Treatment of Transplant Reperfusion with CD47 antibody

描述（由申请人提供）：Vasculox, Inc.正在开发一种人源抗cd47单抗，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，导致移植物功能延迟、移植物初始衰竭和移植物长期存活不良，因此代表了一个重大的未满足医疗需求的领域。增加一氧化氮（NO）信号可以在减少IRI中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。在一些IRI动物模型中，用抗cd47单克隆抗体（anti-CD47 mAb）阻断TSP-1结合可减轻NO信号的抑制，并改善预后。我们最近在离体灌注模型和大鼠肝移植模型中证明了抗cd47单抗改善肝功能的功效。Vasculox已经鉴定出9种小鼠单克隆单抗（400系列单抗），这些单抗在人类、啮齿动物、狗和猪的跨物种反应中具有独特的优势，为临床开发提供了显著的优势。其中三种单克隆抗体可逆转TSP1-CD47介导的no刺激cGMP形成的抑制，其中一种单克隆抗体将用于人源化。在这个第二阶段SBIR拨款的具体目标是：人源化CD47单抗候选药物，为临床前研究生产研究级材料。目标2。建立CD47 mAb在大鼠同基因肝移植模型中的疗效的最佳条件，包括给药和给药方式（单独预处理器官，单独治疗受体或同时治疗）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）Aim 2B。使用Aim 2A中确定的优化治疗方式，在大型动物（猪）移植模型中证明人源化单抗的有效性。目标3。使用CD47人源化单抗在大鼠和非人灵长类动物中开展非GLP（初步）药代动力学和安全性研究，为GLP ind启用研究做准备。这一II期提案将解决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.