Development of new passive immunization strategies for anthrax

开发新的炭疽被动免疫策略

• 批准号: 8230240
• 负责人: Arturo Casadevall
• 金额: $ 56.78万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8230240
• 关键词: Acids; Affinity; Anthrax disease; Antibodies; Antigens; Bacillus anthracis; Complement Activation; Complex; Development; Dose; Fc Receptor; Goals; Human; Immunity; Immunoglobulin Somatic Hypermutation; Immunoglobulins; Immunotherapy; In Vitro; Mediating; Passive Immunization; Reagent; Receptor Activation; Specificity; Structure-Activity Relationship; System; Technology; Therapeutic; Toxin; anthrax lethal factor; anthrax toxin; biodefense; capsule; design; edema factor; microbial; protective efficacy

The efficacy of antibodies (Abs) to toxins and capsules is a complex function of dose, specificity, isotype, complement activation and FcR engagement. However, 120 years after Ab-mediated immunity was first discovered, the relationships between affinity, isotype, and Fc receptor activation have not been rigorously defined for any microbial toxin or capsule. Our group has generated mAbs to five Bacillus anthracis antigens including anthrax toxin components protective antigen, lethal factor, and edema factor, capsule poly((-Dglutamic acid) (PGA), and Anthrolysin. This application proposes to investigate the structure-function relationship for these immunoglobulins with the goal of identifying the optimal combination of affinity, isotype, and specificity that determines protective efficacy. We propose to apply several state of the art technologies available to us in the form of in vitro somatic hypermutation, human FcR technology, V region expression, and Veloclmmune¿ system to carry out the first comprehensive analysis of this fundamental immunological question while also generating new Ab reagents that are candidates for passive immune therapies. Three specific aims are proposed: Aim 1. To investigate the relationship between affinity and efficacy capacity for Abs to anthrax toxins and PGA; Aim 2. To investigate the efficacy of constant (C) regions in Abneutralization of anthrax toxins and PGA; Aim 3. To investigate the relationship between human Fc type and Ab-neutralization of anthrax toxins and PGA, We anticipate that the information generated from these studies will result in the design of more effective passive therapeutic strategies.

毒素和胶囊抗体（ABS）的效率是剂量，特异性，同种型， 补充激活和FCR参与。但是，AB介导的免疫力120年首次是 发现，亲和力，同种型和FC受体激活之间的关系并不严格 为任何微生物毒素或胶囊定义。我们的小组已经对五个芽孢杆菌抗原产生了mAbs 包括炭疽毒素成分保护剂，致死因子和水肿因子，胶囊poly（ - dglutamic 酸）（PGA）和蒽蛋白酶。此应用程序提案要研究结构功能 这些免疫球蛋白的关系，目的是确定亲和力，同型的最佳组合 以及决定保护效率的特异性。我们建议采用几种艺术技术 以体外体细胞超含义，人类FCR技术，v区域表达的形式可供我们使用， 和Veloclmmune�系统将对此基本免疫学进行首次全面分析 问题同时，还产生了新的AB试剂，这些试剂是被动免疫疗法的候选者。三 提出了具体目的：目标1。研究亲和力与效率能力之间的关系 ABS到炭疽毒素和PGA；目的2。研究恒定区域在余质化中的效率 炭疽毒素和PGA；目的3。调查人类FC类型与 炭疽毒素和PGA的AB-中和化，我们预计从这些信息产生的信息 研究将导致设计更有效的被动治疗策略。