Effects of ASKP1240 combined with tacrolimus or mycophenolate mofetil on renal allograft survival in Cynomolgus monkeys.

Costimulatory signals play crucial roles in fully activating T cells that are involved in allograft rejection (1–3). The CD40-CD154 costimulatory pathway has previously been shown to be an important interaction that mediates both the humoral and cellular immune responses (4–7). It has been demonstrated that blocking CD40-CD154 signaling pathway is a successful strategy to reduce allograft rejection (8–10). CD154 was initially chosen as primary therapeutic target, but further studies encountered setbacks because of the unexpected thromboembolic complications associated with the administration of anti-CD154 antibodies (11–14). Targeting CD40 as an alternate therapeutic strategy was developed when it was recognized that these thrombotic complications were CD40-independent (15, 16). To date, several anti-CD40 antibodies that are engineered as immunoglobulin G (IgG)1 or IgG4 chimeric isotypes or fully human IgG4 have been shown to prevent allograft rejection in experimental studies (17–21). ASKP1240 is an anti-CD40 monoclonal antibody (mAb) consisting of fully human IgG4. It interrupts the CD40-CD154 pathway by preventing the interaction between CD40 and CD154. In addition, ASKP1240 does not cause antibody-dependent cell-mediated cytotoxicity or complement dependent cytotoxicity (19, 22). ASKP1240 monotherapy has been demonstrated to delay renal, islet, and hepatic allograft rejection in nonhuman primate (NHP) models (19, 23–25). This study evaluated the effects of ASKP1240 when administered as a monotherapy or in combination with a subtherapeutic dose of tacrolimus or mycophenolate mofetil (MMF) on renal allograft survival in NHPs. We also assessed the pharmacokinetic (PK) profile of ASKP1240 and its effect on cytokine release in transplanted monkeys. We found that ASKP1240 significantly prolonged allograft survival as a monotherapy or in combination with tacrolimus or MMF without causing obvious side effects.