Oral autoantigen therapy for the treatment of Multiple Sclerosis

口服自身抗原疗法治疗多发性硬化症

基本信息

批准号：
10331867
负责人：
KENNETH J PILLER
金额：
$ 29.5万
依托单位：
SOYMEDS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-22 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10331867
关键词：
Address Affect American Amino Acids Animal Model Antigen Presentation Antigens Attenuated Autoantibodies Autoantigens Autoimmune Autoimmune Responses Binding Cells Chimeric Proteins Clinic Clinical Complex Cytoplasmic Tail Development Diagnosis Disease Drug Costs Epitope spreading Epitopes Experimental Animal Model Experimental Autoimmune Encephalomyelitis Extracellular Domain FDA approved Formulation Frequencies Goals Human Immune response Injectable Injections Logic Lymphoid Tissue Modeling Mucous Membrane Multiple Sclerosis Myelin Myelin Basic Proteins Myelin Proteins Neurologic Oligodendroglia Oral Patients Peptides Persons Pharmaceutical Preparations Phase Production Prophylactic treatment Proteins Proteolipids Rattus Recombinant interferon beta-1b Reovirus Risk Route Small Business Innovation Research Grant Soybeans Specificity System Technology Testing Therapeutic Translating Treatment Efficacy cost disability efficacy testing feasibility testing lymphoid organ multiple sclerosis treatment oral tolerance phase 1 study physically handicapped prevent prophylactic protein complex research and development soy success technology development

项目摘要

Abstract Multiple Sclerosis affects millions of people worldwide and while the past decade has seen a wave of disease-modifying drugs and immunomodulating therapies approved by the FDA, these drugs are expensive and there is still no cure for the disease. Furthermore, the chance of disability is fairly certain for many diagnosed patients. For several decades, antigen-specific treatments have been used in experimental autoimmune encephalomyelitis (EAE) animal models to demonstrate their potential for suppressing autoimmune responses. Successes with preventing (prophylaxis) and limiting ongoing disease (therapeutic) have been documented using a wide variety of myelin proteins, peptides, autoantigen-conjugates, and mimics when administered in a variety of ways (systemic injections, intranasal, transdermal). While those successes were not translatable in the clinic, we have learned a great deal about the roadblocks and hurdles that must be addressed if such therapies are to eventually be realized. These include the use of autoantigens containing multiple epitopes, the presentation of antigens in a tolerizing context, and a practical platform that can generate the large amounts of autoantigens needed for therapy without extreme cost. The experimental approach in the accompanying SBIR Phase I application directly addresses current limitations with oral tolerance therapy. We propose to manufacture two autoantigens involved with multiple sclerosis – myelin oligodendrocyte protein (MOG) and proteolipid protein (PLP) – as fusion proteins with reovirus sigma1 protein, using soybean as a practical expression system for production and formulation. We also propose to make a chimeric protein containing domains from myelin basic protein (MBP), MOG and PLP, also fused to sigma1 protein. The logic behind our approach lies in the ability of the reovirus sigma1 protein to bind microfold cells covering mucosal lymphoid tissues. Autoantigens fused to sigma1 protein target the immunogen to these cells and deliver the autoantigen in a “tolerizing context” to limit an ongoing autoimmune response. In previous studies we demonstrated efficacy of a soy-derived sigma1 fusion protein containing the myelin basic protein (MBP) autoantigen. In the current study will expand our R&D to include expression and efficacy testing of MOG-sigma1 and PLP-sigma1 autoantigens expressed in soybean. Our long term goal is to develop a practical cocktail of MBP, MOG and PLP autoantigens that can be formulated for the majority of patients that present with autoantibodies against any of these three proteins.

抽象的多发性硬化症会影响全球数百万的人，而过去十年看到一波改良疾病的药物和免疫调节疗法 FDA，这些药物很昂贵，仍然无法治愈该疾病。此外，对于许多被诊断的患者来说，残疾的机会相当确定。几十年来，抗原特异性治疗已用于实验自身免疫性脑脊髓炎（EAE）动物模型，以证明其潜力抑制自身免疫反应。预防（预防）和限制的成功正在进行的疾病（治疗）已使用多种髓磷脂蛋白记录在案肽，自身抗原偶联和模仿以多种方式给药（系统性注射，鼻内，透皮）。尽管这些成功在诊所无法翻译，但我们已经了解了有关障碍和障碍的很多知识最终将实现疗法。这些包括使用含有的自动抗原多个表位，在容忍环境中呈现抗原的表现以及实用的平台这可以产生用于治疗所需的大量自动抗原，而无需极高的成本。参与SBIR I期应用程序中的实验方法直接通过口服耐受疗法解决当前局限性。我们建议制造两个与多发性硬化症有关的自身抗原 - 髓磷脂少突胶质细胞蛋白（MOG）和蛋白脂蛋白蛋白（PLP） - 用大豆作为一种融合蛋白与葡萄病毒Sigma1蛋白作为融合蛋白生产和配方的实用表达系统。我们还建议做一个来自髓磷脂碱性蛋白（MBP），MOG和PLP的嵌合蛋白，也与Sigma1蛋白融合。我们的方法背后的逻辑在于依肠病毒Sigma1的能力蛋白质结合覆盖粘膜淋巴组织的微膜细胞。自动抗原融合 Sigma1蛋白将免疫原靶向这些细胞，并在“耐受性”中输送自身抗原上下文”以限制正在进行的自身免疫反应。在先前的研究中，我们证明了含有髓磷脂碱性蛋白（MBP）的大豆衍生的Sigma1融合蛋白的功效自动抗原。在当前的研究中，将扩大我们的研发，包括表达和效率测试在大豆中表达的Mog-Sigma1和PLP-Sigma1自动抗原。我们的长期目标是开发MBP，MOG和PLP Autoantigens的实用鸡尾酒，可以为大多数患有自身抗体的患者针对这三种蛋白质中的任何一种。