Oral autoantigen therapy for the treatment of Multiple Sclerosis

摘要 多发性硬化症影响着全世界数百万人，虽然过去十年 看到了一波疾病修饰药物和免疫调节疗法的批准， FDA，这些药物很昂贵，仍然没有治愈这种疾病。而且 残疾的机会是相当确定的许多诊断患者。 几十年来，抗原特异性治疗已经用于实验性的抗肿瘤治疗。 自身免疫性脑脊髓炎（EAE）动物模型，以证明其潜在的 抑制自身免疫反应预防和限制的成功 已经使用多种髓鞘蛋白记录了正在进行的疾病（治疗）， 肽、自身抗原缀合物和模拟物，当以各种方式（全身）施用时 注射、鼻内、透皮）。虽然这些成功在临床上是不可翻译的， 我们已经学到了很多关于必须解决的路障和障碍， 治疗方法最终会实现。这些方法包括使用自身抗原， 多个表位，在耐受性背景下抗原的呈递，以及实用平台 它可以产生大量的治疗所需的自身抗原，而不需要极端的成本。 伴随SBIR第一阶段应用的实验方法直接 解决了目前口服耐受疗法的局限性。我们建议制造两个 与多发性硬化相关的自身抗原-髓鞘少突胶质细胞蛋白（MOG）， 蛋白脂质蛋白（PLP）-作为与呼肠孤病毒sigma 1蛋白的融合蛋白，使用大豆作为 用于生产和配方的实用表达系统。我们还建议， 含有来自髓鞘碱性蛋白（MBP）、MOG和PLP的结构域的嵌合蛋白，还 与sigma 1蛋白融合。我们的方法背后的逻辑在于呼肠孤病毒sigma 1 蛋白质结合覆盖粘膜淋巴组织的微折叠细胞。自身抗原融合至 σ 1蛋白将免疫原靶向这些细胞并以“耐受性”方式递送自身抗原 限制正在进行的自身免疫反应。在以前的研究中，我们证明了 含有髓鞘碱性蛋白（MBP）的大豆来源的σ 1融合蛋白的功效 自身抗原在目前的研究将扩大我们的研发，包括表达和功效测试 MOG-sigma 1和PLP-sigma 1自身抗原在大豆中表达的差异。我们的长期目标是 开发出一种实用的MBP、MOG和PLP自身抗原混合物，可用于 大多数患者存在针对这三种蛋白质中任何一种的自身抗体。

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.