Abstract
Anti-myelin associated glycoprotein (MAG) neuropathy patients exhibit high levels of monoclonal IgM autoantibodies against the carbohydrate epitope HNK-1 (human natural killer-1). This glycoepitope is abundantly presented on the adhesion molecule MAG as well as on other glycoconjugates of the peripheral nervous system. Binding of the autoantibodies results in demyelination of the peripheral nerves causing severe sensorimotor deficits in anti-MAG neuropathy patients, including paresthesias and sensory ataxia. We have previously reported the effective neutralization and removal of anti-HNK-1 IgM autoantibodies in an immunological mouse model with the glycopolymer PPSGG (poly-L-lysine(400) loaded with phenyl disodium 3-O-sulfo-ß-D-glucopyranuronate)-(1 → 3)-ß-D-galactopyranoside). Here, we further explore its physicochemical characteristics and its mode of action. The linear glycopolymer PPSGG is highly negatively charged, with an approximate length of 100 nm, and is readily taken up by liver and spleen resident macrophages through scavenger receptors. No aggregate formation or immune complex deposition in these or other organs is observed and despite fast and extensive uptake of PPSGG into Kupffer cells of the liver, it does not exhibit hepatotoxic effects ex vivo. In the presence of the anti-HNK-1 IgM antibodies, it preferentially forms complexes in a 1:1 or 1:2 binding stoichiometry (PPSGG/anti-HNK-1 IgM), however, without leading to aggregate formation though crosslinking of the multivalent binding partners in vitro. The complexes are actively taken up by murine macrophages in vivo and in human macrophages in vitro. PPSGG is designed to selectively and quickly remove disease-causing anti-HNK-1 IgM antibodies from circulation. Here, we demonstrate the unique mode of action of PPSGG and its therapeutic potential as the first antigen-specific treatment for anti-MAG neuropathy.