Early Plasma Cells as a Source of Anthrax-Neutralizing Antibodies

早期浆细胞作为炭疽中和抗体的来源

• 批准号: 7696156
• 负责人: Patrick Christopher Wilson
• 金额: $ 34.6万
• 依托单位: OKLAHOMA MEDICAL RESEARCH FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7696156
• 关键词: Affinity; Animals; Anthrax Vaccines; Anthrax disease; Antibiotics; Antibodies; Antibody Affinity; Antibody Formation; Antibody Specificity; Antibody Therapy; B-Lymphocytes; Bacillus anthracis; Bacteria; Binding; Biological Assay; Biological Warfare; Breathing; Cells; Collaborations; Diagnostic Reagent; Effectiveness; Epitopes; Flow Cytometry; Frequencies; Genes; Goals; Human; Immunity; Immunization; Immunoglobulin Variable Region; Immunoglobulin-Secreting Cells; Immunologics; Individual; Infection; Kinetics; Memory; Memory B-Lymphocyte; Military Personnel; Modeling; Molecular; Monoclonal Antibodies; Mus; Mutation; Papio; Passive Immunization; Patients; Peptides; Plasma Cells; Production; Reagent; Reproduction spores; Research; Serological; Serum; Soldier; Somatic Mutation; Source; Specificity; Staging; Symptoms; Techniques; Technology; Testing; Therapeutic antibodies; Toxic effect; Toxin; Vaccinated; Vaccination; Vaccines; alternative treatment; anthrax toxin; capsule; enzyme linked immunospot assay; human monoclonal antibodies; insight; interest; monoclonal antibody production; neutralizing antibody; novel strategies; pathogen; research study; response; septic; tool; vaccine efficacy; variable region gene; weapons

The bacterium Bacillus anthracis is highly pathogenic because of its stable spore form that resists treatment with antibiotics, its antiphagocytic capsule, and its production of potent toxins. Thus it has been studied as agent of biological warfare for some 60 years and is an extremely effective terrorist weapon. We have recently developed a novel strategy to rapidly produce fully human monoclonal antibodies after immunization and propose to use this technique to develop therapeutic antibodies against anthrax. These antibodies are derived recombinantly from expression of the immunoglobulin variable region genes of early antibodysecreting cells that arise in a massive, transient burst 7 days after immunization. This technology represents a substantial advance in monoclonal antibody production from humans and provides an opportunity to rapidly develop antibody therapies. We have now used this strategy to produce a limited number of antibodies from recipients of the anthrax vaccine. In collaboration with our U19 team we used serological studies to identify several key peptide epitopes that effectively neutralize anthrax toxin activity. The central goal of this Technology Component is to isolate the monoclonal antibodies that target these epitopes. These antibodies will be valuable as research and diagnostic reagents to assess protective immunity, and could ultimately be developed for safe passive immunization or for treatment of anthrax infection. In addition, analyses of monoclonal antibody reactivity may identify protective antibody specificities that are not dominant in the polyclonal response, or that only arise against non-peptide, structural epitopes. Although a vaccine against anthrax exists and is in limited use, primarily for vaccination of military personnel, its effectiveness is at best only "good". It requires multiple and continued boosts to provide protection, and our U19 group has determined that serum from only half of those immunized can neutralize anthrax toxicity. Thus a second goal of this component is to characterize the induction of long-term B cell immunity (memory) to gain insight into why the vaccine is relatively ineffective in inducing protective immunity.

炭疽杆菌具有高致病性，因为它具有稳定的孢子形式，可以抵抗治疗 它的抗吞噬胶囊，以及它的强效毒素的生产。因此，它被研究为 作为生物战剂已有60多年的历史，是一种极其有效的恐怖主义武器。我们有 最近开发了一种在免疫后快速产生完全人单克隆抗体的新策略 并提议利用这项技术来开发针对炭疽的治疗性抗体。这些抗体 重组衍生自早期抗体分泌的免疫球蛋白可变区基因的表达， 免疫后7天出现大量短暂爆发的细胞。这项技术代表了 在从人类生产单克隆抗体方面取得了实质性进展，并提供了机会， 快速开发抗体疗法。我们现在已经使用这种策略来生产有限数量的 炭疽疫苗接种者体内的抗体与我们的U19团队合作，我们使用血清学 研究确定了几个关键的肽表位，有效地中和炭疽毒素活性。中央 本技术组件的目标是分离靶向这些表位的单克隆抗体。这些 抗体作为评估保护性免疫的研究和诊断试剂将是有价值的，并且可以 最终被开发用于安全的被动免疫或治疗炭疽感染。此外，本发明还提供了一种方法， 单克隆抗体反应性的分析可以鉴定保护性抗体特异性， 在多克隆反应中，或仅针对非肽、结构表位产生。虽然疫苗 针对炭疽存在，并在有限的使用，主要是为军事人员接种疫苗，其有效性是 充其量只是“好”。它需要多次和持续的提升来提供保护，我们的U19小组已经 确定只有一半的免疫者的血清可以中和炭疽毒性。第二个目标 该组分的主要目的是表征长期B细胞免疫（记忆）的诱导，以了解 为什么疫苗在诱导保护性免疫方面相对无效。