Treatment of Transplant Reperfusion with CD47 antibody

CD47抗体治疗移植再灌注

• 批准号: 8313173
• 负责人: PAMELA Ann TOY-MANNING
• 金额: $ 70.67万
• 依托单位: VASCULOX, INC.
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8313173
• 关键词: Address; Adjuvant; Animal Model; Animals; Antibodies; Apoptosis; Area; Arginine; Bile fluid; Binding; Biological Preservation; Blood Circulation; Blood Vessels; Blood flow; Brain; CD47 gene; Canis familiaris; Cardiac Death; Cardiovascular Diseases; Cell Death; Clinical; Clinical Trials; Critical Pathways; Cultured Cells; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Cytoprotection; Data; Development; Disease; Dose; Drug Kinetics; Family suidae; Flushing; Foundations; Gases; Graft Survival; Grant; Guanylate Cyclase; Harvest; Hindlimb; Human; Immunosuppression; Inflammation; Ischemia; Lead; Life; Ligands; Liver; Mediating; Medical; Mitochondria; Modality; Modeling; Monoclonal Antibodies; Monoclonal Antibody Therapy; Mus; Necrosis; Nitric Oxide; Nitric Oxide Donors; Nitric Oxide Signaling Pathway; Nitric Oxide Synthase; Operative Surgical Procedures; Organ; Organ Donor; Organ Preservation; Organ Procurements; Organ Transplantation; Outcome; Pan Genus; Patients; Phase; Procedures; Production; Protocols documentation; Pulmonary Hypertension; Rattus; Reactive Oxygen Species; Reperfusion Injury; Reperfusion Therapy; Research; Rodent; SHFM1 gene; Safety; Series; Signal Transduction; Small Business Innovation Research Grant; Solid; Staging; Stress; System; Techniques; Testing; Therapeutic; Thrombosis; Thrombospondin 1; Tissues; Transplant Recipients; Transplantation; Trauma; Vascular System; Vascular blood supply; arginase; cGMP production; cytotoxicity; delayed graft function; ex vivo perfusion; follow-up; graft failure; improved; inhaled nitric oxide; inhibitor/antagonist; liver function; liver transplantation; meetings; nonhuman primate; pre-clinical; preclinical study; receptor; retransplantation; safety study; sickle cell crisis; soft tissue; success; vasoconstriction

DESCRIPTION (provided by applicant): Vasculox, Inc. is developing a humanized anti-CD47 mAb for reducing ischemia-reperfusion injury (IRI) in organ transplantation. In spite of improvements in surgical technique, organ preservation and immunosuppression, IRI remains a serious limitation and is responsible for delayed graft function, initial graft failure and contribtes to poor long-term graft survival, thus representing an area of significant unmet medical need. Increasing nitric oxide (NO) signaling can provide a substantial therapeutic benefit in reducing IRI. The founders of Vasculox discovered that thrombospondin-1 (TSP1) binding to its receptor, CD47, limits NO signaling in all vascular tissues. Blocking TSP-1 binding with an anti-CD47 monoclonal antibody (anti-CD47 mAb) relieves this inhibition of NO signaling and improves outcomes in several animal models of IRI. We have recently demonstrated efficacy of an anti-CD47 mAb to improve liver function in an ex vivo perfusion model and in a rat liver transplant model. Vasculox has characterized a panel of 9 mouse monoclonal mAbs (400 series mAbs) that are unique in reacting broadly across species with human, rodent, dog and pig providing a significant advantage for clinical development. Three of these mAbs reverse the TSP1-CD47 mediated inhibition of NO-stimulated cGMP formation in cultured cells and one of these will be taken forward for humanization. In this Phase II SBIR grant the specific aims are: Aim 1. Humanize the lead CD47 mAb candidate, produce research grade material for preclinical studies. Aim 2A. Establish optimal conditions for efficacy of CD47 mAb in a rat syngeneic liver transplant model including administration and dosing modality (pre-treat organ alone, treat recipient alone or treat both) and adjuvant treatments to enhance the NO signaling pathway (arginase inhibitors and/or L-arginine) Aim 2B. Demonstrate efficacy of the humanized mAb in a large animal (porcine) model of transplant using the optimized treatment modality as determined in Aim 2A. Aim 3. Carry out non-GLP (preliminary) pharmacokinetic and safety studies in the rat and non-human primate using the CD47 humanized mAb to prepare for GLP IND-enabling studies. This phase II proposal addresses several critical path milestones for Vasculox that will allow us to address transplant IRI as well as additional indications for anti-CD47 therapy including IRI arising from surgical procedures, trauma, sickle cell crisis and pulmonary hypertension. PUBLIC HEALTH RELEVANCE: Ischemia reperfusion injury (IRI) is a complicating factor in many cardiovascular diseases and surgical procedures including organ transplantation. Increasing nitric oxide (NO) signaling can provide a substantial therapeutic benefit in reducing IRI. The founders of Vasculox discovered that a receptor called CD47 limits NO signaling. Blocking CD47 with a monoclonal antibody (CD47mAb) relieves this inhibition of NO signaling and has the potential to enhance organ transplantation and save lives. Vasculox is developing a humanized CD47mAb for reducing IRI in organ transplantation that reacts with many different species. In this proposal we will humanize the lead CD47mAb candidate and determine its optimal dosing modality in rat liver transplantation. We will then confirm its efficacy in pigs, a more human-like species. Finally, we will conduct studies of how long the mAb is available in the circulation and test the CD47mAb for safety in two animal species as required by the FDA. These studies represent critical path milestones for Vasculox and must be accomplished before we can begin clinical trials to improve organ transplantation, allow for more transplantable organs and thereby save more lives.

