333-OR: Hypoimmune Islet Cells Mediate Insulin Independence after Allogeneic Transplantation in a Fully Immunocompetent Nonhuman Primate without Immunosuppression

Abstract

Treatment of type 1 diabetes mellitus (T1DM) via allogeneic donor transplant has limited success due to morbidities from immunosuppression (IS) and a gradual loss of engrafted pancreatic islet function. We report that allogeneic transplantation of engineered, primary, hypoimmune, pseudo-islets (HIP p-islets) engraft into a fully immunocompetent, diabetic non-human primate (NHP), provide stable endocrine function, and enable insulin independence without inducing any detectable immune response in the absence of IS. NHP cadaveric islet cells were engineered to disrupt function of MHC class I and II and overexpress CD47 thus rendering them hypoimmune (HIP). Diabetes was induced in the NHP with streptozotocin and daily insulin injections started to re-establish glucose control. After 78 days, NHP underwent transplantation of HIP p-islets by intramuscular injection resulting in insulin independence. As early as one week after the transplantation, the NHP’s serum c-peptide level had normalized and remained stable throughout the follow-up period of 6 months. The NHP showed tightly controlled blood glucose levels for 6 months, was completely insulin-independent, and continuously healthy. Up to 6 months after HIP p-islet transplantation, PBMCs and serum were obtained for immune analyses. HIP PI showed no T cell recognition, no graft-specific antibodies, and were protected from NK cell and macrophage killing. To prove that the monkey’s insulin-independence was fully dependent on the HIP p-islets graft and there was no regeneration of his endogenous islet cell population, we triggered the destruction of the HIP p-islet transplant using a CD47-targeting strategy resulting in loss of glycemic control and return to exogenous insulin dependence. These data demonstrate evidence for immune evasion of HIP p-islets, graft mediated insulin-independence of the diabetic NHP, and a potential safety strategy. Disclosure X. Hu: Employee; Sana Biotechnology. Stock/Shareholder; Sana Biotechnology. K. White: None. C. Young: Employee; Sana biotechnology. Stock/Shareholder; Sana biotechnology. A.G. Olroyd: Employee; Sana Biotechnology. Stock/Shareholder; Sana Biotechnology. P. Kievit: Consultant; Alnylam Pharmaceuticals, Inc., Embark Bio. Research Support; Sana Biotechnology, Novo Nordisk A/S. A. Connolly: None. T. Deuse: Stock/Shareholder; Sana Biotechnology, Shinobi Therapeutics. S. Schrepfer: Stock/Shareholder; Sana Biotechnology. Employee; Sana Biotechnology.