Targeting novel DAMP mediated signaling pathways to mitigate GVHD

摘要 异基因造血干细胞移植（HSCT）是通过造血干细胞移植治疗白血病的一种成熟的治愈性疗法。 这种免疫治疗效应被称为移植物抗白血病效应（GVL）。然而，利用同种异体HSCT， 由于其最重要的并发症，即移植物抗宿主病（GVHD），严重限制了它的应用。努力有意义地 在人类中将GVHD与GVL分开的方法在很大程度上是不成功的。免疫学中的一个重要概念是， 细胞损伤导致炎症相关分子模式（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，但炎症的作用仍然存在。 抑制或调节DAMPs反应的途径在很大程度上被低估，并且没有被靶向， 临床炎症或免疫病理学。我们最近已经证明了促进对DAMP的负面反应 在实验性allo-HSCT后，通过增强CD 24-SiglecG相互作用（Toubai et al，Blood，2015）减少了实验性 GVHD。但关键的细胞和分子途径仍有待破译。初步临床前实验数据 还证明用新的CD 24 Fc融合蛋白增强该途径减少了实验性GVHD。 重要的是，从那时起，我们已经开发出临床级CD 24 Fc融合蛋白，其在健康人中显示出安全性。 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CD 24 Fc将减少CD 24的表达。 GVHD的严重程度而不影响GVL。因此，在本提案中，我们将基于这些令人兴奋的初步数据， 基础和临床研究。我们的目标是首先将基本观察转化为假设驱动的概念证明 在人体试验中使用CD 24 Fc蛋白，并将其与进一步分析CD 24 Fc蛋白的免疫生物学机制相结合。 CD 24-Siglec轴在同种免疫的负调节中的作用如果成功，我们的建议将导致发展一个 新的治疗策略，同时提供对GVHD的生物学见解。具体目标（SA） 建议如下： SA 1：阐明CD 24-Siglec介导的GVHD调节的细胞和分子机制 在本SA中，我们将检验CD 24 Fc与两种供体T细胞上的抑制性Siglec-G受体的结合 而宿主APC对调节DAMP介导的炎症和GVHD的加重是至关重要的。 SA 2：进行首次大型人体临床试验，以确定是否给予CD 24 Fc融合蛋白 在清髓性条件下，向无关供体异基因HSCT的受者提供蛋白质将减轻GVHD。 我们将探讨这样一种假设，即给予CD 24 Fc融合蛋白是安全的，并能减少严重的GVHD。 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.