Novel Antibody-Oxime Pairing to Reduce Circulating Organophosphate Levels.

新型抗体-肟配对可降低循环有机磷水平。

基本信息

批准号：
10163930
负责人：
Charles Mark Thompson
金额：
$ 63万
依托单位：
HUMAN BIOMOLECULAR RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-15 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10163930
关键词：
4-nitrophenol Acetylcholine Acetylcholinesterase Address Air Antibodies Antibody Formation Atropine Benzodiazepines Binding Biodistribution Blood Blood Circulation Brain Brain Injuries Catalytic Antibodies Chemical Warfare Agents Chemicals Chlorpyrifos Custom Enzyme-Linked Immunosorbent Assay Excision Exposure to Goals Half-Life Haptens Household Immunization Immunize Immunotherapeutic agent Insecticides Intervention Lead Life Measures Medical Methods Midazolam Monoclonal Antibodies Morbidity - disease rate Mus Muscarinic Acetylcholine Receptor Muscle relaxants Nitriles Organophosphates Oximes Paraoxon Parathion Patient-Focused Outcomes Penetration Performance Peroxides Pharmacologic Actions Poisoning Positron-Emission Tomography Property Proteins Proxy Reaction Sarin Seizures Serine Soman Structure Technology Testing Therapeutic Time Tissues Toxic effect Tracer Water Supply Work analog cholinergic design excitotoxicity immunogenic improved in vivo intervention effect mortality neurotoxicity novel novel strategies novel therapeutics pyridine standard of care symptom treatment toxic organophosphate insecticide exposure weapons

项目摘要

Abstract. This project seeks to investigate new methods that can improve upon the current standard of care (SOC) used to treat exposures to organophosphate chemicals such as paraoxon (POX). The components of the SOC in the US are 2-pyridine aldoxime methiodide (2-PAM), atropine and a benzodiazepine (e.g., midazolam) that address the reactivation of OP-inhibited acetylcholinesterase, blocks muscarinic receptors from damaging excitotoxic action from surplus acetylcholine, and acts as an anti-seizure and muscle relaxant. Although this well-developed cocktail of therapeutic action dramatically improves morbidity and mortality from OP exposures, the pharmacological action of these therapeutics does not address removal, destruction or neutralization of the OP in vivo allowing it to circulate freely and continue to act on target and non-target proteins. This is a serious void in the overall efficacy of the SOC particularly when the OP is long lived in circulation. With the addition of a strategy or new therapeutic that could remove surplus OP from blood, the SOC would markedly improve patient outcomes. This application outlines a novel approach in which novel immunotherapeutics will be devised that bind 2-PAM (from the SOC) as a proxy agent to react with paraoxon and remove it from circulation. We will test the hypotheses that catalytic antibodies generated against a transition state representing the reaction between paraoxon and 2-PAM can be produced and when introduced as part of the SOC accelerates the breakdown of POX in the bloodstream. We will address the hypotheses by addressing the following specific aims. SA1. To show that haptens can be designed, synthesized and characterized to generate novel OP- degrading immunotherapeutics. SA 2. To produce and identify monoclonal antibodies that accelerate the breakdown of POX using 2-PAM as a proxy nucleophile. SA 3. To determine the ex vivo and in vivo reduction in POX levels using mAb-oxime pairing as a novel immunotherapeutic.

抽象的。该项目旨在研究可以改善当前护理标准的新方法 (SOC) 用于治疗接触有机磷化学品，如对氧磷 (POX)。的组成部分美国的 SOC 是 2-吡啶醛肟甲硫氨酸 (2-PAM)、阿托品和苯二氮卓类药物（例如，咪达唑仑）可解决 OP 抑制的乙酰胆碱酯酶的重新激活问题，阻断毒蕈碱受体过量乙酰胆碱具有破坏性兴奋毒性作用，并可作为抗癫痫和肌肉松弛剂。尽管这种成熟的治疗作用鸡尾酒极大地降低了发病率和死亡率 OP 暴露，这些疗法的药理作用并不涉及去除、破坏或体内中和 OP，使其能够自由循环并继续作用于靶标和非靶标蛋白。这对 SOC 的整体功效来说是一个严重的缺陷，特别是当 OP 长期处于流通中时。和添加一种策略或新的治疗方法可以去除血液中多余的 OP，SOC 将显着改善患者的治疗效果。该申请概述了一种新的方法，其中新的免疫疗法将被设计了结合 2-PAM（来自 SOC）作为代理剂，与对氧磷发生反应并将其从循环中去除。我们将测试针对代表过渡态的催化抗体产生的假设对氧磷和 2-PAM 之间可以产生反应，当作为 SOC 的一部分引入时，反应会加速 POX 在血液中的分解。我们将通过解决以下具体问题来解决这些假设目标。 SA1。表明半抗原可以被设计、合成和表征以产生新的OP- 降解免疫治疗药物。 SA 2. 生产和鉴定单克隆抗体，加速使用 2-PAM 作为代理亲核试剂分解 POX。 SA 3. 确定离体和体内减少使用单克隆抗体-肟配对作为新型免疫疗法来降低 POX 水平。