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.

这是一项I期STTR，旨在研究一种新型免疫调节剂DRα1-MOG在 临床相关的血栓栓塞性中风模型。我们之前已经证明T细胞被激活， 在中风后，渗透大脑，并加重缺血性脑损伤。减少T细胞活化的策略， 脑组织浸润已被研究作为中风的潜在治疗策略;然而， 特异性抑制T细胞功能是免疫抑制性的。因此，我们开发了重组T细胞受体 (TCR)配体（RTL），是由共价连接的β1和α1链组成的部分MHC II分子 与抗原肽相连早期RTL构建体成功地防止了缺血诱导的 脑损伤，但只有当RTL含有神经抗原肽和匹配的II类MHC部分， 收件人。使用这些早期RTL构建体治疗人中风的一个显著限制是需要快速地 使受体MHC II类与pMHC构建体的β1结构域匹配。因此，我们设计了一部小说 重组蛋白由HLA-DRα1结构域连接到MOG-35-55肽（DRα1-MOG），但缺乏 pMHC中的β1结构域。因为DRα1结构域存在于所有人类中， 作为外来物，使用DRα1构建体的治疗不需要对潜在的受体进行HLA筛查。在一个证明 在原理研究中，我们证明每日4次DRα1-MOG治疗可显著减少梗死面积 在小鼠中风后。然而，这项研究是使用大脑中动脉闭塞进行的。 （MCAO）模型，其导致机械性而不是血栓栓塞性闭塞，这是MCAO最常见的原因。 人类中风为了更真实地模拟临床中风，我们开发了一种新的血栓栓塞模型， 这将构成当前提案的基础。此外，老化和生物性别是很好的 记录了卒中结局的关键决定因素，部分是通过对卒中引起的 炎症反应。拟定的STTR将进一步表征DRα1-MOG的保护作用， 卒中的临床相关血栓栓塞模型，以及初始时间的临床重要变量 治疗、性别和年龄，以估计DRα1-MOG可用于治疗卒中患者的范围。