MIMETICS OF CAPSULAR EPITOPES OF NEISSERIA MENINGITIDIS

脑膜炎奈瑟菌荚膜表位的模拟物

• 批准号: 6374184
• 负责人: Dan M. Granoff
• 金额: $ 56.81万
• 依托单位: CHILDREN'S HOSPITAL & RES CTR AT OAKLAND
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-04-01 至 2005-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6374184
• 关键词: Neisseria meningitidis; antibacterial antibody; antibody formation; autoantibody; bacterial antigens; bacterial polysaccharides; biomimetics; chemical structure; guinea pigs; immunoglobulin genes; laboratory mouse; laboratory rabbit; monoclonal antibody; peptide library; synthetic antigens; tissue /cell culture

Description (Adapted from the applicant's abstract) The long-term objective of this study is to increase our understanding of the immunologic properties of molecular mimetics of a bacterial polysaccharide that also is an autoantigen. Mimetics can act as antigens, bind to antibody receptors on B cells, and elicit serum antibody responses to the nominal antigen. Yet, little is understood about the properties of antigenic mimetics that contribute to their immunogenicity. Nor is much known about the quality of the antibody response with respect to conferring protection against a pathogen. Neisseria meningitidis group B (NmB) polysaccharide is an excellent model to investigate these questions. NmB is a major cause of meningitis and sepsis. The mechanism of protection is well defined (serum antibody), and reliable assays exist for measurement of antibody binding to the polysaccharide antigen, functional antibody against the bacteria, and passive protection in an infant rat model of bacteremia. Efforts to develop a NmB vaccine have been hampered by poor immunogenicity of the polysaccharide capsule, which cross-reacts with host polysialic acid. The PI's laboratory has prepared a panel of murine monoclonal antibodies (Mabs) that react with capsular polysaccharide epitopes on NmB that are distinct from host polysialic acid. These Mabs are bactericidal and confer passive protection in animal models. The PI's hypothesis is that mimetic antigens identified by these Mabs will be able to elicit protective anti-capsular antibody responses that are specific for the pathogen, avoiding the risk of autoantibody. Further, that the best mimetics will be those that adopt relatively stable conformations. To search for such mimetics, the PI proposes to screen phage libraries displaying independently folding peptides, or search for constrained protein mimetics within immunoglobulin scaffolds (single chain variable (ScFv) anti-idiotypes). The mimetics will be investigated for their ability to elicit anticapsular antibody responses. The Ig isotype, antibody functional activity to the bacteria, and immunoglobulin variable region gene usage in response to the mimetics, will be compared to that elicited by the nominal antigen. A central question will be whether a mimetic identified with a Mab that reacts specifically with encapsulated NmB strains, but not with host polysialic acid, will elicit protective antibody responses without autoantibody activity. Additional questions will be whether the repertoire of the antibody response to the mimetic is similar or different than that elicited by the nominal polysaccharide, and what effect, if any, the antibody repertoire may have on protection. Taken together, the data will provide important information on the properties of mimetic antigens with chemical structures that are distinct from that of the nominal polysaccharide antigen. The results also may identify new candidate molecules for inclusion in a future vaccine for prevention of NmB disease.

描述（改编自申请人的摘要） 的长期目标 这项研究是为了增加我们对免疫学特性的了解 细菌多糖的分子模拟物，也是一种自身抗原。 模拟物可以充当抗原，与 B 细胞上的抗体受体结合，并引发 血清抗体对标称抗原的反应。然而，了解甚少 关于抗原模拟物的特性有助于其 免疫原性。人们对抗体反应的质量也知之甚少 关于提供针对病原体的保护。奈瑟菌属 B 组脑膜炎 (NmB) 多糖是研究的绝佳模型 这些问题。 NmB 是脑膜炎和败血症的主要原因。机制 保护作用已明确定义（血清抗体），并且存在可靠的检测方法 测量抗体与多糖抗原的结合，功能性 针对细菌的抗体，以及婴儿大鼠模型中的被动保护 菌血症。开发 NmB 疫苗的努力因贫困而受到阻碍 多糖胶囊的免疫原性，与宿主发生交叉反应 聚唾液酸。 PI实验室制备了一组鼠单克隆抗体 与 NmB 上的荚膜多糖表位发生反应的抗体 (Mab) 与宿主聚唾液酸不同。这些单克隆抗体具有杀菌作用并赋予 动物模型中的被动保护。 PI 的假设是模仿 这些单克隆抗体识别的抗原将能够引发保护性 针对病原体的抗荚膜抗体反应，避免 自身抗体的风险。此外，最好的模仿者将是那些 采用相对稳定的构象。为了寻找这样的模仿者，PI 提议筛选展示独立折叠肽的噬菌体文库， 或在免疫球蛋白支架内寻找受限的蛋白质模拟物 （单链变量（ScFv）抗独特型）。模仿者将是 研究了它们引发抗荚膜抗体反应的能力。这 Ig 同种型、抗体对细菌的功能活性和免疫球蛋白 响应模拟物的可变区基因使用，将与 由标称抗原引起的。一个核心问题是是否 用与封装的 NmB 发生特异性反应的 Mab 鉴定出的模拟物 菌株，但不与宿主聚唾液酸，将引发保护性抗体 无自身抗体活性的反应。其他问题是是否 抗体对模拟物的反应是相似或不同的 比标称多糖引起的效果，以及什么效果（如果有的话） 抗体库可能具有保护作用。综合起来，数据将 提供有关模拟抗原特性的重要信息 与标称多糖不同的化学结构 抗原。结果还可能确定新的候选分子以包含在 未来预防 NmB 疾病的疫苗。