Targeting autoreactive antibodies for the therapy of MOG antibody-associated disease

项目摘要/摘要 该项目的总体目标是开发一种治疗脱髓鞘的新疗法。 涉及针对髓鞘少突胶质细胞糖蛋白(MOG)的自身反应抗体的疾病。 MOG抗体相关疾病(MOGAD)包括水通道蛋白4抗体血清阴性 视神经脊髓炎光谱障碍(NMOSD)、急性播散性脑脊髓炎、视神经 神经炎、脊髓炎和脑干脑脊髓炎，通常影响儿童或年轻人。 该病的病程经常复发，可导致失明、衰弱瘫痪和 认知效应。 目前MOGAD的治疗方案存在严重的局限性。免疫抑制剂 例如强的松/强的松龙或硫唑嘌呤导致全身免疫抑制和其他 严重的副作用。血浆置换以清除自身反应性抗体和其他 炎症介质在很高比例的患者中会导致不良后果。 此外，利妥昔单抗等耗尽B细胞的抗体的交付已导致令人失望 结果，大约30%的患者复发。因此，迫切需要发展 针对MOGAD潜在破坏性影响的新的和改进的治疗方法。 选择性靶向致病抗体的治疗方法的发展是可望的。 以克服目前与治疗MOGAD相关的问题。此应用程序旨在 解决这一问题的方法是开发基于抗体的工程化试剂，这种试剂可以快速、特异地 消耗MOG特异性抗体，同时不影响具有 预防感染等作用。这项新技术被称为Seldeg技术(用于 选择性降解)。 这项研究的具体目的是： 1.设计并表达针对人MOG特异性抗体的Seldegs。 2.分析Seldegs的稳定性和结合活性。 这种方法不仅可以对潜在的 MOGAD的破坏性后果，但也将为类似的 在许多其他临床环境中采取的方法，其中致病抗体导致 疾病。

PROJECT SUMMARY/ABSTRACT The overall goal of this project is to develop a novel therapeutic for the treatment of demyelinating disease involving autoreactive antibodies specific for myelin oligodendrocyte glycoprotein (MOG). MOG antibody-associated disease (MOGAD) encompasses aquaporin-4-antibody seronegative neuromyelitis optica spectrum disorder (NMOSD), acute disseminated encephalomyelitis, optic neuritis, myelitis and brainstem encephalomyelitis and usually affects children or young adults. The disease course is frequently relapsing, and can lead to blindness, debilitating paralysis and cognitive effects. Current treatment regimens for MOGAD suffer from serious limitations. Immunosuppressants such as prednisone/prednisolone or azathioprine lead to general immunosuppression and other severe side effects. Plasma exchange to remove the autoreactive antibodies and other inflammatory mediators results in adverse consequences in a high percentage of patients. Further, the delivery of B cell depleting antibodies such as rituximab has led to disappointing results, with relapses in around 30% patients. Consequently, there is a pressing need to develop new and improved therapies for the potentially devastating effects of MOGAD. The development of therapeutics to selectively target the pathogenic antibodies is expected to overcome the current problems associated with treating MOGAD. This application seeks to address this by generating engineered, antibody-based reagents that specifically and rapidly deplete MOG-specific antibodies, whilst not affecting the levels of antibodies that have a protective role against infection etc. This novel technology is called Seldeg technology (for selective degradation). The Specific aims of the study are: 1. To design and express Seldegs to target human MOG-specific antibodies. 2. To analyze the stability and binding activity of the Seldegs. This approach could not only be transformative for the management of the potentially devastating consequences of MOGAD, but would also lay the foundations for analogous approaches to be taken in many other clinical settings where pathogenic antibodies lead to disease.