Pharmacokinetics and Pharmacodynamics of ASKP1240, a Fully Human Anti-CD40 Antibody, in Normal and Renal Transplanted Cynomolgus Monkeys

T cells play a central role in mediating transplant rejection by orchestrating the inflammatory events that ultimately lead to graft destruction. Immunosuppressants have been the primary treatment for preventing transplant rejection for the past 50 years. The aim of immunosuppressive therapies is to block T cell activation, thereby attenuating these processes. However, long-term use of immunosuppressants carries an increased risk of infection and cancer (1–3). As a new immunotherapy, monoclonal antibody (mAb) therapy has been used in transplantation, cancer, and autoimmune diseases (4–6). Activation of naive T cells requires costimulatory signals provided by the B7 and tumor necrosis factor (TNF) families, in which the CD40-CD154 pathway is preeminent in the T cell response after alloantigen presentation (7–10). Blocking the CD40-CD154 costimulatory pathway for T-cell activation has been shown to be effective in several models of transplantation and autoimmune diseases (11–13). Recent experimental studies (14–19) and early clinical trials (20) have reported that a humanized anti-CD154 antibody can induce long-term allograft survival, but the clinical trial was interrupted by unexpected thromboembolic complications. Thus, inhibition of the counter molecule for CD154, CD40, has become an alternative approach in transplantation. ASKP1240 has been demonstrated to inhibit human CD154-induced proliferation of peripheral blood mononuclear cells, suppress the delayed-type hypersensitivity reaction and tetanus toxoid-specific antibody formation in nonhuman primates, and exhibit potent immunosuppressive effects to prolong renal allograft survival in Cynomolgus monkeys (21–23). This study aimed to investigate the serum concentration of ASKP1240 in a pharmacokinetic (PK) study, evaluate the binding ability of ASKP1240 in CD20+ B cells in a pharmacodynamics (PD) study, and clarify the PK/PD relationship in normal and renal transplanted monkeys. These results will be helpful to select the optimal dose and timing for ASKP1240 therapy in clinical trials.