Synthesis and Evaluation of Zwitterionic Carbohydrate Immunostimulants

两性离子碳水化合物免疫增强剂的合成与评价

• 批准号: 9109179
• 负责人: Hien M Nguyen
• 金额: $ 18.66万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-15 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9109179
• 关键词: Address; Adjuvant; Aluminum Hydroxide; Antibodies; Antigen-Presenting Cells; Antigens; Bacterial Infections; Bacteroides fragilis; Binding; CD4 Positive T Lymphocytes; CD8B1 gene; Carbohydrates; Charge; Chemistry; Circular Dichroism; Clinical; Communicable Diseases; Development; Dose; Evaluation; Event; Galactose; Generations; Glycoconjugates; Goals; Haptens; Health; Human; Immune response; Immunity; Immunologic Adjuvants; Immunology; Iowa; Isomerism; Methodology; Microbiology; Molecular Conformation; Mus; Nickel; Oligosaccharides; Organic solvent product; Polysaccharides; Process; Production; Regulation; Research Personnel; Role; Safety; Salts; Signal Transduction; Source; Structure; Structure-Activity Relationship; T cell response; T-Lymphocyte; Tetanus Toxoid; Toxic effect; Tumor-Associated Carbohydrate Antigens; Universities; Vaccination; Vaccine Adjuvant; Vaccines; Variant; aluminum phosphate; aluminum sulfate; analog; base; biphenyl hydrolase-related protein; chemical synthesis; clinically relevant; combat; cytokine; glycosylation; immune function; immunogenic; immunogenicity; improved; in vivo; mouse model; novel vaccines; preclinical evaluation; public health relevance; research study; response; success; tool; tumor

 DESCRIPTION (provided by applicant): Although the use of vaccines to combat infectious diseases has greatly improved human health, they are poorly immunogenic and requires multiple doses for protection. As such, vaccines are co-administered with an adjuvant to enhance immunity. Numerous classes of vaccine adjuvants have been developed and showed the desired immune response over the past several decades. Unfortunately, only a few adjuvants are considered to be sufficiently potent and clinically liable for use in humans. Alum, a mixture of aluminum hydroxide and phosphate salts, remains the dominant adjuvant with extensive safety record approved for use in human vaccination. In efforts to discover new adjuvants, an unusual class of carbohydrates, zwitterionic polysaccharides (ZPSs), containing both negative and positive charge motifs in their repeating units, were found to activate CD4+ T-cell-dependent immune responses and modulate host cytokine responses to bacterial infection. ZPSs when co-administered with antigen tetanus toxoid increase the specific antibody tier, illustrating their capacity to serve as potential vaccine adjuvants in vivo. One of the best characterized ZPSs is zwitterionic polysaccharide PS A1, isolated from capsular Bacteroides fragilis. Studies showed that glycoconjugates, generated from conjugation of PS A1 to tumor-associated mucin antigen TN, elicits high titer antibodies that are specific and selective for the TN hapten. Despite the promise of PS A1 as a potential adjuvant, obtaining it from natural sources is a complicated process of extraction and purification that results in the production of minute, relatively impure quantities and could alter its structure. Since FDA has strict regulation regarding the purity and quality of vaccine adjuvants for use in humans, a synthetic source must be developed for PS A1 to be utilized as a clinically relevant adjuvant. The main goal of this proposal will address these challenges through the chemical synthesis of natural and non-natural PS A1 oligosaccharides with defined repeating units utilizing our recently developed nickel-catalyzed α-glycosylation methodologies. This proposed effort will deliver defined PS A1 molecules in high purity without batch-to-batch variation and provide tools for studying their roles as adjuvants and exploring structure-relationship activity (SAR) studies. 1

 描述(申请人提供)：虽然使用疫苗来对抗传染病极大地改善了人类健康，但它们的免疫原性很差，需要多次接种才能保护。因此，疫苗与佐剂联合接种以增强免疫力。在过去的几十年里，许多种类的疫苗佐剂已经被开发出来，并显示出理想的免疫反应。不幸的是，只有少数佐剂被认为是足够有效的，临床上可以用于人类。明矾，一种 氢氧化铝和磷酸盐的混合物，仍然是主要的佐剂，有广泛的安全记录，被批准用于人类疫苗接种。在寻找新的佐剂的过程中，发现了一类不寻常的碳水化合物--两性离子多糖(ZPS)，它的重复单元中既含有正负电荷基序，又能激活CD4+T细胞依赖的免疫反应，并调节宿主细胞因子对细菌感染的反应。当ZPS与破伤风类毒素抗原联合注射时，可以增加特异性抗体水平，说明它们在体内作为潜在的疫苗佐剂的能力。最具特性的ZPS之一是从脆弱类杆菌胶囊中分离得到的两性离子多糖PS A1。研究表明，PS A1与肿瘤相关粘蛋白抗原TN偶联产生的糖偶联物可诱导针对TN半抗原的高滴度抗体。尽管PS A1有望成为一种潜在的佐剂，但从天然来源获得PS A1是一个复杂的提取和纯化过程，导致产生微小的、相对不纯的数量，并可能改变其结构。由于FDA对人类使用的疫苗佐剂的纯度和质量有严格的规定，因此必须开发一种合成来源，才能将PS A1用作临床相关佐剂。这项提案的主要目标是利用我们最近开发的镍催化α糖基化方法，通过化学合成具有特定重复单元的天然和非天然PS A1寡糖来应对这些挑战。这项拟议的工作将提供定义的PS A1分子的高纯度，没有批次到批次的变化，并为研究它们作为佐剂的作用和探索结构关系活性(SAR)研究提供工具。1