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，它将通过以下方式从根本上改变目前的抗毒素开发方法 引入一项新战略，使安全、有效的 开发和产品成本低、保质期长的抗毒素产品。微生物产生的毒素和 其他来源继续造成严重的人类和兽医病理，属于严重的A类 和B生物安全威胁。毒素暴露的治疗通常仅限于抗毒素的可用性。 探员们。抗体和抗血清产品是难以大量制备和价格昂贵的试剂， 存在质量控制和安全问题，保质期有限。这是一个特别严重的问题 用于储存和储存抗毒素，为可能发生的生物恐怖事件做准备。我们发现一个水池 一系列小的毒素结合剂，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 当与单个抗标签单抗一起给药时。在本提案中，我们将开发基于标记的骆驼VHH 肉毒杆菌神经毒素(BONT)和志贺毒素结合剂作为抗毒素。我们将优化交付 制备并检测与猪传染性支气管炎单抗联合应用的抗毒素效果 不同的同工型。通过这项建议，抗毒素药物能够防止两种中毒 不同的BONT血清型(A和B)和两种不同的志贺毒素(STX1和2)将被开发和服用 通过体内试验。如果成功，这一策略应该会在抗毒素方面得到广泛应用 发展，以及可能需要加速清除目标的其他疗法。基于VHH的 产品规模化生产经济，保质期长，毒性低