Targeting novel DAMP mediated signaling pathways to mitigate GVHD

摘要 异基因造血干细胞移植(HSCT)是一种公认的治疗白血病的方法。 强大的免疫治疗效应被称为移植物抗白血病效应(GVL)。然而，异基因造血干细胞移植的利用 严重受限于其最严重的并发症，即移植物抗宿主病(GVHD)。努力有意义地 人类GVHD和GVL的分离在很大程度上是不成功的。免疫学中的一个重要概念是 细胞损伤导致危险相关分子模式(DAMP)的释放，这是炎症的主要原因 HSCT后。虽然刺激炎症的几种分子和途径越来越受到重视，但 抑制或调节对潮气的反应的通路在很大程度上被低估了，也没有被作为靶点。 临床炎症或免疫病理。我们最近展示了促进对湿气的负面反应。 通过增强CD24-SiglecG相互作用进行实验性allo-HSCT后(Toubai等人，血液，2015)减少了实验性allo-HSCT GVHD。但关键的细胞和分子途径仍有待破译。初步临床前数据实验 还证明了用一种新的CD24Fc融合蛋白增强这一途径可以减少实验性移植物抗宿主病。 重要的是，从那时起，我们已经开发出临床级别的CD24Fc融合蛋白，显示出对健康人类的安全性 志愿者。这些关键的初步数据构成了我们的中心假设的基础，即CD24Fc将降低 GVHD的严重程度不影响GVL。因此，在这项提案中，我们将以这些令人兴奋的初步数据为基础，带来 基础研究和临床研究相结合。我们的目标是将基本观察转化为假设驱动的概念证明，首先 在人体试验中使用CD24Fc蛋白，并将其与进一步剖析的免疫生物学机制相结合 CD24-Siglec轴在同种异体免疫负性调节中的作用如果成功，我们的建议将导致开发一个 新的治疗策略，同时提供对GVHD的生物学见解。项目的具体目标(SA) 建议包括： SA 1：阐明CD24-Siglec调节GVHD的细胞和分子机制 在这个SA中，我们将测试CD24Fc与两个供体T细胞上的抑制性Siglec-G受体结合的假设 宿主APC在调节湿性炎症和GVHD加重中起关键作用。 SA 2：进行一项大型的、首次人类临床试验，以确定CD24Fc融合的用药 清髓后给非血缘异基因HSCT受者注射蛋白质可减轻移植物抗宿主病。 我们将探讨使用CD24Fc融合蛋白将是安全的，并减少严重移植物抗宿主病的假设 多中心IIa/b期临床试验。

ABSTRACT Allogeneic hematopoietic stem cell transplantation (HSCT) is an established curative therapy for leukemia through the potent immune-therapeutic effect called the graft vs leukemia effect (GVL). However, utilization of allogeneic HSCT has been severely limited by its most significant complication, namely graft vs host disease (GVHD). Efforts to meaningfully separate GVHD from GVL in humans have been largely unsuccessful. An important concept in immunology is that cellular injuries cause releases of danger-associated molecular patterns (DAMPs), which are major causes of inflammation after HSCT. While several molecules and pathways that stimulate inflammation are increasingly appreciated, the role of pathways that are inhibitory or regulate responses to DAMPs have largely been underappreciated and not been targeted in clinical inflammatory or immune-pathologies. We have recently demonstrated promoting negative responses to DAMPs after experimental allo-HSCT by enhancing CD24-SiglecG interaction (Toubai et al, Blood, 2015) reduced experimental GVHD. But the key cellular and molecular pathways remain to be deciphered. Preliminary preclinical data experimental also demonstrate that enhancing this pathway with a novel CD24Fc fusion protein reduced experimental GVHD. Importantly, since then we have developed clinical grade CD24Fc fusion protein that shows safety in healthy human volunteers. These key preliminary data form the foundation for our central hypothesis that CD24Fc will reduce the severity of GVHD without affecting GVL. Thus, in this proposal we will build on these exciting preliminary data to bring together basic and clincial studies. We aim to translate basic observations into a hypothesis driven, proof of concept, first in human trial with CD24Fc protein and meld it with further dissection of the immune-biological mechanisms of the CD24-Siglec axis in negative regulation of allo-immunity. If successful, our proposal will lead to the development of a novel therapeutic strategy while simultaneously providing biological insights into GVHD. The specific aims (SA) of the proposal are: SA 1: Elucidate the cellular and molecular mechanisms of CD24-Siglec mediated regulation of GVHD In this SA we will test the hypothesis that binding of CD24Fc to the inhibitory Siglec-G receptors on both donor T cells and host APCs is critical for regulating DAMP mediated inflammation and aggravation of GVHD. SA 2: To perform a large, first in human clinical trial to determine whether administration of CD24Fc fusion protein to recipients of unrelated donor allogeneic HSCT following myeloablative condition will mitigate GVHD. We will explore the hypothesis that administration of CD24Fc fusion protein will be safe and reduce severe GVHD in a multicenter Phase IIa/b clinical trial.