[S8-3] Therapeutic strategy for Tetanus by the neutralizing human antibody
Tetanus is not only severe fatal disease, but also disaster-related infectious disease caused by tetanus neurotoxin (TeNT). TeNT is secreted from Clostridium tetani and composed of a light chain (Lc) and a heavy chain, the latter of which is classified into two domains, N-terminus Hn and C-terminus Hc. It has been clarified how TeNT induces neurotoxic disease by molecular dissections of TeNT subdomains. However, it remains unclear which TeNT domains are involved in the pathogenesis. Here we try to elucidate the molecular pathogenesis by which TeNT causes lethality by utilizing the recombinant monoclonal antibodies (rmAb) which are produced from cloned Immunoglobulin genes of human peripheral blood lymphocytes. Biochemical analysis revealed that several TeNT-reactive rmAbs bind to each TeNT domain, one of which is responsible for ganglioside GT1b-binding involved in the TeNT entry. Neutralizing activity was exhibited and enhanced with combination of antibodies when administrating TeNT in mice. Meanwhile, computational structural analysis indicates that pharmaceutical optimization with antibody grafting or 3D-docking simulation brings potent ability of antibody as therapeutics to Tetanus treatment. We will also discuss the application of human antibody based on Tetanus treatment.