Treatment of Transplant Reperfusion with CD47 antibody

描述(申请人提供)：Vasculox公司正在开发一种人源化的抗CD47单抗，以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，但IRI仍然是一个严重的限制因素，是移植物功能延迟、最初的移植物失败和移植物长期存活率较低的原因，因此是一个重要的未得到满足的医学需求领域。增加一氧化氮(NO)信号可以在减少IRI方面提供实质性的治疗益处。Vasculox的创始人发现，血栓反应蛋白-1(TSP1)与其受体CD47结合，限制了所有血管组织中的NO信号。用抗CD47单抗(抗CD47单抗)阻断TSP-1的结合可以解除这种对NO信号的抑制，并改善几种IRI动物模型的结果。我们最近在体外灌流模型和大鼠肝移植模型中证明了抗CD47单抗改善肝功能的有效性。Vasculox已经确定了一组由9个鼠类单抗(400系列单抗)组成的小组，这些单抗在与人、啮齿动物、狗和猪的广泛反应中是独一无二的，为临床开发提供了显著的优势。其中三株单抗逆转了TSP1-CD47介导的抑制NO刺激的cGMP形成的作用，其中一株将用于人源化。在这一阶段的SBIR资助的具体目标是：目标1。人源化领先的CD47单抗候选者，为临床前研究制作研究级材料。目标2 A。建立CD47mAb在大鼠同基因肝移植模型中有效的最佳条件，包括给药和给药方式(单独处理器官、单独治疗受体或两者都治疗)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。在大型动物(猪)移植模型中，使用目标2A中确定的优化治疗方式，展示人源化mAb的有效性。目的3.利用CD47人源化单抗在大鼠和非人灵长类动物体内进行非GLP(初步)药代动力学和安全性研究，为GLP IND使能研究做准备。这项第二阶段提案涉及Vasculox的几个关键路径里程碑，这些里程碑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。 公共卫生相关性：缺血再灌注损伤(IRI)是许多心血管疾病和包括器官移植在内的外科手术的复杂因素。增加一氧化氮(NO)信号可以在减少IRI方面提供实质性的治疗益处。Vasculox的创始人发现，一种名为CD47的受体限制了NO信号。用一种单抗(CD47mAb)阻断CD47可以解除这种对NO信号的抑制，并有可能加强器官移植和挽救生命。Vasculox正在开发一种人源化CD47mAb，用于减少器官移植中与许多不同物种发生反应的IRI。在这项建议中，我们将人源化CD47mAb的主要候选者并确定其在大鼠肝移植中的最佳给药方式。然后我们将证实它在猪身上的疗效，猪是一种更像人类的物种。最后，我们将按照FDA的要求，进行单抗在循环中可用多久的研究，并测试CD47mAb在两个动物物种中的安全性。这些研究代表着Vasculox的关键里程碑，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。

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.