Tagged binding agents as improved anti-toxin therapeutics

标记结合剂作为改进的抗毒素疗法

基本信息

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
项目类别：
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

项目摘要

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，该平台将从根本上改变当前的抗毒素开发方法推出一项新战略，允许安全、有效的药物快速开发和商业化抗毒素产品的开发和产品成本低，保质期长。来自微生物和其他来源继续造成严重的人类和兽医病理，并且属于严重的 A 类 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代理。抗体和抗血清产品是难以大量制备且昂贵的试剂，并且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。我们发现有一个水池小毒素结合剂，每种都有共同的表位标签，将有效保护小鼠免受中毒当与单一抗标签单克隆抗体一起施用时。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。我们将优化交付格式化并测试与单克隆抗标签抗体共同施用的药物的抗毒素功效不同的同种型。通过该提案，抗毒素剂能够通过两种方式防止中毒将开发并采用不同的 BoNT 血清型（A 和 B）和两种不同的志贺毒素（Stx1 和 2）通过体内测试。如果成功，该策略应该在抗毒素领域得到广泛应用开发，以及可能需要加速清除靶标的其他疗法。基于VHH的产品规模化生产经济且保质期长且毒性低