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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.

说明(申请人提供)：预防流感、结核病和疟疾等世界范围内已知的主要致死原因的传染病，以及可能释放引起鼠疫、兔热病和梅毒的生物毒剂，需要产生体液和T细胞反应的疫苗。有效成分疫苗需要添加佐剂以提高其免疫原性。直到最近，需要重复应用且倾向于基于T辅助细胞的免疫(体液)而不是基于TH1的免疫的明矾盐(细胞)是唯一被批准用于人类疫苗的佐剂。最近，在FDA批准的两种疫苗(Cervarx(人乳头瘤病毒)和Fendrix(乙肝病毒))中，类脂A佐剂(单磷酰脂A，MPL)已与明矾(AS04)结合。此外，也通过Toll样受体4(TLR4)发出信号的合成类脂A模拟氨基烷基氨基葡萄糖磷酸盐(AGPs)正被研究为佐剂或独立的免疫原性化合物。因此，TLR4激动剂在成分疫苗中作为佐剂的应用前景广阔。然而，已被批准的TLR4激动剂MPL在效力和结构一致性方面都存在明显的不足，而且AGPs是劳动密集型的，合成成本很高。因此，此次修订的R21应用程序的目标是采用一种新的方法，利用细菌酶组合化学(BECC)通过修改来自减毒(BSL-2批准)的鼠疫耶尔森氏菌(YP)菌株的脂寡糖(LOS)的脂A结构来制造合理设计的脂A结构。这种方法将使用由该YP菌株合成的存在于LOS中的非刺激性、低酰化和双磷酸化的类脂A结构作为支架，通过异源修饰从各种细菌背景获得的类脂A生物合成酶的反式表达，该生物合成酶具有去除或添加脂肪酸链、磷酸盐部分和碳水化合物到类脂A主干的特异性，该方法允许安全、经济有效和高效地设计具有免疫刺激潜力的分子。我们将在体外和体内测试这些新分子的免疫治疗潜力，以确定代表佐剂和/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，如MPL和已知的脂多糖结构，作为与BECC合成的分子的比较。这种创造新佐剂的新方法在高度相关的体内动物模型(S)中成功展示保护性先天/获得性免疫反应，可能在抗原识别、配方和疫苗设计领域具有重要意义。