A SHORT-TERM TREATMENT WITH A COMBINATION OF IL-2/Fc AND MUTANT IL-15/Fc FUSION PROTEINS PROLONGED ISLET GRAFT SURVIVAL IN DIABETIC CYNOMOLGUS MONKEYS

Abstract

O332* Aims: Pre-clinical studies in non-human primates are useful to evaluate the safety and efficacy of new approaches for clinical islet transplantation. The NHP model is particularly useful as a means to evaluate the therapeutic efficacy of human therapeutic proteins. Broadly reactive anti-T cell antibodies can lead to potent immunosuppression. Nonetheless, the consequences of such treatment include profound and long-lived T cell depletion and the potential problems that attend homeostatic proliferation in the lymphopenic host. We hypothesize that a strategy that selectively destroys activated cytopathic donor reactive T cells while sparing resting- and immunoregulatory T- cells might by an effective means of producing long-term engraftment and tolerance without disrupting global immunity. Herein, we show a novel means of creating tolerance by combining rapamycin, and IL-2/Fc and mutant antagonist type IL-15/Fc cytolytic fusion proteins (Power mix) for 28 days. Methods: Islet transplants were performed in streptozotocin induced diabetic cynomolgus monkeys. The islets were infused into the portal vein. The sirolimus dose of 1mg/kg (systemically daily) produced blood levels of >10 ng/ml. IL-2- and IL-15-related cytolytic fusion proteins given at 0.5mg/kg but not 0.2mg/kg produced therapeutic levels of the protein in the serum of the cynomolgus monkeys.FigureResults: * Functional Survival = time to FBG>250 for >4days ** C-Peptide = level during period of insulin independence vs. level upon return to insulin dependence Conclusions: These results demonstrate that allogeneic islet transplants can survive for greater then 190 days in monkeys after short-term immunosuppression of RPM, IL-2/Fc-, and mutant IL-15/Fc- cytolytic fusion proteins) for only 28 days.