Thompson_2026_J.Med.Chem__

A key challenge in organophosphorus (OP) research is to develop efficient means to decrease OP levels after exposure. Scavenging, capturing, or degrading circulating OPs in vivo could minimize OP penetration into the brain and other organs, and decrease toxicity. OPs produce acute effects primarily through acetylcholinesterase (AChE) inhibition, leading to neurotoxic events. Current standard of care (SOC) for OP exposure includes the AChE reactivator 2-PAM as well as atropine, and midazolam or diazepam. However, SOC therapeutics only address AChE symptomatic toxicity but do not increase clearance. SOC does not degrade OPs. Using haptens designed employing transition state analogy, we procured and characterized monoclonal antibodies (mAbs) that, in the presence of 2-PAM, increased the hydrolysis of paraoxon (POX) and promoted degradation of nerve agent mimics. The ability of these novel antibodies to combine with 2-PAM and selectively recognize and degrade OPs suggests that they could provide a new approach to decrease OP-induced toxicity.