描述（由申请人提供）：Vasculox，Inc.正在开发用于减少器官移植中的缺血再灌注损伤（IRI）的人源化抗CD 47 mAb。尽管在手术技术、器官保存和免疫抑制方面有所改进，但IRI仍然是一个严重的局限性，并导致移植物功能延迟、初始移植物衰竭和长期移植物存活率差，因此代表了一个显著未满足的医疗需求领域。增加一氧化氮（NO）信号传导可以在减少IRI方面提供实质性的治疗益处。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，限制了所有血管组织中的NO信号传导。用抗CD 47单克隆抗体（抗CD 47 mAb）阻断TSP-1结合可缓解NO信号传导的抑制作用，并改善几种IRI动物模型的结局。我们最近证明了抗CD 47 mAb在离体灌注模型和大鼠肝移植模型中改善肝功能的功效。Vasculox已对一组9种小鼠单克隆mAb（400系列mAb）进行了表征，这些mAb在与人、啮齿动物、犬和猪的广泛种属反应方面具有独特性，为临床开发提供了显著优势。这些mAb中的三种逆转了培养细胞中TSP 1-CD 47介导的NO刺激的cGMP形成的抑制，其中一种将用于人源化。 在第二阶段SBIR赠款的具体目标是：目标1。人源化主要候选CD 47 mAb，生产用于临床前研究的研究级材料。目标2A。在大鼠同基因肝移植模型中建立CD 47 mAb有效性的最佳条件，包括给药和给药方式（仅预处理器官、仅治疗受体或同时治疗两者）和辅助治疗，以增强NO信号传导途径（腺苷酸酶抑制剂和/或L-精氨酸）目的2B。使用目标2A中确定的优化治疗方式，证明人源化mAb在大型动物（猪）移植模型中的疗效。目标3.使用CD 47人源化mAb在大鼠和非人灵长类动物中进行非GLP（初步）药代动力学和安全性研究，为GLP IND使能研究做准备。 该第二阶段提案解决了Vasculox的几个关键路径里程碑，使我们能够解决移植IRI以及抗CD 47治疗的其他适应症，包括外科手术引起的IRI、创伤、镰状细胞危象和肺动脉高压。 公共卫生关系：缺血再灌注损伤（IRI）是许多心血管疾病和外科手术（包括器官移植）的复杂因素。增加一氧化氮（NO）信号传导可以在减少IRI方面提供实质性的治疗益处。Vasculox的创始人发现一种名为CD 47的受体限制了NO信号传导。用单克隆抗体（CD 47 mAb）阻断CD 47可以缓解这种对NO信号传导的抑制，并有可能促进器官移植和挽救生命。Vasculox正在开发一种人源化CD 47 mAb，用于减少与许多不同物种反应的器官移植中的IRI。在这项提案中，我们将人源化的领导CD 47单抗候选人，并确定其最佳的剂量模式在大鼠肝移植。然后，我们将在猪身上证实其疗效，猪是一种更像人类的物种。最后，我们将研究mAb在循环中的可用时间，并根据FDA的要求在两种动物中测试CD 47 mAb的安全性。这些研究代表了Vasculox的关键路径里程碑，必须在我们开始临床试验之前完成，以改善器官移植，允许更多可移植器官，从而挽救更多生命。