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引入一种新策略，该战略将允许快速开发和商业化安全，有效抗毒素产品的开发和产品成本较低，并且保质期长。来自微生物的毒素和其他来源继续引起大量的人类和兽医病理学，是严重的类别和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代理商。抗体和抗血清产品是困难且昂贵的代理，可以大量准备有问题的质量控制和安全问题以及保质期有限。这是一个特别严重的问题用于储存和储存抗毒素，以准备可能的生物恐怖事件。我们发现一个游泳池小型毒素结合剂（每种均具有共同的表位标签）将有力保护小鼠免受醉酒用单个抗标签mAb给药时。在此提案中，我们将开发标签的，骆驼的基于VHH 肉毒杆菌神经毒素（BONT）和志贺毒素结合剂作为抗毒素。我们将优化交货格式和测试与单克隆抗TAG抗体共同采用的药物的抗毒素疗效不同的同种型。通过此提案，抗毒素剂能够防止两种将开发和采取不同的BONT血清型（A和B）和两个不同的志贺毒素（STX1和2）通过体内测试。如果成功，该策略应在抗毒素中广泛应用需要开发以及可能加速目标清除目标的其他疗法。基于VHHB 产品将是经济的，以长长的保质期和低毒性生产