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.

针对毒素和胶囊的抗体（Ab）的功效是剂量、特异性、同种型、 补体激活和FcR接合。然而，在Ab介导的免疫首次被发现120年后， 尽管已经发现，亲和力、同种型和Fc受体活化之间的关系尚未得到严格的研究， 用于任何微生物毒素或胶囊。我们的小组已经产生了针对五种炭疽杆菌抗原的mAb 包括炭疽毒素成分保护性抗原、致死因子和水肿因子， 酸）（PGA）和人溶素。本申请旨在研究结构-功能 这些免疫球蛋白的关系，目的是鉴定亲和力，同种型， 和特异性决定了保护效果。我们建议应用几种最先进的技术 我们可以通过体外体细胞超突变，人FcR技术，V区表达， 和Veloclmmune系统进行了第一次全面的分析，这一基本免疫学 同时也产生了新的抗体试剂，这些抗体试剂是被动免疫疗法的候选者。三 具体目标如下：目标1。探讨亲和性与药效容量之间的关系， 炭疽毒素和PGA抗体;目标2。研究恒定区（C）在中和过度中的作用 炭疽毒素和PGA;目标3。为了研究人Fc型与 中和炭疽毒素和PGA，我们预计，从这些产生的信息 研究将导致设计更有效的被动治疗策略。