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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：
10413859
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 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10413859
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.

摘要。该项目旨在研究可以改善当前护理标准的新方法