Announcement • Jun 18
Sana Biotechnology, Inc. Presents Data at ISSCR 2022 Annual Meeting Showing Survival of Transplanted Hypoimmune iPSC-Derived Differentiated Cell Types Without Immunosuppression in Non-Human Primates
Sana Biotechnology, Inc. presented data showing survival of transplanted allogeneic, hypoimmune cells of several different types in a variety of locations in non-human primates (NHPs). The transplanted cells were induced pluripotent stem cell (iPSC)-derived cardiomyocytes, retinal pigment epithelium (RPE) cells, and islet cells, which were engineered to include Sana’s hypoimmune gene modifications that enable immune evasion. Data were presented by Sonja Schrepfer, M.D., Ph.D., Head of Hypoimmune Platform at Sana, during sessions at the International Society for Stem Cell Research (ISSCR) 2022 Annual Meeting taking place from June 15, 2022 through June 19, 2022 in San Francisco. Transplanting cells or tissues from a donor to a different recipient currently requires intense immunosuppression to prevent rejection of the transplant. Sana’s HIP platform goal is to eliminate the need for immunosuppression by cloaking cells from immune recognition. The platform includes disruption of the major histocompatibility (MHC) class I and MHC class II expression to hide cells from the adaptive immune system, which includes antibody and T cell responses. These changes alone make cells susceptible to innate immune cell killing, in particular by natural killer (NK) cells. However, Sana’s HIP platform additionally provides for evasion from innate cell killing, including via the overexpression of CD47, a molecule that protects HIP-modified cells from innate cell killing involving either NK cells or macrophages. HIP-modified pluripotent stem cells can serve as the starting material for the differentiation of specialized cell types to serve as cell-based therapeutics. Sana’s goal is to use these HIP-modified cells to replace damaged or missing cells in the body in a number of different diseases, including, among others, cancer, type 1 diabetes, and cardiac disease. Survival of HIP-modified islet cells for type 1 diabetes: Primary NHP pancreatic islet cells: In this study, allogeneic primary pancreatic islet cells were HIP edited and transplanted intramuscularly into a healthy NHP without immunosuppression (n=1) as proof-of-concept. Islet cell survival was followed by in vivo bioluminescence imaging. The imaging showed that transplanted cells survived for the duration of the study (three months at data lock) with no evidence of a systemic immune response, including no T cell activation, antibody production, or NK cell activity as seen previously with other HIP edited cell types in NHPs (iPSC, cardiomyocytes, and RPE). Allogeneic unmodified primary pancreatic islet cells disappeared rapidly within 2 weeks. Autoimmune mice: Type 1 diabetes is a disease in which the patient’s immune system attacks and kills their pancreatic beta cells. Therefore, allogeneic transplanted cells in type 1 diabetes need to overcome both allogeneic and autoimmune rejection. Autoimmune diabetes arises spontaneously in non-obese diabetic (NOD) mice, and the pathophysiology of this disease shares many similarities with human type 1 diabetes. Since its development in 1980, this model has represented the gold standard of spontaneous disease models, allowing for investigation of autoimmune diabetes disease progression and susceptibility traits, as well as to test a wide array of potential treatments and therapies. In this study, syngeneic or allogeneic mouse islet cells were transplanted intramuscularly without immunosuppression into diabetic autoimmune mice (n=15), split into three cohorts. The first cohort received unmodified syngeneic islet cells, the second cohort received unmodified allogeneic islet cells, and the third cohort received allogeneic HIP islet cells. The unmodified cells disappeared rapidly in the allogeneic setting (within 10 days) as well as in the syngeneic setting (within two weeks) due to autoimmune recognition. Neither cohort had a decrease in glucose levels. The HIP islet cells survived in all five diabetic mice for the duration of the study (one month at data lock), and glucose levels dropped, demonstrating therapeutic function of the HIP islet cells. Survival of HIP-modified cardiomyocytes (iPSC-derived): In this study, allogeneic iPSC-derived cardiomyocytes were transplanted without immunosuppression into the hearts of healthy NHPs split into two cohorts. The first cohort received unmodified allogeneic iPSC-derived cardiomyocytes (WT; n=2), while the second cohort received allogeneic HIP iPSC-derived cardiomyocytes (HIP; n=4). The unmodified cells were almost eliminated in all NHPs, with significant T cell activation in addition to antibody production and binding. The HIP cardiomyocytes survived in all four monkeys for the duration of the study (up to two months at data lock), and there was no evidence of a systemic immune response, including no T cell activation, antibody production, or NK cell activity. After two months, injection sites were recovered, and local immune cells were analyzed for their donor-specific cell recognition and killing. While local immune cells kill unmodified cardiomyocytes, HIP cardiomyocytes were not recognized by these immune cells. Survival of HIP-modified retinal pigmental epithelial (RPE) cells (iPSC-derived): In this study, allogeneic iPSC-derived RPEs were transplanted into the eye of healthy NHPs without immunosuppression split into two cohorts. The first cohort received unmodified allogeneic iPSC-derived RPE (WT; n=3), while the second cohort received allogeneic HIP iPSC-derived RPE (HIP; n=3). The unmodified cells were almost completely eliminated in all NHPs within three weeks, with significant T cell activation, antibody production and local microglial activation, demonstrating in this context that the eye is not an immunoprivileged site. The HIP RPE survived in all three monkeys for the duration of the study (three weeks at data lock), and there was no evidence of a systemic immune response, including no T cell activation, antibody production, microglial or NK cell activity. Two weeks after the initial dose, the NHPs were re-injected with the same cell type into the second eye, so that the NHPs received a total of two doses. Unmodified WT RPEs again evoked a rapid systemic immune response in all NHPs, with activation of T cells and antibody production, and cells almost completely eliminate within one week. HIP RPE cells continued to survive even after re-injection without stimulation of adaptive or innate immune responses. These data suggest the potential to re-administer HIP RPE cells. Sana intends to submit the data behind its presentations for publication in a peer-reviewed journal.