A Modulator of Innate Immunity for Preventing Hospital-Acquired Infections

用于预防医院获得性感染的先天免疫调节剂

• 批准号: 7670579
• 负责人: James D. Thacker
• 金额: $ 34.44万
• 依托单位: THERIMUNEX PHARMACEUTICALS, INC
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-04 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7670579
• 关键词: AIDS/HIV problem; Abate; Acute-Phase Proteins; Address; Animal Model; Animals; Anti-Bacterial Agents; Anti-Infective Agents; Antibiotic Resistance; Antibiotics; Bacteremia; Biological; Biological Products; CCL2 gene; Canis familiaris; Catheterization; Cattle; Cause of Death; Cells; Chemicals; Clinical Trials; Data; Development; Disease Progression; Dose; Drug Formulations; Elderly; Environmental air flow; Escherichia coli; Granulocyte-Macrophage Colony-Stimulating Factor; Hospitals; Host Defense; Hour; Human; Human Activities; IL8 gene; Immune; Immune response; Immune system; Immunoglobulin M; Immunomodulators; In Vitro; Incidence; Infection; Interleukin-6; Lead; Leukocytes; Marketing; Mediating; Milk; Modeling; Molecular Structure; Morbidity - disease rate; Mus; National Institute of Allergy and Infectious Disease; Natural Immunity; Nosocomial Infections; Parvovirus; Patients; Peptides; Peritonitis; Pharmaceutical Preparations; Phase; Post-Translational Protein Processing; Prevention; Procedures; Proteins; Radiation therapy; Reference Standards; Respiratory Burst; Risk Factors; Safety; Sepsis; Small Business Innovation Research Grant; Soft Tissue Disorder; Streptococcus; Structure; Survival Rate; Technology; Testing; Therapeutic; Therapeutic Index; Therapeutic immunosuppression; Thigh structure; Tissues; Toxic effect; United States; Whole Blood; Work; bacterial resistance; bactericide; base; cell injury; chemokine; chemotherapy; cytokine; drug candidate; improved; macrophage; macrophage stimulatory lipopeptide 2; mastitis; methicillin resistant Staphylococcus aureus; microbicide; monocyte; mortality; mouse model; neonate; novel; pathogen; patient population; pre-clinical; prevent; programs; prophylactic; protein aminoacid sequence; public health relevance; research study

DESCRIPTION (provided by applicant): The product that will result from this proposal will be a potent biological regulator of innate immunity, 1- peptidyl-2,3-diacylglyceride (PDAG), for use in the prevention of hospital-acquired (nosocomial) infections in highly-susceptible patient populations. Nosocomial infection is a rapidly growing cause of morbidity and mortality in U.S. hospitals and nosocomial bloodstream infections have been estimated to be the eighth leading cause of death in the United States. The burden of the nosocomial infection rate is largely borne by patients who are undergoing prolonged invasive procedures (e.g. indwelling catheterization, ventilation) and/or who are undergoing immunosuppressive therapies or are characterized by immuno-compromising risk factors (e.g. neonates, the elderly, chemo- or radiotherapy patients, HIV/AIDS patients). The increasing incidence of nosocomial infections can be attributed in large part to the alarming rate at which pathogens are acquiring resistance to antibiotics, such as methicillin-resistant Staphylococcus aureus (MRSA). This problem is compounded by the fact that, in over thirty years, only two new classes of antibiotics have reached the market. It is clear that prophylactic strategies that provide alternatives or adjuncts to conventional antibiotics are urgently needed to protect highly-susceptible patient groups from nosocomial infection. We have recently identified that PDAG is an immunomodulator. Our hypothesis is that PDAG is an activator of innate immune responses to cell injury, and that its effects are mediated by activation of monocyte derived macrophage. Moreover, we believe that PDAG is the mammalian equivalent of the macrophage activating lipopeptide MALP- 2. Here, we propose to develop a therapeutic immunoregulatory biological agent, based on the structure of PDAG, for use in protecting highly susceptible patient groups from nosocomial infections. PDAG is well-suited for this indication since, unlike existing immune regulating therapies, it is a regulator of the non-specific innate immune response, the first line of host defenses. Our preliminary data demonstrate that, while PDAG is not itself bactericidal, it induces a phagocytic cytokine/chemokine profile in human leukocytes, it up-regulates at least two downstream effectors - opsonic acute phase proteins and IgM, and it confers protection in an animal model of bacteremia. These observations strongly suggest that PDAG has considerable utility as a novel, immunoregulatory, prophylactic, anti-infective agent. To initiate development of PDAG for human use, and to demonstrate the feasibility of the final product, we will manufacture and formulate PDAG in a drug product (Aim I), we will further delineate PDAG's immunological mode of action (Aim II), determine a therapeutic index, demonstrate that PDAG does not induce a cytokine storm, and show the efficacy of the formulated drug product in a MRSA SSTI that is directly relevant to hospital acquired infections (Aim III). PUBLIC HEALTH RELEVANCE: This proposal will reduce the growing incidence of hospital-acquired infections by developing a drug-like compound that can be used to protect highly susceptible patients. Hospital-acquired infections often involve bacteria that are resistant to conventional antibiotics. The product being developed in this proposal will reduce the need to use antibiotics, because it works by stimulating the phagocytic activity of the human innate immune system.

