Novel Antibody-Oxime Pairing to Reduce Circulating Organophosphate Levels.

抽象的。该项目旨在研究能够改善当前护理标准的新方法。 (SOC)用于治疗暴露于对氧磷(POX)等有机磷化学品。的组件 美国的SOC是2-吡啶醛肟甲碘(2-PAM)、阿托品和苯二氮卓(例如， 咪达唑仑)，解决OP抑制的乙酰胆碱酯酶的重新激活，阻断M受体 破坏过量乙酰胆碱的兴奋毒性作用，并起到抗癫痫和肌肉松弛的作用。 尽管这种成熟的治疗行动鸡尾酒极大地提高了发病率和死亡率 OP暴露，这些疗法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。 这在SOC的整体效力上是一个严重的空白，特别是在OP长期流通的情况下。使用 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将显著 改善患者的预后。这项申请概述了一种新的方法，其中新的免疫疗法将 设计了结合2-PAM(来自SOC)作为代理剂，与对氧磷反应并将其从循环中移除。 我们将测试这样的假设，即生成的催化抗体与代表 对氧磷和2-PAM之间可以发生反应，当作为SOC的一部分引入时，会加速反应 水痘在血液中的分解。我们将通过解决以下具体问题来解决这些假设 目标。SA1.为了证明半抗原可以被设计、合成和表征以产生新的OP- 降级免疫疗法。SA 2.制备和鉴定可加速小鼠胸腺细胞死亡的单抗 使用2-PAM作为代理亲核试剂分解痘。SA 3.测定大鼠体内、外药物的减量 使用单抗-肟配对作为一种新的免疫疗法的POX水平。

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.