Long-Term Hepatic Allograft Acceptance Based on CD40 Blockade by ASKP1240 in Nonhuman Primates

Abstract

Blockade of the CD40-CD154 costimulatory signal is an attractive strategy for immunosuppression and tolerance induction in organ transplantation. Treatment with anti-CD154 monoclonal antibodies (mAbs) results in potent immunosuppression in nonhuman primates (NHPs). Despite plans for future clinical use, further development of these treatments was halted by complications. As an alternative approach, we have been focusing on the inhibition of the counter receptor, CD40 and have shown that a novel human anti-CD40 mAb, ASKP1240, markedly prolongs renal allograft survival in NHPs, although allografts eventually underwent chronic allograft nephropathy. On the basis of our previous findings that a CD40-CD154 costimulation blockade induces tolerance to hepatic, but not cardiac, allografts in rodents, we tested here our hypothesis that a blockade of CD40 by ASKP1240 allows acceptance of hepatic allografts in NHPs. A 2-week ASKP1240 induction treatment prolonged liver allograft survival in NHPs; however, the graft function deteriorated due to chronic rejection. In contrast, a 6-month ASKP1240 maintenance monotherapy efficiently suppressed both cellular and humoral alloimmune responses and prevented rejection on the hepatic allograft. No serious side effects, including thromboembolic complications, were noted in the ASKP1240-treated monkeys. We conclude that CD40 blockade by ASKP1240 would be a desirable immunosuppressant for clinical liver transplantation.

ASKP1240, a Fully Human Anti-CD40 Monoclonal Antibody, Prolongs Pancreatic Islet Allograft Survival in Nonhuman Primates

“…In this study, we adopted induction and maintenance treatment protocols for ASKP1240 at a dose of 10 mg/kg in an allogeneic islet transplantation model in cynomolgus monkeys, based on our previous findings in kidney and liver transplantation studies (21)(22)(23). Herein, we demonstrate that ASKP1240 monotherapy markedly prolonged the survival of pancreatic islet allografts.…”

“…The frequency of interferon (IFN)-g-secreting T cells reactive to donor antigens or third-party antigens (leukocytes from a third-party monkey) was determined using the ELIspot PLUS Monkey IFN-g kit (Mabtech, Cleveland, OH), as described previously (23).…”

“…In parallel with other researchers, we have been attempting to develop a new anti-CD40 mAb. Previously, we demonstrated that a fully human anti-CD40 mAb, ASKP1240, strongly inhibited both cellular and humoral alloimmune responses, and markedly prolonged renal and hepatic allograft survival in cynomolgus monkeys without causing apparent adverse effects including thromboembolism (21)(22)(23). In this study, we evaluated the effect of ASKP1240 on allogeneic PITx in cynomolgus monkeys.…”

Technique for Orthotopic Liver Transplantation in Cynomolgus Monkeys (Macaca Fascicularis)

“…Experiments in ro dents and nonhuman primates (NHP) have improved our understanding of this phenomenon [1][2][3][4]. However, further studies are necessary to achieve immunological tolerance in a clinical setting.…”

“…Due to the presence of resident regulatory cells and cytokines, the liver is the most tolerogenic solid organ with comparably lower rejection rates and immunosuppressant require ments [5]. Based on this phenomenon, recent studies have utilized animal models of liver transplantation (LT) to investigate new strategies to modulate the immune system [2,3,6]. However, intestinal congestion during the anhepatic phase of LT remains a crucial problem for achieving reliable survival of animal models.…”