CLINICAL ISLET TRANSPLANTATION

M. Watanabe¹, K. Yamashita², D. Fukumori¹, T. Suzuki³, H. Kamachi³, D. Kuraya³, Y. Koshizuka⁴, M. Ogura³, T. Yoshida³, F. Sakai⁵, T. Miura⁶, M. Matsushita³, S. Todo^7
1First Department Of Surgery, Hokkaido University School of Medicine, Sapporo/JAPAN, ²First Department Of General Surgery, Hokkaido University, Sapporo/JAPAN, ³1st Department Of Surgery, Hokkaido University, Sapporo/JAPAN, ⁴First Department Of Surgery, Hokkaido university, sapporo/JAPAN, ⁵Astellas?pharma Inc., Drug Discovery Research, Tsukuba/JAPAN, ⁶, Kyowa Hakko Kirin Co., Shizuoka/JAPAN, ⁷First Department Of Surgery, Hokkaido University, Sapporo/JAPAN

Body: Introduction. CD154 (CD40L) blockade by anti-CD154 monoclonal antibodies (mAbs) markedly prolonged islet allograft survival in nonhuman primates; however, clinical development was halted due to their thromboembolic side-effect. In contrast, the effect of chimeric CD40 mAb, chi220 on islet survival was modest, while synergistic effect was achieved when combined with CTLA4Ig. Previously, we have reported that ASKP1240 (4D11), a novel fully human anti-CD40 mAb, significantly prolongs kidney and liver allograft survival in cynomolgus monkeys without causing thromboembolic or any other side-effects. In this study, we evaluated the effect of 4D11 on islet transplantation (ITx) in cynomolgus monkeys. Methods. Diabetes mellitus was induced in 12 male cynomolgus monkeys (age: 5.2±0.9 y.o., BW: 5.3±0.8 kg) by total pancreatectomy (TP). Two weeks after TP, pancreatic islets were isolated from a donor cynomolgus monkey (ABO blood-type: identical, MLR: SI>5, age: 4.9±0.7 y.o., BW: 5.2±1.1 kg), and were transplanted into the liver. In the treatment groups, 4D11 (10 mg/kg) was given IV on postoperative days (PODs) 0, 4, 7, 11 and 14 (Induction, n=5), or 4D11 (5 mg/kg) was administered IV weekly until 6 months thereafter (Maintenance, n=4). Control animals received no immunosuppression (n=3). Graft survival, fasting blood glucose (BG), C-peptide and insulin levels were examined. Rejection was defined as the point where fasting BG level exceeded 250 mg/dl for 3 consecutive days. Results. After TP, fasting serum C-peptide level was <0.25 ng/ml in all animals. Intravenous glucose tolerance test (IVGTT) showed no response in serum C-peptide and insulin levels. A single donor-derived allogeneic ITx was performed except for one in the Control group (from two donors). Following ITx (8201-12438 IEQ/kg), BG level normalized promptly without exogenous insulin. Control islet allografts were rejected within 9 days. In contrast, the induction 4D11 treatment prolonged graft survival to >15, >24, >38, >38, >82 days [Fig.1]. Two animals in this group died with good functioning islet grafts on POD 15 and POD 24 due to internal hernia and peritonitis, respectively. At present, all grafts under cover of maintenance 4D11 treatment are surviving for >37, >37, >84, >84 days. IVGTT revealed a normal pattern for BG levels, and both C-peptide and insulin responses recovered in the 4D11 treated animals. [Fig.2] Anti-donor immune response as assessed by IFN-γ ELISPOT on POD 5 was lower in the treatment group when compared to Control. No drug-related adverse events were noted.Conclusion. 4D11 efficiently maintained normoglycemia in cynomolgus monkeys who received islet transplantation from asingle donor after total pancreatectomy. 4D11 appears to be a promising agent for treatment in clinical islet transplantation.

Disclosure: All authors have declared no conflicts of interest.