Immunotherapeutic Potential of Modified Lipooligosaccharides and Lipid A's

修饰脂寡糖和脂质 A 的免疫治疗潜力

基本信息

批准号：
8675799
负责人：
Robert K Ernst
金额：
$ 23.02万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-06-10 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8675799
关键词：
Address Adjuvant Adjuvanticity Agonist Anabolism Animal Disease Models Animal Model Animals Antibody Formation Antigens Area Attenuated Baltimore Biological Assay Carbohydrates Cause of Death Cells Cervarix Chemicals Clinical Trials Complement Core Facility Data Development Disease Dose Drug Formulations Emulsions Engineering Enzymes Equilibrium Evaluation Excision FDA approved Fatty Acids Funding Future Goals Hepatitis B Virus Heterogeneity Human Human Papillomavirus Humoral Immunities Hydrolysis Immune response Immune system Immunity Immunologic Adjuvants Immunotherapeutic agent In Vitro Infection Infectious Agent Inflammation Influenza Intramuscular Investments Knowledge Lead Licensing Link Lipid A Lipids Location Malaria Maryland Mass Fragmentography Mass Spectrum Analysis Mediating Methodology Modeling Modification Mus Mutation Nature Oils Pharmacy facility Plague Preclinical Testing Process Production Property Reaction Reagent Regulator Genes Research Research Personnel Risk Salts Signal Transduction Specificity Structure T cell response Technology Testing Therapeutic Toxic effect Tuberculosis Tularemia Universities Vaccine Antigen Vaccine Design Vaccines Vertebral column Viral Viral Pathogenesis Virus Water Yersinia pestis aluminum sulfate base candidate selection cell type combat combinatorial chemistry cost effective design enzyme biosynthesis human TLR4 protein immunogenic in vivo inorganic phosphate interest lipooligosaccharide mimetics monophosphoryl lipid A novel novel strategies novel vaccines pathogenic bacteria preclinical study public health relevance research clinical testing response scaffold screening success toll-like receptor 4 vaccine development vaccine efficacy vaccinology

项目摘要

DESCRIPTION (provided by applicant): Protection from infectious agents known to be major causes of death worldwide, such as influenza, tuberculosis, and malaria, as well as potential release of bioweaponized agents which cause plague, tularemia, and meilloidosis require vaccines that generate humoral and T-cell responses. Effective component vaccines require the addition of adjuvants to increase their immunogenic capacities. Until recently alum salts, which require repeated applications and tend to be skewed towards T helper TH2-based immunity (humoral) rather than TH1, (cellular) were the only adjuvants approved for use in human vaccines. Recently, the lipid A mimetic (monophosphoryl lipid A, MPL) adjuvant has been combined with alum (AS04) in two FDA-approved vaccines (Cervarix (Human Papilloma Virus), and Fendrix (Hepatitis B Virus)). Additionally, synthetic lipid A mimetics aminoalkyl glucosaminide phosphates (AGPs) that also signal through Toll-Like Receptor 4 (TLR4) are being studied as both adjuvants or stand-alone immunogenic compounds. Thus, TLR4 agonists show great promise for use as adjuvants in component vaccines. However, the approved TLR4 agonist, MPL has distinct deficiencies both in potency and structural consistency and AGPs are labor intensive and costly to synthesize. Therefore, the goal of this revised R21 application is to undertake a novel approach of using Bacterial Enzymatic Combinatorial Chemistry (BECC) to make rationally-designed lipid A structures by modifying the lipid A structure of the lipooligosaccharide (LOS) from an attenuated (BSL-2 approved) Yersinia pestis (Yp) strain. This approach will use the non-stimulatory, hypoacylated, and bisphosphorylated lipid A structure present in LOS synthesized by this Yp strain as a scaffold to be modified by heterologous in trans expression of lipid A biosynthesis enzymes obtained from a wide variety of bacterial backgrounds with specificities for the removal or addition of fatty acid chain, phosphates moieties, and carbohydrates to the lipid A backbone, This process allow for the safe, cost effective, and efficient design of molecules with immunostimulatory potential. We will test the immunotherapeutic potential of these new molecules in vitro and in vivo to identify novel molecules representing adjuvants and/or immunomodulating reagents. We will also include well-characterized immunostimulants, such as MPL and known LPS structures as comparisons to the molecules synthesized by BECC. The successful demonstration of protective innate/adaptive immune responses by this novel approach of creating new adjuvants, in highly relevant in vivo animal model(s) could have important implications in the field of antigen recognition, formulation, and vaccine design.

描述（由申请人提供）：免受已知是全世界死亡主要原因的感染剂的保护，例如流感，结核病和疟疾，以及潜在的生物高压剂释放，引起瘟疫，tular虫和息肉病，需要产生幽默和T-cell反应的疫苗。有效的成分疫苗需要添加佐剂才能增加其免疫原性。直到最近，需要重复应用并倾向于将基于T Helper Th2的免疫力（体液）而不是TH1偏向的明矾盐是唯一被批准用于人疫苗的辅助药物。最近，在两种FDA批准的疫苗（Cervarix（Cervarix（Human Papilloma病毒））和Fendrix（Hepatisitis B Virus）中，脂质A模拟（单磷酸脂质A，MPL）辅助剂已与明矾（AS04）合并。另外，研究了通过Toll样受体4（TLR4）发出信号的合成脂质A氨基烷基葡萄糖胺磷酸盐（AGP），作为佐剂或独立的免疫原性化合物。因此，TLR4激动剂在组成疫苗中用作佐剂显示出巨大的希望。但是，经批准的TLR4激动剂，MPL在效力和结构一致性方面都有明显的缺陷，而AGP的劳动力很大，并且综合构成了昂贵。因此，此修订的R21应用程序的目标是采用一种新的方法，即通过通过修饰脂质（BSL-2批准的）yersinia pestis（yp）菌株来修饰脂质（LOS）的脂质A结构，以使用细菌酶联合化学（BECC）来制造合理设计的脂质A结构。这种方法将使用该YP菌株合成的LOS中存在的非刺激性，次级和双磷酸化的脂质A结构作为脚手架，可通过在脂质表达的反式表达中进行异态化，从而从脂质表达中进行生物合成酶，这些酶从脂肪中获得了多种细菌量，又有多种细菌的含量，又是脂肪供应量，富含脂肪的含量，这些含量是脂肪的含量，该酶是对脂肪的含量，并赋予了脂肪的含量。脂质的骨干，此过程允许具有免疫刺激潜力的分子的安全，成本效益和有效的设计。我们将在体外和体内测试这些新分子的免疫治疗潜力，以鉴定代表辅助和/或免疫调节试剂的新分子。我们还将包括特征良好的免疫刺激剂，例如MPL和已知的LPS结构，作为与BECC合成的分子的比较。在高度相关的体内动物模型中，通过这种新的新方法来成功证明了保护性先天/适应性免疫反应，这可能在抗原识别，配方和疫苗设计的领域具有重要意义。