描述（由申请人提供）：本提案产生的产品将是先天免疫的有效生物调节剂，1-肽基-2,3-二酰基甘油酯（PDAG），用于预防医院获得性（院内）高度易感患者群体中的感染。医院感染是美国医院发病率和死亡率迅速增长的一个原因，医院血流感染估计是美国第八大死因。医院感染率的负担主要由接受长期侵入性操作（例如留置导尿、通气）和/或正在接受免疫抑制治疗或具有免疫受损危险因素（例如新生儿、老年人、化疗）的患者承担。 - 或放射治疗患者、艾滋病毒/艾滋病患者）。医院感染发生率的增加在很大程度上可归因于病原体对抗生素产生耐药性的惊人速度，例如耐甲氧西林金黄色葡萄球菌（MRSA）。三十多年来，只有两种新型抗生素进入市场，这一事实使问题变得更加复杂。显然，迫切需要提供传统抗生素替代品或辅助手段的预防策略，以保护高度易感的患者群体免受院内感染。我们最近发现 PDAG 是一种免疫调节剂。我们的假设是，PDAG 是对细胞损伤的先天免疫反应的激活剂，其作用是通过单核细胞衍生的巨噬细胞的激活介导的。此外，我们相信PDAG是巨噬细胞激活脂肽MALP-2的哺乳动物等价物。在这里，我们建议基于PDAG的结构开发一种治疗性免疫调节生物制剂，用于保护高度易感的患者群体免受医院感染。 PDAG 非常适合这种适应症，因为与现有的免疫调节疗法不同，它是非特异性先天免疫反应（宿主防御的第一道防线）的调节剂。我们的初步数据表明，虽然 PDAG 本身并不杀菌，但它会在人类白细胞中诱导吞噬细胞因子/趋化因子谱，上调至少两个下游效应子 - 调理性急性期蛋白和 IgM，并在动物模型中提供保护菌血症。这些观察结果强烈表明，PDAG 作为一种新型免疫调节、预防、抗感染剂具有相当大的实用性。为了启动人类使用的 PDAG 的开发，并证明最终产品的可行性，我们将在药品中制造和配制 PDAG（目标 I），我们将进一步描述 PDAG 的免疫学作用模式（目标 II），确定治疗指数，证明 PDAG 不会诱发细胞因子风暴，并显示配制的药物产品在与医院获得性感染直接相关的 MRSA SSTI 中的功效（目标 III）。 公共健康相关性：该提案将通过开发一种可用于保护高度易感患者的类药物化合物来减少日益增长的医院获得性感染发生率。医院获得性感染通常涉及对传统抗生素具有抗药性的细菌。该提案中正在开发的产品将减少使用抗生素的需求，因为它通过刺激人类先天免疫系统的吞噬活性发挥作用。