We previously identified a human monoclonal antibody, termed HIgM12 that stimulates spontaneous locomotor activity in a chronically demyelinating mouse model of multiple sclerosis. When tested as a molecular substrate, HIgM12 stimulated neurite outgrowth in vitro. We recently reported that polysialic acid (PSA) attached to the neural cell adhesion molecule (NCAM) is one of the cellular antigens for HIgM12. Fluorescent double-labeling of astrocytes using HIgM12 and commercially available anti-PSA antibody showed dramatic co-localization. Neural tissue homogenates and primary CNS cultures from mice lacking the three major NCAM splice variants NCAM180, NCAM140 and NCAM120 (NCAM KO) were no longer able to bind HIgM12. Furthermore, enzymatic digestion of PSA on wild type (WT) glia abolished HIgM12-binding. Moreover, neurons and glia from NCAM KO animals did not attach to HIgM12-coated nitrocellulose in neurite outgrowth assays. We conclude that HIgM12 targets PSA attached to NCAM, and that the PSA moiety mediates neuronal and glial adhesion and subsequent neurite outgrowth in our in vitro assay. Therefore, this anti-PSA antibody may serve as a future therapeutic to stimulate functional improvement in multiple sclerosis patients and other neurodegenerative diseases.
Watzlawik JO, Painter MM, Wootla B, Rodriguez M A human anti-polysialic acid antibody as a potential treatment to improve function in multiple sclerosis patients.J Nat Sci. 2015 Aug;1(8). pii: e141.
HigM2 is a remyelinating antibody that we have been hearing about for years and years but I’m not sure I have heard of how it is supposed to work so now it is said that it works via Polysialic acid is an unusual posttranslational modification that occurs on neural cell adhesion molecules (NCAM). Polysialic acid is considerably anionic. This strong negative charge gives this modification the ability to change the protein’s surface charge and binding ability. In the synapse, polysialation of NCAM prevents its ability to bind to NCAM’s on the adjacent membrane.Neural cell adhesion molecule (NCAM), also called CD56, is a glycoprotein expressed on the surface of neurons, glia, skeletal muscle and natural killer cells. NCAM has been implicated as having a role in cell–cell adhesion, neurite outgrowth, and synaptic formation. Anti-LINGO another remylinating agent also can affect nerve outgrowth but also effects the maturation of oligodendrocytes and myelination.
So now we know how it works will it move forward. This molecule has been in development for so long now, I wonder if it will ever make it.