Anti-CD47 mAb Therapy to Improve Kidney Transplantation

描述（由申请人提供）：对于终末期肾病患者来说，器官移植是一种挽救生命的选择。尽管在器官获取、移植手术和免疫抑制方面取得了许多进步，但缺血再灌注损伤（IRI）造成的损伤仍然存在问题，导致原发性移植物无功能、移植物功能延迟和移植物失败。供体肾脏的严重短缺增加了扩展标准器官 (ECD) 和心源性死亡后捐献 (DCD) 器官的使用，这些器官更容易受到 IRI 损伤。因此，降低 IRI 不仅可以提高标准标准（SCD）器官的成功率，还可以更多地使用 ECD 和 DCD 器官，从而增加可进行的移植数量和可挽救的生命。增强的一氧化氮 (NO) 信号传导有利于在运输过程中保护肾脏并减轻移植后的 IRI。然而，Vasculox 的创始人发现血小板反应蛋白-1 (TSP1) 与其受体 CD47 结合，限制了整个血管系统的 NO 信号传导，从而恶化了 IRI。使用抗 CD47 单克隆抗体 (CD47mAb) 阻断 TSP1-CD47 系统可显着改善肾、肝、脑、后肢和软组织 IRI 模型的结果。在我们的第一阶段资助期间，我们已经证明在 6 小时之前用 CD47mAb 处理收获的大鼠肾脏。冷缺血的治疗可提供针对组织学损伤的实质性保护，并改善肾脏损伤和功能的标志物。最重要的是，用 CD47mAb 治疗供体肾脏还可以提高受体的生存率。 Vasculox 已成功将 CD47mAb (CD47humAb) 人源化，用于移植，该抗体具有与许多物种（包括啮齿动物、猪和人类）结合的独特特性。在这里，我们将在小型（大鼠）和大型（猪）动物肾移植模型中测试 CD47humAb。我们的具体目标是： 目标 1. 大鼠肾 SCD 和 DCD 移植。 1A。在同基因移植模型中确定是否可以通过用 CD47humAb 治疗供体肾脏和/或受体来挽救模拟 DCD 肾脏的热缺血时间的肾脏。 1B.在 SCD 和 DCD 条件下使用免疫抑制药物（他克莫司）来模拟人类供体/受体发生的错配，测试 CD47humAb 在同种异体（Brown挪威至 Lewis）大鼠肾移植模型中的功效。目标 2. 猪肾 DCD 移植。确定 CD47humAb 疗法是否可以改善经历一段热缺血期的肾脏的性能，以模拟边缘 DCD 肾脏的移植。 Douglass Hanto 博士是我们这项研究的顾问，他在猪身上开发了这个模型。按照他的方案，我们将在收获和冷藏之前引入 60 分钟的热缺血时间，以模拟人类 DCD 肾移植。这将为大型动物模型中的 CD47humAb 治疗建立概念证明，以使用更容易受到 IRI 影响的边缘器官，从而导致更差的移植结果。

DESCRIPTION (provided by applicant): Organ transplantation is a lifesaving option for those with end stage renal disease. In spite of many improvements in organ procurement, transplant procedures and immune suppression, the damage done by ischemia-reperfusion injury (IRI) remains problematic, leading to primary graft nonfunctional, delayed graft function and graft failure. The critical shortage of donor kidneys has increased the use of expanded criteria organs (ECD) and donation after cardiac death (DCD) organs that are even more susceptible to IRI damage. Thus reducing IRI will not only improve the success rate of standard criteria (SCD) organs, but may also allow greater use of ECD and DCD organs, thus increasing the number of transplants that can be performed and lives that can be saved. Enhanced nitric oxide (NO) signaling can benefit preservation of kidneys during transport and alleviate IRI upon transplantation. However, the founders of Vasculox discovered that thrombospondin-1 (TSP1) binding to its receptor, CD47, limits NO signaling throughout the vascular system thereby worsening IRI. Blocking the TSP1-CD47 system with anti-CD47 monoclonal antibodies (CD47mAbs) dramatically improves outcomes in models of kidney, liver, brain, hindlimb and soft tissue IRI. In our Phase I grant period, we have shown that treatment of harvested rat kidneys with CD47mAbs prior to 6 hr. of cold ischemia provides substantial protection against histological damage and improves markers of both kidney damage and function. Most significantly, treatment of donor kidneys with a CD47mAb also enhances survival of the recipient. Vasculox has successfully humanized a CD47mAb (CD47humAb) for use in transplantation that has the unique property of binding to many species including rodent, pig and human. Here we will to test the CD47humAb in both small (rat) and large (pig) animal models of kidney transplantation. Our specific aims are: Aim 1. Rat kidney SCD and DCD transplants. 1A. Determine in a syngeneic transplant model if kidneys subjected to warm ischemic times to mimic DCD kidneys can be rescued by treating the donor kidney and/or recipient with CD47humAb. 1B. Test the efficacy of the CD47humAb in an allogeneic (Brown Norway to Lewis) rat kidney transplant model with the use of an immunosuppressive drug (tacrolimus) under SCD and DCD conditions to mimic the mismatch that occurs with human donors/recipients. Aim 2. Porcine kidney DCD transplants. Determine if CD47humAb therapy can improve the performance of kidneys subjected to a period of warm ischemia to mimic the transplantation of marginal DCD kidneys. Dr. Douglass Hanto, who developed this model in pigs, is our consultant for this study. Following his protocol, we will introduce a 60 minute warm ischemic time prior to harvest and cold storage to mimic human DCD kidney transplantation. This will establish proof of concept for CD47humAb treatment in a large animal model for the use of marginal organs that are more susceptible to IRI and therefore worse transplant outcomes.