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，旨在研究新型免疫调节剂 DRα1-MOG 在 临床相关的小鼠血栓栓塞性中风模型。我们之前已经证明T细胞被激活 中风后，浸润大脑，加剧缺血性脑损伤。减少 T 细胞活化的策略 脑组织浸润已被研究为中风的潜在治疗策略；然而，非 特异性抑制T细胞功能是免疫抑制。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。早期的 RTL 结构成功地防止了缺血引起的 脑损伤，但前提是 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 RTL 构建体治疗人类中风的一个重要限制是需要快速 将受体 MHC II 类与 pMHC 构建体的 β1 结构域相匹配。因此我们设计了一部小说 重组蛋白由与 MOG-35-55 肽 (DRα1-MOG) 连接的 HLA-DRα1 结构域组成，但缺乏 pMHC 中发现的 β1 结构域。因为 DRα1 结构域存在于所有人类中并且不会被识别 与国外一样，使用 DRα1 构建体进行治疗不需要对潜在接受者进行 HLA 筛查。在一个证明中 在原理研究中，我们证明每天四次使用 DRα1-MOG 治疗可显着减少梗塞面积 小鼠中风后。然而，该研究是使用腔内大脑中动脉闭塞进行的 （MCAO）模型，它导致机械闭塞，而不是血栓栓塞闭塞，这是最常见的原因 人类中风。为了更忠实地模拟临床中风，我们开发了一种新型血栓栓塞模型 鼠标中风，这将构成当前提案的基础。此外，衰老和生物性别也很重要 记录了中风结果的关键决定因素，部分是通过对中风诱发的不同影响 炎症反应。拟议的 STTR 将进一步表征 DRα1-MOG 的保护作用 临床相关的中风血栓栓塞模型，以及临床上重要的初始时间变量 治疗、性别和年龄，以估计 DRα1-MOG 可广泛用于治疗中风患者。