Tagged binding agents as improved anti-toxin therapeutics

标记结合剂作为改进的抗毒素疗法

• 批准号: 8233432
• 负责人: Charles Bix Shoemaker
• 金额: $ 46.1万
• 依托单位: HARVARD MEDICAL SCHOOL
• 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/8233432
• 关键词: Affinity; Antibodies; Antitoxins; Binding; Bontoxilysin; Botulinum Toxin Type A; Botulinum Toxins; Categories; Child; Development; Disease; Disease Outbreaks; Drug Kinetics; Epitopes; Escherichia coli O157; Event; Future; General Population; Gerda brand of difluprednate; Goals; Health; Hepatitis B Antigens; Human Pathology; Immune Sera; Intoxication; Kidney Failure; Life; Liver; Mediating; Mus; New England; Peptides; Positioning Attribute; Preparation; Property; Quality Control; Recombinants; Research; Role; Safety; Serotyping; Serum; Shiga Toxin; Site; Source; Spinach - dietary; Technology; Testing; Therapeutic; Therapeutic Agents; Time; Toxic effect; Toxin; Veterinary Pathology; animal efficacy; base; biodefense; biosecurity; botulinum; botulinum toxin type B; commercialization; cost; effective therapy; efficacy testing; foodborne; improved; in vivo; microbial; novel; pathogen; polyclonal antibody; prevent; product development; prototype

We propose a platform which will radically change the current approach to antitoxin development by introducing a new strategy that will permit rapid development and commercialization of safe, effective antitoxin products having low development and product costs and long shelf lives. Toxins from microbial and other sources continue to cause substantial human and veterinary pathology and are serious Category A and B biosecurity threats. Treatment for toxin exposure is generally limited to the availability of antitoxin agents. Antibody and antisera products are difficult and expensive agents to prepare in large quantities and have problematic quality control and safety issues and limited shelf life. This is a particularly serious problem for stockpiling and storing antitoxins in preparation of possible bioterrorist events. We have found that a pool of small toxin binding agents, each with a common epitopic tag, will potently protect mice against intoxication when administered with a single anti-tag mAb. In this proposal, we will develop tagged, camelid VHH-based botulinum neurotoxin (BoNT) and Shiga toxin binding agents as anti-toxins. We will optimize the delivery format and test the antitoxin efficacy of the agents co-administered with monoclonal anti-tag antibodies of different isotypes. Through this proposal, antitoxin agents capable of protecting against intoxication with two different BoNT serotypes (A and B) and two different Shiga toxins (Stx1 and 2) will be developed and taken through in vivo testing. If successful, this strategy should have widespread application in antitoxin development, and possibly other therapies in which accelerated clearance of a target is required. The VHHbased products will be economical to produce at scale with long shelf-life and low toxicity

我们提出了一个平台，它将从根本上改变目前的抗毒素开发方法， 采用新的战略，使安全、有效、 抗毒素产品具有低的开发和生产成本以及长的保存期。来自微生物和 其他污染源继续造成人类和兽医的严重疾病，属于A类 和B生物安全威胁。毒素暴露的治疗通常限于抗毒素的可用性 剂.抗体和抗血清产品是难以大量制备且昂贵的试剂， 存在质量控制和安全问题以及有限的保质期。这是一个特别严重的问题 用于储存抗毒素，为可能发生的生物恐怖事件做准备。我们发现一个水池 小的毒素结合剂，每个都有一个共同的表位标签，将有效地保护小鼠免受中毒 当与单一抗标签mAb一起施用时。在这项提案中，我们将开发标记的，骆驼VHH为基础的 肉毒杆菌神经毒素（BoNT）和滋贺毒素结合剂作为抗毒素。我们将优化交付 形成并测试与以下单克隆抗标签抗体共同施用的药剂的抗毒素功效： 不同的同种型通过这一提议，能够防止两种药物中毒的抗毒素剂 将开发和采集不同的BoNT血清型（A和B）和两种不同的滋贺毒素（Stx 1和2 通过体内测试。如果成功，这种策略将在抗毒素方面得到广泛应用 开发，以及可能需要加速清除靶标的其他疗法。基于VHH的 产品大规模生产将是经济的，保质期长，毒性低