Anti-CD47 mAb Therapy to Improve Kidney Transplantation

抗 CD47 mAb 疗法改善肾移植

• 批准号: 8125722
• 负责人: PAMELA Ann TOY-MANNING
• 金额: $ 27.62万
• 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 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8125722
• 关键词: Accounting; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Antibodies; Apoptosis; Apoptotic; Bile fluid; Binding; Biological Availability; Biological Preservation; Blood Circulation; Blood Vessels; Blood flow; Brush Border; CD47 gene; Cardiac Death; Cells; Clinical Trials; Creatinine; Cryopreservation; Cyclic GMP; Data; Development; Dialysis procedure; Disease; Dose; Enzymes; Evaluation; Excision; Flushing; Gases; Genetic; Goals; Guanylate Cyclase; Harvest; Heart; Hindlimb; Human; Hypoxia; Ice; Immunosuppression; Inflammation; Inflammation Mediators; Intestines; Ischemia; Kidney; Kidney Transplantation; Knock-out; Life; Ligands; Liver; Lung; Malignant Neoplasms; Modeling; Modern Medicine; Monitor; Monoclonal Antibodies; Monoclonal Antibody Therapy; Mus; Myocardial Infarction; Nitric Oxide; Nitric Oxide Donors; Nitric Oxide Synthase; Nitrites; Operative Surgical Procedures; Organ; Organ Donor; Organ Harvestings; Organ Procurements; Organ Transplantation; Outcome; Patients; Perfusion; Phase; Plasma; Prevention; Procedures; Production; Rattus; Reactive Oxygen Species; Renal function; Renal tubule structure; Reperfusion Injury; Reperfusion Therapy; Respiratory Burst; Risk; Shock; Signal Transduction; Solid; Staging; Stress; Stroke; Support System; System; Therapeutic; Thrombosis; Thrombospondin 1; Tissues; Transplant Recipients; Transplantation; Trauma; Urine; Vascular System; Vascular blood supply; Vasodilation; Warm Ischemia; Work; base; cytokine; efficacy testing; follow-up; graft function; improved; in vivo; in vivo Model; indexing; inhaled nitric oxide; meetings; prevent; receptor; soft tissue; success; vasoconstriction

DESCRIPTION (provided by applicant): Organ transplantation is one of the great success stories of modern medicine. However, the supply of suitable organs lags far behind the need and many patients die while waitlisted for organs. While there have been many recent strides in organ procurement, preservation and follow-up immune suppression, prevention of ischemia-reperfusion injury (IRI) remains problematic. IRI occurs when the ischemic/hypoxic organ is connected to the recipient's circulation. This storm of reactive oxygen species, inflammatory mediators and prothombotic factors damages the new organ and wreaks havoc upon the recipient as well. Current work indicates that enhancing the beneficial, low levels of nitric oxide (NO) produced by eNOS and nNOS can dramatically improve IRI and transplant outcomes. The founders of Vasculox have discovered a ligand-receptor system, thrombospondin-1 (TSP1) and CD47, that continually opposes the action of beneficial NO in all vascular cells. Knocking out CD47 in mice or blocking CD47 with a monoclonal antibody (mAb) results in enhanced tissue perfusion in a number of surgical ischemia models and substantial protection in models of liver and hindlimb IRI. Further, our initial studies in an ex vivo rat liver machine perfusion system support the efficacy of anti- CD47 therapy for IRI. In this phase one proposal, we seek to perform proof of concept studies in a well-characterized in vivo model of rat kidney transplantation. In Aim 1, we will test the efficacy of anti-CD47 mAb treatment of the donor kidney during cold ischemia to protect it from IRI. Preliminary studies indicate that the anti-CD47 mAb can be administered in the cold preservation medium flush at organ harvest. Aim 2 will determine if parenteral anti-CD47 mAb treatment of the recipient (in addition to pretreatment of the donor kidney) will further improve transplant outcomes. In both aims, readouts of kidney function (urine production, creatinine, BUN and soluble enzyme release) and cytokine levels will be monitored. Cyclic GMP levels in kidneys and plasma nitrite levels will be determined to confirm the mechanism of anti-CD47 mAb action in this model. The data obtained in this phase I project will establish proof of concept for anti-CD47 mAb therapy in kidney transplantation. PUBLIC HEALTH RELEVANCE: The founders of Vasculox Inc, have discovered a regulatory receptor, CD47, that inhibits nitric oxide signaling in all vascular tissues. Nitric oxide provides many beneficial effects in the vascular system, including limiting ischemia-reperfusion injury. Therefore blocking CD47 and preventing nitric oxide inhibition improves ischemia-reperfusion injury and holds promise as a means to improve the condition of organs destined for transplant and to control the damage to the recipient caused by ischemia reperfusion injury. Vasculox is developing a monoclonal antibody that targets CD47 and in this project aims to test the efficacy of such an antibody in an animal model of kidney transplantation. This will provide critical proof of concept for development of a humanized anti-CD47 antibody for use in organ transplantation thereby improving the outcome for all transplant recipients and expanding the number of organs available for transplantation.

描述（申请人提供）：器官移植是现代医学最伟大的成功案例之一。然而，合适器官的供应远远落后于需求，许多患者在等待器官时死亡。虽然最近在器官获取、保存和后续免疫抑制方面取得了许多进展，但缺血再灌注损伤（IRI）的预防仍然存在问题。当缺血/缺氧器官与受体循环相连时，IRI就会发生。这种由活性氧、炎症介质和促凝因子组成的风暴破坏了新器官，也对受体造成了严重破坏。目前的研究表明，增强eNOS和nNOS产生的有益的低水平一氧化氮（NO）可以显著改善IRI和移植结果。Vasculox的创始人已经发现了一种配体受体系统，血小板反应蛋白-1 （TSP1）和CD47，在所有血管细胞中持续对抗有益NO的作用。在小鼠中敲除CD47或用单克隆抗体（mAb）阻断CD47可增强许多手术缺血模型中的组织灌注，并对肝脏和后肢IRI模型具有实质性保护作用。此外，我们在离体大鼠肝机灌注系统中的初步研究支持抗CD47治疗IRI的有效性。在这个第一阶段的建议中，我们寻求在一个具有良好特征的大鼠肾移植体内模型中进行概念验证研究。在Aim 1中，我们将测试在冷缺血期间抗cd47单抗治疗供体肾脏以保护其免受IRI的功效。初步研究表明，抗cd47单抗可以在器官收获时的冷保存培养基中使用。目的2将确定受体的肠外抗cd47单抗治疗（除了供体肾脏的预处理）是否会进一步改善移植结果。在这两个目的中，将监测肾功能读数（尿量、肌酐、尿素氮和可溶性酶释放）和细胞因子水平。在该模型中，将测定肾脏中的环GMP水平和血浆亚硝酸盐水平，以确认抗cd47 mAb作用的机制。在这个I期项目中获得的数据将建立抗cd47单抗治疗肾移植的概念证明。

项目成果

CD47 blockade reduces ischemia-reperfusion injury and improves outcomes in a rat kidney transplant model.

• DOI: 10.1097/tp.0000000000000252
• 发表时间: 2014-08-27
• 期刊: Transplantation
• 影响因子: 6.2
• 作者: Lin Y;Manning PT;Jia J;Gaut JP;Xiao Z;Capoccia BJ;Chen CC;Hiebsch RR;Upadhya G;Mohanakumar T;Frazier WA;Chapman WC
• 通讯作者: Chapman WC