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。

• 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
• 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

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。该项目旨在研究新的方法，可以改善目前的护理标准 (SOC)用于治疗暴露于有机磷化学品，如对氧磷（POX）。的组件 美国的SOC是2-吡啶醛肟甲基碘化物（2-PAM）、阿托品和苯并二氮杂（例如， 咪达唑仑），解决OP抑制的乙酰胆碱酯酶的再活化，阻断毒蕈碱受体， 过量乙酰胆碱的破坏性兴奋毒性作用，并作为抗癫痫和肌肉松弛剂。 虽然这种开发良好的鸡尾酒治疗行动显着改善发病率和死亡率， OP暴露，这些治疗药物的药理作用不涉及清除、破坏或 在体内中和OP，使其自由循环并继续作用于靶蛋白和非靶蛋白。 这是SOC总体有效性的严重空白，特别是当OP在循环中长期存在时。与 增加一种策略或新的治疗方法，可以从血液中去除多余的OP，SOC将明显 改善患者预后。本申请概述了一种新的方法，其中将使用新的免疫治疗剂。 设计了结合2-PAM（来自SOC）作为代理试剂与对氧磷反应并将其从循环中除去。 我们将测试的假设，催化抗体产生的过渡状态代表了 对氧磷和2-PAM之间的反应可以产生，并且当作为SOC的一部分引入时， 血液中POX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。SA 1.为了表明半抗原可以被设计、合成和表征以产生新的OP- 降解免疫治疗剂。SA 2.为了生产和鉴定单克隆抗体， 使用2-PAM作为代理亲核试剂分解POX。SA 3.为了测定离体和体内的 使用mAb-肟配对作为新型免疫抑制剂的POX水平。