Medical Aspects of Chemical Warfare (2008) - The Black Vault

Nerve Agent Bioscavenger: Development of a New Approach to Protect Against Organophosphorus Exposurehighly toxic OPs in circulation before they reach theirphysiological targets. 11The use of enzymes as therapeutic agents is notunique; enzymes are used in wound healing, proteolysis,fibrinolysis, and depletion of metabolites incancer. Enzymes have many advantages; they arespecific, highly efficient, operate under physiologicalconditions, and cause essentially no deleterious sideeffects. However, there are certain requirements foran enzyme to be an effective therapy for OP toxicityin vivo: (a) it should react rapidly, specifically, and irreversiblywith all OP nerve agents; (b) it should havea sustained half-life in circulation for it to be effectiveas a scavenger for long periods; (c) it should be readilyavailable in sufficient quantities; and (d) it should notbe immunogenic. The bioscavengers that have beenexplored to date for the detoxification of OPs fall intothree categories: (1) those that stoichiometrically bindto OPs (ie, 1 mole of enzyme neutralizes 1 mole ofOP, inactivating both), such as cholinesterase (ChE),carboxylesterase (CaE), and other related enzymes; (2)a group generally termed “pseudo catalytic,” such asthose combining AChE and an oxime so the catalyticactivity of OP-inhibited AChE can rapidly and continuouslybe restored in the presence of oxime; and (3)those that can naturally catalytically hydrolyze OPsand thus render them nontoxic, such as OP hydrolase,OP anhydrase, and paraoxonase.PLASMA-DERIVED STOICHIOMETRIC BIOSCAVENGERSCandidate stoichiometric bioscavengers are naturallyoccurring human proteins that bind and reactwith nerve agents, including enzymes such as ChEsand CaEs. Each of these stoichiometric scavengers hasthe capacity to bind one molecule of nerve agent permolecule of protein scavenger.CholinesterasesWolfe et al were the first to report the use of exogenouslyadministered AChE as a bioscavenger. 12They demonstrated that pretreatment of mice withfetal bovine serum (FBS) AChE afforded completeprotection against VX, while providing a much lowerlevel of protection against soman. However, FBS AChEpretreatment in conjunction with postexposure administrationof atropine and 2-pralidoxime protected micefrom both VX and soman. The authors also reportedthat animals displayed no detectable side effects inresponse to the administration of FBS AChE alone.Maxwell et al conducted a similar set of experimentswith rhesus monkeys. 13 Monkeys pretreatedwith FBS AChE that were challenged with either 1.5or 2.5 times the LD 50of soman received total protectionwithout decreased performance when assessed by aserial probe recognition task. Subsequently, Maxwellet al compared the relative protection afforded to miceagainst soman by three different treatment regimens:(1) pyridostigmine pretreatment with postexposureatropine therapy, (2) postexposure asoxime chloridewith atropine therapy, and (3) FBS AChE pretreatmentalone. 14 The researchers concluded that the FBS AChEpretreatment alone not only prevented the lethality ofanimals exposed to 8 to 10 times the LD 50of soman, butalso protected against behavioral incapacitation.Boomfield et al were the first to study the protectionafforded by butyrylcholinesterase (BChE). Theyreported that a commercial preparation of equine serum(Eq) BChE afforded complete protection to rhesusmonkeys against 2 times the LD 50challenge of soman,with no supporting therapy, and against 3 to 4 timesthe LD 50challenge of soman when combined with postexposuretherapy with atropine. 15 Protection against asingle LD 50of sarin without supporting therapy wasalso demonstrated. Furthermore, when animals wereassessed for behavioral deficits using a serial proberecognition task, they all returned to baseline performancelevels following soman exposure.Raveh et al conducted the first study demonstratingthe in vivo stoichiometry of OP neutralization by thebioscavenger. 16 They demonstrated that approximately90% to 95% of FBS AChE that was administered by intravenous(IV) injection was found in the circulation ofmice. Circulating enzyme concentrations rose to peaklevels in 30 minutes to 1 hour and were maintainedfor up to 6 hours. This provided a window in whichOP challenge of animals yielded a linear correlationbetween the moles of OP administered and the molesof enzyme neutralized. Ashani et al compared theOP scavenging properties of plasma-derived human(pHu) BChE with those of FBS AChE in mice, rats, andrhesus monkeys against several different nerve agentsas well as other OPs. 17 They observed that in mice andrats, the same linear correlation existed between theconcentration of pHu BChE in blood and the levelof protection afforded against soman, sarin, or VX.They further noted that to be effective, a scavengerhad to be present in circulation before OP exposurebecause the nerve agent had to be scavenged withinone blood circulation time period. The window todetermine stoichiometry of enzyme and OP becameuseful even when the enzyme was administered byintramuscular (IM) injection and the OP by subcutaneousinjection. 18,19 Raveh et al reported that the same245