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

Abstract

A strategy for inhibiting CD40 has been considered as an alternative approach for immunosuppression because of undesirable effects of anti-CD154 monoclonal antibodies (mAbs). Previously, we demonstrated that ASKP1240, which is a fully human anti-CD40 mAb, significantly prolonged kidney and liver allograft survival in cynomolgus monkeys without causing thromboembolic complications. Herein, we evaluated the effect of ASKP1240 on pancreatic islet transplantation (PITx) in cynomolgus monkeys. Diabetes was induced by total pancreatectomy, and islet allografts were transplanted into the liver. Following PITx (8201-12 438 IEQ/kg), blood glucose levels normalized promptly in all animals. Control islet allografts were rejected within 9 days (n ¼ 3), whereas ASKP1240 (10 mg/kg) given on postoperative days 0, 4, 7, 11 and 14 (induction treatment, n ¼ 5) significantly prolonged graft survival time (GST) to >15, >23, 210, 250 and >608 days, respectively. When ASKP1240 (5 mg/kg) was administered weekly thereafter up to post-PITx 6 months (maintenance treatment, n ¼ 4), GST was markedly prolonged to >96, >115, 523 and >607 days. During the ASKP1240 treatment period, both antidonor cellular responses and development of antidonor antibodies were abolished, and no serious adverse events were noted. ASKP1240 appears to be a promising candidate for immunosuppression in clinical PITx.

Long-Term Control of Diabetes in Immunosuppressed Nonhuman Primates (NHP) by the Transplantation of Adult Porcine Islets

“…An additional promising candidate would be an anti-CD40 antibody, ASKP1240 (4D11); this drug has been demonstrated to be effective in prolonging graft survival in NHP allotransplantation of kidney, liver and islets, and had an excellent safety profile in a phase I clinical trial (31)(32)(33)(34). Another promising alternative to anti-CD154 monoclonal antibody is CDP7657, which is a novel monovalent Fab' PEG anti-human CD154 antibody.…”

In vitro testing of an anti-CD40 monoclonal antibody, clone 2C10, in primates and pigs

“…Several anti-CD40mAbs, e.g., Chi220, 3A8, 5D12, 4D12, and 2C10, have shown promise in various transplant models without thromboembolic complication [4-6, 9-19, 21-24]. However, some of these anti-CD40 mAbs (i.e., Chi220, 3A8) have been associated with potentially adverse effects, e.g., as a B cell agonist or associated with substantial peripheral B cell depletion [9, 16, 19, 23].…”

“…A fully human mAb to CD40, clone 4D11 (IgG4 isotype), has recently been shown to prolong renal, hepatic, and islet allograft survival in cynomolgus monkeys [12, 13, 18, 21, 42]. Phase I clinical trials in renal transplantation using 4D11 are currently in progress.…”

“…As a result, anti-CD40mAb has gained increasing attention, and various clones (e.g., Chi220, 3A8, 5D12, 4D11, and 2C10) have been developed to block the CD40/CD154 pathway [4-6, 9-19, 21-24]. …”

Costimulation Blockade in Kidney Transplantation

“…78 Similar results have been obtained for pancreatic islet allografts in nonhuman primates. 79 The association of ASKP1240 with tacrolimus or mycophenolate mofetil further increased kidney allograft survival in the same nonhuman primate model. 80 In addition, good correlations were found between the pharmacokinetic and pharmacodynamic parameters.…”