rBPI21 & Endotoxin-directed Innate Immunity in Stem Cell Transplantation

重组BPI21

• 批准号: 7465106
• 负责人: EVA C GUINAN
• 金额: $ 26.63万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7465106
• 关键词: Acute Graft Versus Host Disease; Address; Alloantigen; Allogenic; Animal Model; Benign; Binding; Biological; Blood Circulation; CD14 Antigen; Clinical; Clinical Trials; Cohort Studies; Cytoplasmic Granules; Data; Disease; Dose; Drug Kinetics; Elements; End Point; Endotoxemia; Endotoxins; Event; Functional disorder; Goals; Hematopoietic Stem Cell Transplantation; Human; Immune; Immune response; Immunosuppressive Agents; In Vitro; Individual; Inflammation; Inflammatory Response; Infusion procedures; Intestines; Intravenous; Laboratories; Lipopolysaccharides; Malignant - descriptor; Marrow; Mediating; Modeling; Molecular; Morbidity - disease rate; N-terminal; Natural Immunity; Patients; Peripheral; Phase; Pilot Projects; Plasma; Population; Production; Protein Deficiency; Protein Fragment; Proteins; Public Health; Reaction; Recombinants; Risk; Role; Safety; Schedule; Specificity; Spiral Computed Tomography; Stem cell transplant; T-Lymphocyte; TLR4 gene; TNF gene; Time; Tissues; Toxic effect; Transplantation; Treatment Protocols; bactericidal permeability increasing protein; cohort; conditioning; cytokine; design; endotoxin receptor; human study; in vivo; intravenous administration; monocyte; mortality; neutrophil; novel; novel therapeutics; rBPI21; research study; response; success

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.

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。动物模型和人体研究均表明，aGVHD 的一个重要触发因素是脂多糖（LPS，或内毒素），据信，由于清髓性预处理方案造成肠道损伤，脂多糖会进入外周循环。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有关，BPI 是一种中性粒细胞衍生的分子，具有有效且特异的 LPS 中和活性。因此，当内源性抗内毒素防御 BPI 严重缺乏时，接受清髓性 HSCT 的患者就会出现内毒素血症。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 产生和其他下游事件的风险，从而导致 aGVHD 和治疗相关毒性的风险增加。拟议临床试验的前提是，早期输注生物活性重组 N 端 BPI 片段（rBPI21，Opebacan；XOMA U.S. LLC）具有有效的内毒素中和活性，并在人体临床试验中证明了安全性，将迅速取代缺陷的 BPI保护患者免受内毒素引起的炎症反应。在具体目标 1 中，我们将确定 BPI 缺陷的 HSCT 受者中 rBPI21 的耐受性和药代动力学，以便了解有效阻断 LPS 介导的毒性的剂量和时间表。 rBPI21 输注对血浆内毒素调节活性的影响将在具体目标 2 中进行研究。具体目标 3 将重点确定 rBPI21 输注对由 MD-2、TLR4 和 TLR4 组成的内毒素受体功能表达的影响。 mCD14。该临床实验及其生物学终点将确定 rBPI21 是否调节 HSCT 患者内毒素介导的病理生理学。此外，从拟议实验中获得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。公共健康相关性：造血干细胞移植是许多疾病的潜在治疗方法，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，清髓性移植与内毒素中和蛋白（BPI）的血浆水平严重降低有关，从而增加了内毒素诱导事件的风险，从而导致aGVHD和其他毒性。在这里，我们将进行临床试验和实验室实验，以确定施用 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的影响，从而引发包括 aGVHD 在内的移植毒性。