Research Project
9782548
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.
