Oral autoantigen therapy for the treatment of Multiple Sclerosis

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.