Anti-CD47 mAb Therapy to Improve Kidney Transplantation

描述（由申请人提供）：器官移植是终末期肾病患者的救命选择。尽管在器官获取、移植程序和免疫抑制方面有许多改进，但由缺血再灌注损伤（IRI）造成的损伤仍然是问题，导致原发性移植物无功能、移植物功能延迟和移植物衰竭。供体肾脏的严重短缺增加了对扩展标准器官（ECD）和心源性死亡后捐赠（DCD）器官的使用，这些器官更容易受到IRI损伤。因此，减少IRI不仅可以提高标准标准（SCD）器官的成功率，而且还可以允许更多地使用ECD和DCD器官，从而增加可以进行的移植数量和可以挽救的生命。增强的一氧化氮（NO）信号传导可以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（TSP 1）与其受体CD 47结合，限制了整个血管系统的NO信号传导，从而使IRI恶化。用抗CD 47单克隆抗体（CD 47 mAbs）阻断TSP 1-CD 47系统显著改善了肾脏、肝脏、大脑、后肢和软组织IRI模型的结果。在我们的I期资助期间，我们已经证明，在6小时的冷缺血之前用CD 47单克隆抗体治疗收获的大鼠肾脏提供了对组织学损伤的实质性保护，并改善了肾损伤和功能的标志物。最重要的是，用CD 47 mAb治疗供体肾也提高了受体的存活率。Vasculox成功地人源化了用于移植的CD 47 mAb（CD 47 humAb），该抗体具有与许多物种（包括啮齿动物、猪和人）结合的独特性质。在此，我们将在小型（大鼠）和大型（猪）肾移植动物模型中测试CD 47 humAb。我们的具体目标是：目标1。大鼠肾脏SCD和DCD移植。1A.在同系移植模型中确定是否可以通过用CD 47 humAb处理供体肾脏和/或受体来挽救经受热缺血时间以模拟DCD肾脏的肾脏。1B.在SCD和DCD条件下，使用免疫抑制药物（他克莫司）在同种异体（Brown Norway至刘易斯）大鼠肾移植模型中检测CD 47 humAb的有效性，以模拟人类供体/受体发生的错配。目标2.猪肾DCD移植。确定CD 47 humAb治疗是否可以改善热缺血期肾脏的性能，以模拟边缘DCD肾脏的移植。Douglass Hanto博士在猪身上开发了这个模型，他是我们这项研究的顾问。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DCD肾移植。这将在一个大型动物模型中建立CD 47 humAb治疗的概念验证，以使用更易受IRI影响的边缘器官，因此移植结果更差。

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.