Anti-CD40LG monoclonal antibody, clone 39H5 [R-PE]

Pancreatic islet transplantation is a promising treatment for treatment of type 1 diabetes; however, transplantation outcomes have been disappointing due to early graft loss that is mediated by many immune responses. Immune cells not only directly damaged islet but also produced reactive oxygen species (ROS), which is highly toxic to islet cells. Metallothionein (MT) can provide protection against oxidative stress by scavenging various ranges of ROS including superoxide, hydroxyl radical, hydrogen peroxide and nitric oxide. For scavenging immune response-induced ROS, cell-penetrating Tat peptide-metallothionein (Tat-MT) was delivered into islets. The viability of Tat-MT-treated islets was not damaged during co-culture with macrophages or ROS-generating paraquat. When Tat-MT-treated islets were xenotransplanted, ROS production was significantly attenuated at the islets. Eventually, the survival time of Tat-MT-treated islets was significantly enhanced without any immunosuppressant medicine. Additionally, we confirmed that the survival time of Tat-MT-treated islets in all animals was dramatically improved when accompanied with low dose immunosuppressive agents (tacrolimus and anti-CD154 monoclonal antibody), indicating that Tat-MT delivery could have synergistic effect with immunosuppressants. Collectively, this new combination therapy of Tat-MT delivery with low dose immunosuppressant would be a powerful remedy for successful outcome of islet xenotransplantation.

Antibody formation against therapeutic agents, such as tumor necrosis factor inhibitors and Factor VIII, that leads to treatment failure has become a major challenge in the treatment of rheumatoid arthritis and hemophilia. It is well known that anti-CD154 antibodies have the highest potential to inhibit these types of adverse immune responses. Nevertheless, the formation of thromboemboli is the major hurdle in the clinical application of these anti-CD154 blocking antibodies. For this, we attempted to derive an idea as to how this major complication can be eliminated. Consequently, we developed a novel anti-CD154 chimeric antibody, which was made by genetic modification of a portion of human IgG4 Fc. This antibody has an almost comparable antigen binding affinity to a previously developed 5C8 clone and near completely inhibited CD40-CD154 interaction and T cell-dependent B cell activation in vitro. Even under the condition, where we injected immune complexes comprised of RD-05 and CD154 antigen, the formation of thromboembolism was not seen in human Fc gamma RIIA-transgenic mice, whereas the converse was exactly true in the case of 5C8 antibody. Notably, just two injections of RD-05 antibody was sufficient to inhibit the antibody formation against adalimumab during 3-4 months in cynomolgus macaques, in which adalimumab was repeatedly injected for 12 weeks. Based on these findings, we suggest that this RD-05 antibody can be applied to antibody-mediated autoimmune diseases, including systemic lupus erythematosus and immune thrombocytopenic purpura. (C) 2018 Elsevier Inc. All rights reserved.