ИСТИНА

Multiple Sclerosis (MS) is a dreadful disease associated with inflammation in the central nervous system white matter and is thought to be mediated by autoimmune processes. Clonal expansion of B-cells, their antibody products, and T-cells, hallmarks of inflammation in the central nervous system are found in MS. Autoreactive B-Cells depletion by anti-CD20/19 monoclonal antibody Retuximab® may raise a new era in MS therapy. In this work we tried to create more specific and effective way to eliminate pathogenic B-Cells. We have designed immunotoxins based on Barnase, Pseudomonas toxin, Shiga-like toxin E.coli and Fc domain of human antibody IgGγ1 fused with c-myc epitope sequence. C-MYC hybridoma cell line producing anti-c-myc IgG was chosen as model of autoreactive B-cells. c-myc sequence fused with toxins provide address delivery of toxic agent to target cells. We demonstrated functional activity of design immunotoxins in vitro and showed that obtained fusion molecules were recognized by antibodies produced by targeted hybridoma. Finally we tested created immunotoxins in vivo using C-MYC and irrelevant hybridoma cell lines. Pseudomonas-containing immunotoxin showed one of the highest cytotoxic effects on the model cells but possessed promiscuous specificity. Agent based on Shiga-like toxin demonstrated mild both cytotoxicity and specificity. In case of Barnase and Fc-containing immunotoxins our data suggest that these molecules are best choice for B-Cells depletion due to the excellent balance between their legibility and toxic properties.