rBPI21 & Endotoxin-directed Innate Immunity in Stem Cell Transplantation

描述（由申请人提供）：造血干细胞移植（HSCT）是一种治疗恶性和良性淋巴造血系统疾病的潜在疗法，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的重要触发因素是脂多糖（LPS或内毒素），据信其由于清髓性预处理方案引起的肠损伤而进入外周循环。我们的初步数据表明，清髓性HSCT与杀菌/通透性增加蛋白（BPI）的血浆水平严重降低相关，BPI是一种中性粒细胞衍生的分子，具有有效和特异性的LPS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（BPI）严重不足时发生内毒素血症。我们假设BPI缺乏会损害接受HSCT的个体中和LPS的能力，增加LPS诱导的TNF-1产生的风险，以及导致aGVHD和方案相关毒性风险增加的其他下游事件。所提出的临床试验的前提是，早期输注具有有效内毒素中和活性并在人体临床试验中证明安全性的生物活性重组N-末端BPI片段（rBPI 21，Opebacan; XOMA U. S. LLC）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，我们将确定rBPI 21在BPI缺陷HSCT受者中的耐受性和药代动力学，以了解有效阻断LPS介导的毒性的剂量和时间表。将在特定目的2中研究rBPI 21输注对血浆内毒素调节活性的影响。具体目标3将侧重于确定rBPI 21输注对由MD-2、TLR 4和mCD 14组成的内毒素受体的功能表达的影响。该临床实验及其生物学终点将确定rBPI 21是否调节HSCT患者中内毒素介导的病理生理学。此外，从拟议的实验中获得的数据将提供必要的临床和科学信息，以设计关键性研究，这些研究将检查这种新颖且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潜在的治疗多种疾病的方法，但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，清髓性移植与内毒素中和蛋白（BPI）的血浆水平严重降低相关，从而增加了导致aGVHD和其他毒性的内毒素诱导事件的风险。在这里，我们将进行临床试验和实验室实验，以确定是否给予BPI将结合内毒素和屏蔽患者的内毒素诱导的炎症反应，触发移植毒性，包括aGVHD。

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.