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

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.PROJECT NARRATIVE Treatments that are currently available for antibody-mediated autoimmune diseases such as MOG antibody-associated disease (MOGAD) are generally immunosuppressive, are associated with adverse events and/or have limited efficacy. To address this issue, in this application we propose to develop a novel treatment that selectively removes the autoreactive antibodies which are involved in the disease process, without affecting the levels of other antibodies that are important for protection against infectious agents such as bacteria and viruses. This approach has the potential to be a game-changer for the clinical management of MOGAD, in addition to having broader relevance for the treatment of other antibody-mediated autoimmune diseases.