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.

中文翻译：

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333-OR：免疫功能低下的胰岛细胞在无免疫抑制的情况下在完全免疫功能的非人灵长类动物中进行同种异体移植后介导胰岛素独立性


由于免疫抑制 (IS) 引起的发病率和移植胰岛功能的逐渐丧失，通过同种异体供体移植治疗 1 型糖尿病 (T1DM) 的成功有限。我们报告说，将工程化的原代低免疫性伪胰岛（HIP p-islet）同种异体移植到具有完全免疫功能的糖尿病非人灵长类动物（NHP）中，提供稳定的内分泌功能，并实现胰岛素独立性，而不诱导任何可检测到的免疫在没有IS的情况下的响应。 NHP 尸体胰岛细胞经过工程改造，可破坏 I 类和 II 类 MHC 的功能并过度表达 CD47，从而使其免疫功能低下 (HIP)。使用链脲佐菌素在 NHP 中诱发糖尿病，并开始每天注射胰岛素以重新建立血糖控制。 78 天后，NHP 通过肌内注射进行 HIP p 胰岛移植，从而实现胰岛素依赖性。早在移植后一周，NHP 的血清 C 肽水平就已恢复正常，并在整个 6 个月的随访期间保持稳定。 NHP 显示出 6 个月内血糖水平受到严格控制，完全不依赖胰岛素​​，并且持续健康。 HIP p-胰岛移植后 6 个月，获取 PBMC 和血清用于免疫分析。 HIP PI 没有表现出 T 细胞识别，没有移植物特异性抗体，并且免受 NK 细胞和巨噬细胞杀伤。为了证明猴子的胰岛素非依赖性完全依赖于 HIP p-胰岛移植物，并且其内源性胰岛细胞群没有再生，我们使用 CD47 靶向策略触发了 HIP p-胰岛移植物的破坏，导致损失血糖控制并恢复外源性胰岛素依赖。 这些数据证明了 HIP p-胰岛的免疫逃避、移植介导的糖尿病 NHP 的胰岛素独立性以及潜在的安全策略的证据。披露 X. Hu：员工；萨那生物技术公司。股票/股东；萨那生物技术公司。 K.怀特：没有。 C. 年轻人：雇员；萨那生物技术。股票/股东；萨那生物技术。 A.G. Olroyd：员工；萨那生物技术公司。股票/股东；萨那生物技术公司。 P. Kievit：顾问； Alnylam 制药公司，Embark Bio。研究支持； Sana 生物技术公司、诺和诺德公司。 A. 康诺利：没有。 T. Deuse：股票/股东； Sana 生物技术公司、Shinobi 治疗公司。 S. Schrepfer：股票/股东；萨那生物技术公司。员工;萨那生物技术公司。