A novel cyclic peptide that blocks human autoimmune antibodies for the treatment of Multiple sclerosis

Multiple sclerosis (MS) is a chronic autoimmune disease causing demyelination in the central nervous system, with binding of auto-reactive (auto)antibodies to myelin auto-antigens such as GlialCAM protein, myelin basic protein (MBP) and myelin oligodendrocyte glycoprotein (MOG) contributing to myelin destruction. Current MS therapeutics are largely non-specific to the molecular underpinnings of disease, primarily suppressing B- and/or T-cell sub/populations to combat autoimmunity. We hypothesized that selectively blocking disease-specific autoantibodies from binding autoantigen represents a targeted, less pan-immunosuppressive approach to treat autoantibody-related pathology in MS patients. Here, we describe the rational in silico design of a single 8-mer cyclic peptide candidate (called 'CAP8') designed to target the CDRL3 loops of 23x human MS autoantibodies that bind GlialCAM, MBP or MOG epitopes. To address the recently identified pathology of human anti-GlialCAM autoantibodies in MS, our preliminary in vitro MST studies suggested preferential binding of CAP8 to human anti-GlialCAM autoantibody under the tested conditions. We further employed a modified Western blot protocol that provided preliminary support for a reduction in anti-GlialCAM autoantibody binding to its phospho-epitope in the presence of CAP8, relative to control peptides. To our knowledge, this approach represents a first-in-class therapeutic platform aimed at designing more targeted, less pan-immunosuppressive therapeutic cyclic peptides for the alleviation of autoantibody-related pathology in MS.