Treatment of Transplant Reperfusion with CD47 antibody

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CD47 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CD47结合，限制了所有血管组织中的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信号传导的抑制作用，并改善几种IRI动物模型的结局。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TSP1-CD47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CD47 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CD47 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使能研究做准备。 该II期提案涉及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，包括外科手术、创伤、镰状细胞危象和肺动脉高压引起的IRI。

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.