rBPI21 & Endotoxin-directed Innate Immunity in Stem Cell Transplantation

描述(申请人提供)：造血干细胞移植(HSCT)是一种治疗恶性和良性淋巴造血疾病的潜在疗法，其影响受到急性移植物抗宿主病(AGVHD)的限制。动物模型和人类研究都表明，aGVHD的一个重要触发因素是脂多糖(LPS，或内毒素)，它被认为是清髓性预适应方案对肠道造成损害的结果，进入了外周循环。我们的初步数据表明，清髓性HSCT与血浆杀菌/通透性增加蛋白(BPI)水平严重降低有关，BPI是一种中性粒细胞衍生的分子，具有强大而特异的内毒素中和活性。因此，接受清髓性HSCT的患者在内源性抗内毒素防御系统BPI严重不足的情况下发生内毒素血症。我们假设，BPI缺乏损害了接受HSCT的个体中和内毒素的能力，增加了内毒素诱导的肿瘤坏死因子-1产生和其他下游事件的风险，从而增加了移植物抗宿主病和方案相关毒性的风险。拟议临床试验的前提是，早期输注具有生物活性的重组BPI片段(rBPI21，Opebacan；XOMA U.S.LLC)，具有强大的内毒素中和活性，并在人体临床试验中证明是安全的，将取代缺陷的BPI，从而快速保护患者免受内毒素诱导的炎症反应。在具体目标1中，我们将测定BPI缺陷的HSCT受者对rBPI21的耐受性和药代动力学，以建立对有效阻断内毒素介导的毒性的剂量和时间表的理解。RBPI21输注对血浆内毒素调节活性的影响将在特异靶2中进行研究。特异靶3将重点研究rBPI21输注对内毒素受体MD-2、TLR4和mCD14功能表达的影响。这项临床实验及其生物学终点将确定rBPI21是否调节HSCT患者的内毒素介导的病理生理。此外，来自拟议实验的数据将为设计关键研究提供必要的临床和科学信息，这些研究将检验这种新的和独特的非免疫抑制方法改善HSCT发病率和死亡率的主要原因之一的潜力。公共卫生相关性：造血干细胞移植是一种治疗许多疾病的潜在疗法，其成功受到急性移植物抗宿主病(AGVHD)的限制。我们的初步数据表明，清髓性移植与血浆内毒素中和蛋白(BPI)水平严重降低有关，从而增加了内毒素诱导的事件导致移植物抗宿主病(GVHD)和其他毒性反应的风险。在这里，我们将进行临床试验和实验室实验，以确定给予BPI是否会结合内毒素，并保护患者免受内毒素诱导的炎症反应，这些反应会引发包括aGVHD在内的移植毒性。

DESCRIPTION (provided by applicant): The impact of hematopoietic stem cell transplantation (HSCT), a potentially curative therapy for both malignant and benign lymphohematopoietic diseases, is limited by acute graft-versus-host disease (aGVHD). Both animal models and human studies indicate that an important trigger of aGVHD is lipopolysaccharide (LPS, or endotoxin) that is believed to enter the peripheral circulation as a consequence of intestinal damage due to myeloablative conditioning regimens. Our preliminary data demonstrate that myeloablative HSCT is associated with severely diminished plasma levels of bactericidal/permeability-increasing protein (BPI), a neutrophil- derived molecule with potent and specific LPS-neutralizing activity. Thus, patients undergoing myeloablative HSCT are endotoxemic at a time when an endogenous anti-endotoxin defense, BPI, is severely deficient. We hypothesize that BPI deficiency compromises the ability of individuals undergoing HSCT to neutralize LPS, increasing risk for LPS-induced TNF-1 production and other downstream events that result in an increased risk for aGVHD and regimen-related toxicity. The premise of the proposed clinical trial is that early infusion of a bioactive recombinant N-terminal BPI fragment (rBPI21, Opebacan; XOMA U.S. LLC) with potent endotoxin- neutralizing activity and demonstrated safety in human clinical trials, will replace the deficient BPI thereby rapidly shielding patients from endotoxin-induced inflammatory responses. In Specific Aim 1, we will determine the tolerability and pharmacokinetics of rBPI21 in BPI-deficient HSCT recipients in order to establish an understanding of the dose and schedule that will effectively block LPS mediated toxicity. The effects of rBPI21 infusion on the endotoxin-modulating activity of plasma will be investigated in Specific Aim 2. Specific Aim 3 will focus on determining the effect of rBPI21 infusion on the functional expression of the endotoxin receptor composed of MD-2, TLR4, and mCD14. This clinical experiment and its biological endpoints will establish whether rBPI21 modulates endotoxin mediated pathophysiology in HSCT patients. Moreover, the data derived from the proposed experiments will provide the necessary clinical and scientific information to design pivotal studies that will examine the potential of this novel and uniquely non-immunosuppressive approach to ameliorate one of the major causes of HSCT morbidity and mortality. PUBLIC HEALTH RELEVANCE: The success of hematopoietic stem cell transplantation, a potentially curative therapy for many diseases, is limited by acute graft-versus-host disease (aGVHD). Our preliminary data demonstrate that myeloablative transplant is associated with severely diminished plasma levels of the endotoxin-neutralizing protein (BPI), thereby increasing risk for endotoxin-induced events that result in aGVHD and other toxicities. Here, we will conduct a clinical trial and laboratory experiments to determine whether administering BPI will bind endotoxin and shield patients from endotoxin-induced inflammatory responses that trigger transplant toxicity including aGVHD.