Multidimensional development of high-affinity anti-glycan antibodies to fight deadly bacterial infections

多维开发高亲和力抗聚糖抗体以对抗致命细菌感染

• 批准号: 10549640
• 负责人: Luc Teyton
• 金额: $ 202.5万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-09 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10549640
• 关键词: Acetylation; Achievement; Affinity; Animal Model; Antibiotic Resistance; Antibiotics; Antibodies; Antibody Affinity; Antigens; B-Lymphocytes; Bacteria; Bacterial Antibiotic Resistance; Bacterial Infections; Bacteriology; Binding; Carbohydrates; Cell Wall; Characteristics; Chemicals; Chemistry; Communication; Complement; Complex; Dangerousness; Data; Development; Dimensions; Drug resistance; Fab Immunoglobulins; Fc Immunoglobulins; Fimbriae Proteins; Glycopeptides; Goals; Health; Immune; Immune response; Immune system; Immunoglobulin Fragments; Immunologist; Immunology; Immunotherapy; Infectious Skin Diseases; Klebsiella pneumoniae; Knowledge; Life; Link; Mediating; Medical; Modification; Molecular; Monoclonal Antibodies; Mus; Nature; Neisseria gonorrhoeae; Oligosaccharides; Peptides; Peptidoglycan; Polysaccharides; Positioning Attribute; Preparation; Productivity; Publishing; Qualifying; Reporting; Research Personnel; Resistance to infection; Science; Serotyping; Staphylococcus aureus; Structural Biologist; Structure; Surface; T-Lymphocyte; Therapeutic; United States National Institutes of Health; Vaccines; Variant; World Health Organization; chemotherapy; design; fighting; glycosylation; immunogenic; in vivo; in vivo Model; monomer; nanoparticle delivery; pathogen; pathogenic bacteria; polyclonal antibody; preclinical study; programs; resistant strain; small molecule; structural biology; vaccine effectiveness; vaccine immunogenicity; web site

Abstract The development of immunotherapies focused on the surface glycans of bacteria is hypothesized to be a potential paradigm shift in the fight against life-threatening and antibiotic-resistant bacteria, an emerging and increasing health concern for which therapeutic options are limited. Our PO1 team will use chemistry to deconstruct and display bacterial glycan structures on an artificial platform to make them immunogenic and recognized by the immune system. Immune responses will be analyzed and dissected by bacteriologists, cellular and structural immunologists to determine the characteristics of what makes a vaccine or an antibody against glycans effective as an antibiotic and deployable in pre-clinical studies. This program that assembles some of the world experts in their respective fields is ambitious and intends to pioneer the effort of placing immunotherapy next to chemotherapy for the treatment of bacterial infections. Our unique combination of chemistry-immunology- bacteriology-structural biology will provide the necessary mechanistic understanding of what qualifies a vaccine or an antibody to be effective in immunotherapy. The team is already productive and has published the proofs of principle of the approach on which the science of this application is based: very high affinity antibodies can be produced against bacterial glycans exposed at the surface of antibiotic resistant bacteria and are effective at combating infectious challenges. We will expand our strategy to the surface glycans of three bacterial pathogens listed by WHO as “critical” or “high” priority: Staphylococcus aureus, Klebsiella pneumoniae, and Neisseria gonorrhea. The fundamental knowledge that we will gain from our studies should establish a very detailed blueprint of the immune recognition of glycans and glycopeptides by the immune system. The integration of the chemistry, immunology, and structural biology facets of the project directly into the bacteriology and in vivo models, will identify glycans targets and strategies to initiate pre-clinical studies.

摘要 针对细菌表面聚糖的免疫疗法的发展被假设为是一种新的免疫疗法。 在对抗威胁生命和耐药性细菌的斗争中，一种新兴的， 日益增加的健康问题，其治疗选择有限。我们的PO 1团队将利用化学反应， 在人工平台上解构和展示细菌聚糖结构以使其具有免疫原性， 被免疫系统识别。免疫反应将由细菌学家、细胞学家、 和结构免疫学家来确定疫苗或抗体的特性 聚糖作为抗生素是有效的，可用于临床前研究。这个程序集合了一些 在各自领域的世界专家雄心勃勃，并打算开拓免疫治疗的努力， 仅次于化学疗法来治疗细菌感染。我们独特的化学免疫学组合 细菌学-结构生物学将提供必要的机制，了解什么是合格的疫苗 或抗体以在免疫治疗中有效。该小组已经是富有成效的，并已公布的证据 本申请的科学所基于的方法的原理是： 针对暴露在抗生素抗性细菌表面的细菌聚糖产生，并且有效地 应对传染病挑战。我们将把我们的策略扩展到三种细菌病原体的表面聚糖 世卫组织列为“危重”或“高度”优先：金黄色葡萄球菌、肺炎克雷伯菌和奈瑟菌 淋病我们从学习中获得的基本知识应该建立一个非常详细的 免疫系统对聚糖和糖肽的免疫识别蓝图。的整合 化学，免疫学和结构生物学方面的项目直接进入细菌学和体内 模型，将确定聚糖的目标和战略，以启动临床前研究。