelin glycoprotein; post stroke; preclinical efficacy; protective effect; receptor; response; screening; sex; somatosensory; stroke treatment; young adult

This is a Phase I STTR to investigate the preclinical efficacy of a novel immunomodulator, DRα1-MOG, in a clinically relevant thromboembolic stroke model in mice. We have previously shown that T cells are activated after stroke, infiltrate brain, and exacerbate ischemic brain damage. Strategies that reduce T cell activation and brain tissue infiltration have been investigated as potential therapeutic strategies for stroke; however, non- specific inhibition of T cell function is immunosuppressive. We therefore developed Recombinant T cell receptor (TCR) Ligands (RTLs), which are partial MHC II molecules comprised of covalently linked β1 and α1 chains tethered to antigenic peptides. Early RTL constructs were successful in protecting against ischemia-induced brain injury but only if the RTL contains a neuroantigen peptide and the matched Class II MHC moiety of the recipient. A significant limitation for using these early RTL constructs to treat human stroke is the need to rapidly match recipient MHC class II with the β1 domain of the pMHC construct. We, therefore, designed a novel recombinant protein comprised of the HLA-DRα1 domain linked to MOG-35-55 peptide (DRα1-MOG) but lacking the β1 domain found in pMHC. Because the DRα1 domain is present in all humans and would not be recognized as foreign, treatment using DRα1 constructs would not require HLA screening of potential recipients. In a proof of principle study, we demonstrated that four daily treatments with DRα1-MOG significantly reduced infarct size after stroke in mice. That study, however, was conducted using the intraluminal middle cerebral artery occlusion (MCAO) model, which causes mechanical, rather than thromboembolic occlusion, the most common cause of human stroke. To more faithfully mimic clinical stroke, we have developed a novel thromboembolic model of stroke in mouse, which will form the basis of the current proposal. Furthermore, aging and biological sex are well documented key determinants of stroke outcome, in part by exerting differential influences on stroke-induced inflammatory response. The proposed STTR will further characterize the protective effect of DRα1-MOG using the clinically relevant thromboembolic model of stroke, and the clinically important variables of time of initial treatment, sex and age to estimate how broadly DRα1-MOG could be used to treat stroke patients.

这是研究新型免疫调节剂DRα1-MOG的临床前效率的I期。 小鼠临床相关的血栓栓塞中风模型。我们以前已经表明T细胞被激活 中风后，浸润大脑和加剧缺血性脑损伤。减少T细胞激活和 脑组织浸润已被研究为中风的潜在治疗策略。但是，非 特异性抑制T细胞功能是免疫抑制的。因此，我们开发了重组T细胞受体 （TCR）配体（RTL），是部分MHC II分子，由共价连接的β1和α1链组成 早期的RTL构建体成功地防止缺血诱导 脑损伤，但只有RTL含有神经抗原肽和匹配的II类MHC部分 接受者。使用这些早期的RTL构造来治疗人类中风的重要限制是需要快速 将受体MHC II与PMHC构建体的β1结构域进行匹配。因此，我们设计了一本小说 与MOG-35-55肽（DRα1-MOG）相关的HLA-DRα1结构域积累的重组蛋白，但缺乏 在PMHC中发现的β1结构域。因为DRα1域在所有人类中都呈现，并且不会被识别 作为外国，使用DRα1构建体的处理不需要HLA筛查潜在的受体。在证明中 在原则研究中，我们证明了四种DRα1-MOG的每日治疗可显着降低梗塞大小 中风后的小鼠。然而，该研究是使用腔内脑中动脉阻塞进行的 （MCAO）模型，它导致机械而不是血栓闭塞，这是最常见的原因 人类中风。为了更忠实地模仿临床中风，我们开发了一种新颖的血栓栓塞模型 小鼠中的中风将构成当前建议的基础。此外，衰老和生物性别很好 记录的关键确定中风结果，部分是通过对中风引起的差异影响 炎症反应。提出的STTR将进一步表征DRα1-MOG的受保护作用 中风的临床相关血小板模型以及初始时间的临床上重要变量 治疗，性别和年龄，以估计如何使用DRα1-MOG来治疗中风患者。