Anti-CD47 mAb Therapy to Improve Kidney Transplantation

抗 CD47 mAb 疗法改善肾移植

• 批准号: 8738640
• 负责人: PAMELA Ann TOY-MANNING
• 金额: $ 49.72万
• 依托单位: VASCULOX, INC.
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8738640
• 关键词: Address; Allogenic; Animal Model; Antibodies; Apoptosis; Binding; Biological Availability; Blood Vessels; Brain; CD47 gene; Cardiac Death; Cell Death; Clinical Research; Cryopreservation; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Data; Development; Dialysis procedure; Drug Kinetics; End stage renal failure; Family suidae; Gases; Goals; Grant; Guanylate Cyclase; Harvest; Hindlimb; Human; Immunosuppression; Immunosuppressive Agents; Inflammation; Ischemia; Kidney; Kidney Transplantation; Life; Ligands; Liver; Mitochondria; Modeling; Monoclonal Antibodies; Necrosis; Nitric Oxide; Nitric Oxide Donors; Nitric Oxide Synthase; Norway; Organ; Organ Donations; Organ Donor; Organ Procurements; Organ Transplantation; Outcome; Patients; Performance; Pharmaceutical Preparations; Phase; Procedures; Production; Property; Protocols documentation; Rattus; Reperfusion Injury; Rodent; Safety; Signal Transduction; Stress; System; Tacrolimus; Testing; Therapeutic immunosuppression; Thrombosis; Thrombospondin 1; Time; Tissues; Translating; Transplant Recipients; Transplantation; Vascular System; Vascular blood supply; Warm Ischemia; cGMP production; delayed graft function; efficacy testing; graft failure; humanized monoclonal antibodies; improved; inhaled nitric oxide; kidney preservation; phase 2 study; pre-clinical; preclinical study; prevent; public health relevance; receptor; research study; soft tissue; success; vasoconstriction

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.

描述(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、移植过程和免疫抑制方面有了许多改进，但缺血再灌注损伤(IRI)造成的损伤仍然存在问题，导致原发移植物无功能、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扩大标准器官(ECD)和心源性死亡(DCD)器官的使用，这些器官更容易受到IRI的损害。因此，减少IRI不仅将提高标准标准(SCD)器官的成功率，还可能允许更多地使用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)信号传递有助于肾脏在运输过程中的保存，并减轻移植后的IRI。然而，Vasculox的创始人发现，血栓反应蛋白-1(TSP1)与其受体CD47结合，限制了血管系统中的NO信号，从而加重了IRI。用抗CD47单抗(CD47mAbs)阻断TSP1-CD47系统可显著改善肾、肝、脑、后肢和软组织IRI模型的结果。在我们的第一阶段赠款期间，我们已经证明，在6小时之前用CD47mAbs处理采集的大鼠肾脏。冷缺血的治疗提供了对组织损伤的实质性保护，并改善了肾脏损伤和功能的标志物。最重要的是，用CD47mAb治疗供体肾脏也能提高受者的存活率。Vasculox成功地人源化了CD47mAb(CD47humAb)，用于移植，它具有与包括啮齿动物、猪和人在内的多种物种结合的独特性质。在这里，我们将在小鼠(大鼠)和大(猪)肾移植动物模型中测试CD47humAb。我们的具体目标是：目的1.大鼠肾脏SCD和DCD移植。1A.在同种异体移植模型中，确定经历热缺血时间以模拟DCD肾脏的肾脏是否可以通过用CD47humAb治疗供体肾脏和/或受体来挽救。1B.在SCD和DCD条件下使用免疫抑制药物(他克莫司)，模拟人类供者/受者不匹配的情况，在同种异体(从布朗·挪威到刘易斯)大鼠肾移植模型中测试CD47humAb的有效性。目的2.猪肾DCD移植。确定CD47抗体治疗是否能改善处于热缺血状态的肾脏的功能，以模拟边缘DCD肾脏移植。道格拉斯·汉托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前引入60分钟的热缺血时间，以模拟人类DCD肾移植。这将在使用边缘器官的大型动物模型中建立CD47humAb治疗的概念证据，这些边缘器官更容易受到IRI的影响，因此移植结果更差。

项目成果

Enhanced immunosuppression improves early allograft function in a porcine kidney transplant model of donation after circulatory death.

增强的免疫抑制可改善循环死亡后捐献的猪肾移植模型的早期同种异体移植物功能。

• DOI: 10.1111/ajt.15098
• 发表时间: 2019
• 期刊: American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons
• 作者: Xu,Min;Garcia-Aroz,Sandra;Banan,Babak;Wang,Xuanchuan;Rabe,BrianJ;Zhou,Fangyu;Nayak,DeepakK;Zhang,Zhengyan;Jia,Jianluo;Upadhya,GundumiA;Manning,PamelaT;Gaut,JosephP;Lin,Yiing;Chapman,WilliamC
• 通讯作者: Chapman,WilliamC