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.

抽象的 专注于细菌表面聚糖的免疫疗法的发展正在竞相发展 对抗危及生命和抗生素耐药性的细菌的潜在范式转变是一种新兴的和 对于治疗选择有限的日益增加的健康问题，我们的 PO1 团队将使用化学来治疗。 在人工平台上解构和展示细菌聚糖结构，使其具有免疫原性和 免疫系统将由细菌学家、细胞学家分析和剖析免疫反应。 和结构免疫学家来确定疫苗或抗体的特征 聚糖作为一种有效的抗生素，可用于临床前研究。该程序汇集了一些聚糖。 世界各国专家在各自领域雄心勃勃，有意开创免疫疗法的先河 我们独特的化学-免疫学组合治疗细菌感染。 细菌学-结构生物学将为疫苗的资格提供必要的机制理解 或在免疫治疗中有效的抗体，该团队已经富有成效并已发布证据。 本申请的科学依据的方法原理：非常高亲和力的抗体可以 针对暴露在抗生素抗性细菌表面的细菌聚糖而产生，并且有效 我们将把我们的策略扩展到三种细菌病原体的表面聚糖。 世界卫生组织将其列为“关键”或“高”优先级：金黄色葡萄球菌、肺炎克雷伯菌和奈瑟菌 我们将从研究中获得的基础知识应该建立一个非常详细的基础知识。 免疫系统对聚糖和糖肽的免疫识别蓝图。 该项目的化学、免疫学和结构生物学面向直接进入细菌学和体内 模型，将确定聚糖靶标和启动临床前研究的策略。