A human anti-CD40 monoclonal antibody, 4D11, for kidney transplantation in cynomolgus monkeys: induction and maintenance therapy

Abstract

Blockade of CD40-CD154 signaling pathway is an attractive strategy to induce potent immunosuppression and tolerance in organ transplantation. Due to its strong immunosuppressive effect shown in nonhuman primate experiments, anti-CD154 monoclonal antibodies (mAbs) have been tried in clinical settings, but it was interrupted by unexpected thromboembolic complications. Thus, inhibition of the counter molecule, CD40, has remained an alternative approach. In the previous preliminary study, we have shown that 4D11, a novel fully human anti-CD40 mAb, has a fairly potent immunosuppressive effect on kidney allograft in nonhuman primates. In this study, we aimed to confirm the efficacy and untoward events of the 2-week induction and 180-day maintenance 4D11 treatments. In both, 4D11 significantly suppressed T-cell-mediated alloimmune responses and prolonged allograft survival. Addition of weekly 4D11 administration after the induction treatment further enhanced graft survival. Complete inhibition of both donor-specific Ab and anti-4D11 Ab productions was obtained only with higher-dose maintenance therapy. No serious side effect including thromboembolic complications was noted except for a transient reduction of hematocrit in one animal, and decrease of peripheral B-cell counts in all. These results indicate that the 4D11 appears to be a promising candidate for immunosuppression in clinical organ transplantation.