Treatment of Transplant Reperfusion with CD47 antibody

CD47抗体治疗移植再灌注

• 批准号: 8458123
• 负责人: PAMELA Ann TOY-MANNING
• 金额: $ 82.7万
• 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 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8458123
• 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.

描述（由申请人提供）：Vasculox, Inc.正在开发一种人源化抗CD47 mAb，用于减少器官移植中的缺血再灌注损伤（IRI）。尽管在手术技术、器官保存和免疫抑制方面有所改进，IRI 仍然是一个严重的限制，并导致移植物功能延迟、最初的移植物失败并导致长期移植物存活率低，因此代表了一个严重未得到满足的医疗需求的领域。增加一氧化氮 (NO) 信号传导可以为减少 IRI 提供显着的治疗益处。 Vasculox 的创始人发现血小板反应蛋白-1 (TSP1) 与其受体 CD47 结合，限制所有血管组织中的 NO 信号传导。用抗 CD47 单克隆抗体（抗 CD47 mAb）阻断 TSP-1 结合可缓解 NO 信号传导的抑制，并改善几种 IRI 动物模型的结果。我们最近证明了抗 CD47 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 9 种小鼠单克隆单克隆抗体（400 系列单克隆抗体）进行了表征，这些单克隆抗体在与人类、啮齿动物、狗和猪的跨物种广泛反应方面具有独特性，为临床开发提供了显着优势。其中三种 mAb 可逆转 TSP1-CD47 介导的对培养细胞中 NO 刺激的 cGMP 形成的抑制作用，其中一种将用于人源化。 在第二阶段 SBIR 资助中，具体目标是： 目标 1. 将主要 CD47 mAb 候选者人性化，生产用于临床前研究的研究级材料。目标2A。建立 CD47 mAb 在大鼠同基因肝移植模型中发挥功效的最佳条件，包括给药和给药方式（单独预处理器官、单独治疗受体或两者治疗）和辅助治疗以增强 NO 信号通路（精氨酸酶抑制剂和/或 L-精氨酸）目标 2B。使用目标 2A 中确定的优化治疗方式，在大型动物（猪）移植模型中展示人源化 mAb 的功效。目标 3. 使用 CD47 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 启用研究做好准备。 该 II 期提案解决了 Vasculox 的几个关键路径里程碑，这将使我们能够解决移植 IRI 以及抗 CD47 治疗的其他适应症，包括由外科手术、创伤、镰状细胞危象和肺动脉高压引起的 IRI。