Oral autoantigen therapy for the treatment of Multiple Sclerosis

摘要 多发性硬化症影响着全球数百万人，而过去十年 看到了一波疾病修改药物和免疫调节疗法的浪潮 FDA表示，这些药物价格昂贵，目前仍无法治愈这种疾病。此外， 对于许多确诊的患者来说，残疾的机会是相当确定的。 几十年来，抗原特异性治疗一直在实验中使用 自身免疫性脑脊髓炎(EAE)动物模型的建立 抑制自身免疫反应。预防(预防)和限制方面的成功 正在进行的疾病(治疗)已经使用各种髓鞘蛋白进行了记录， 以多种方式给药时的多肽、自身抗原结合物和模拟物(全身性 注射、鼻腔注射、经皮注射)。虽然这些成功在临床上是不可翻译的， 我们已经了解了大量的路障和障碍，如果这样做，必须加以解决 治疗最终是要实现的。这包括使用含有以下物质的自身抗原 多表位、抗原在可容忍的背景下的呈现以及实用平台 这可以产生治疗所需的大量自身抗原，而不需要极端的成本。 伴随SBIR第一阶段直接应用的实验方法 解决目前口服耐受治疗的局限性。我们计划生产两个 与多发性硬化相关的自身抗原-髓鞘少突胶质细胞蛋白(MOG)和 蛋白脂蛋白(PLP)作为呼肠孤病毒Sigma1蛋白的融合蛋白，以大豆为例 生产和配方的实用表达系统。我们还建议制定一项 含有髓鞘碱性蛋白(MBP)、MOG和PLP结构域的嵌合蛋白，也 融合成Sigma1蛋白。我们方法背后的逻辑在于呼肠孤病毒Sigma1的能力 结合覆盖黏膜淋巴组织的微折叠细胞的蛋白质。融合的自身抗原 Sigma1蛋白将免疫原靶向这些细胞，并将自身抗原传递给这些细胞 以限制正在进行的自身免疫反应。在之前的研究中，我们证明了 含有髓鞘碱性蛋白(MBP)的大豆来源的Sigma1融合蛋白的疗效 自身抗原。在目前的研究中，将扩大我们的研发，以包括表达和有效性测试 MOG-Sigma1和PLP-Sigma1自身抗原在大豆中的表达。我们的长期目标是 开发一种实用的MBP、MOG和PLP自身抗原鸡尾酒，可用于 大多数出现针对这三种蛋白中任何一种的自身抗体的患者。

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.