TAK-079 is a high affinity monoclonal antibody that effectively mediates CD38+ cell depletion

Abstract

TAK-079 is a fully human, non-agonistic, IgG1 cell-depleting monoclonal antibody that binds human CD38 with high affinity (K_D 1.2 nM, KinExA) and cross reacts with cynomolgus monkey CD38. CD38 is a cADPR hydrolase expressed on human plasmablasts, plasma cells, NK cells and activated T and B cells, but not on mature platelets or red blood cells, based on TAK-079 binding. In patients with rheumatoid arthritis (RA) and systemic lupus erythematousus (SLE), plasma cells, as well as activated B and T cells may be important contributors to disease. Unlike other B cell-selective therapies which target CD20 and do not directly deplete plasmablasts, which are CD20^low/negative, CD38 is expressed at high levels on plasmablasts and plasma cells making these cells a direct target of TAK-079. In vitro studies with human blood cells and cell lines showed that binding of TAK-079 to CD38 did not result in PBMC cytokine activation demonstrating that TAK-079 is not an agonist. Rather, it mediated depletion of human B lineage cell lines by ADCC and CDC and in most cases cell lines with increased CD38 expression were more susceptible to cell lysis. This is consistent with findings in healthy cynomolgus monkeys where the efficiency of depletion correlated with level of CD38 expression and TAK-079 dose level. NK cells, which express high levels of CD38, were depleted to a greater extent than CD20+ B cells and CD3+ T cells, which express less CD38. In vivo, TAK-079 potently suppressed the human B cell recall responses to antigen in a mouse adoptive transfer model. Together these data support the further investigation of TAK-079 in autoimmune diseases.