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

Medical Aspects of Chemical WarfareMost efficacy studies conducted to date have usedIV or subcutaneous challenge of OPs. A study in whichguinea pigs were administered soman by inhalationchallenge following pretreatment with pHu BChE (IVor IM) showed that only 26% to 30% of enzyme wasneutralized. 35 Because it is most likely that humans willbe exposed to nerve agent through inhalation, more efficacystudies using inhalation are needed before the protectivedose of enzyme can be established for humans.Immunological Safety of Plasma-DerivedButyrylcholinesteraseA critical prerequisite for any potential bioscavengeris a prolonged circulatory residence time and the absenceof antienzyme antibodies following repeated injectionsof the enzyme. Previously, it was demonstratedthat multiple injections of Eq BChE into rabbits, rats, orrhesus monkeys resulted in an MRT spanning severaldays and the induction of antienzyme antibodies. 38–41In these experiments, blood enzyme activity appearedto correlate negatively with anti-BChE immunogammaglobulin(IgG) levels. On the other hand, administeringpurified macaque BChE into macaques of thesame species resulted in much longer MRT (225 ± 19 h)compared to that reported for heterologous Hu BChE(33.7 ± 2.9 h). A smaller second injection of macaqueBChE given 4 weeks later attained predicted peakplasma levels of enzyme activity, although the fourmacaques showed wide variation in the MRT (54 to 357h). No antibody response was detected in macaquesfollowing either injection of enzyme. 42More recently, the consequences of repeated injectionsof pHu BChE and plasma-derived mouse (pMo)BChE from CD-1 mice were examined in Balb/c 43and CD-1 36 mice following two IM injections 4 weeksapart. The effects of two heterologous (pHu BChE) andhomologous (pMo BChE) injections were monitoredby following blood BChE activity and anti-BChE IgGlevels. In Balb/c mice, the clearance of pMo BChEactivity following the first injection occurred slowly(MRT = 91.8 h), compared to the heterologous pHuBChE injection (MRT = 56.7 h). As expected, the secondinjection of pHu BChE cleared much faster fromthe circulation of mice compared to the first injection.Surprisingly, the second injection of pMo BChE did notattain the predicted peak enzyme level, and a shorterMRT (61.6 h) was observed. No circulating anti-pHuBChE IgG was detected following the first pHu BChEinjection, and significant levels of antibodies to pHuBChE could be detected 2 days after the second pHuBChE injection. As expected, no circulating anti-pMoBChE IgG was detected following the first pMo BChEinjection. However, antibodies to pMo BChE, although100-fold less than the levels observed with pHu BChE,were detected 5 days after the second Mo BChE injection.This could be due to differences in pBChEs fromthe two strains of mice and was subsequently resolvedby repeating the study in CD-1 mice.In CD-1 mice, the clearance of homologous pMoBChE activity following the first injection also occurredslowly (MRT = 73 h), compared to the heterologousHu BChE injection (MRT = 48 h). As expected, thesecond injection of Hu BChE cleared much faster fromthe circulation of mice compared to the first injection(MRT = 26 h). The second injection of homologous MoBchE, on the other hand, attained a peak enzyme levelthat was similar to that observed following the firstinjection and a similar MRT of 79 hours. As expected,circulating anti-Hu BChE IgG could be detected 5days following the first pHu BChE injection, whichincreased dramatically after the second injection. Nosignificant antibody response was detected followingeither of the two homologous pMo BChE injections.The absence of antibody responses following eitherinjection in a homologous system are in agreementwith the long retention times and the absence ofsignificant adverse effects following administrationof homologous macaque BChE into macaques. Theobservation that the second injection of pMo BChEresulted in a pharmacokinetic profile that was similarto that of the first injection is in agreement with thelack of a humoral response to the injected enzyme.The observed extended stability of exogenously administeredpMo BChE into mice and macaque BChEinto macaques suggests that even a single injectionof homologous BChE is sufficient to maintain the enzymeat a long-lasting therapeutic level. The results ofboth studies with two injections of BChE have clearlydemonstrated the utility of homologous BChE as aneffective and safe scavenger, exhibiting high stabilityand low immunogenicity in recipient animals. Withrespect to the potential use of pHu BChE in humans,these results are consistent with a reported in-vivohalf-life of 8 to 11 days and the absence of reporteduntoward immunological and physiological side effectsfollowing blood transfusions and IV injections ofpartially purified pHu BChE into humans. 28,29,44,45Behavioral Safety of Plasma-DerivedButyrylcholinesteraseBecause the major use of bioscavengers is prophylactic,administered days or weeks prior to a potentialexposure, it is essential that the enzyme be devoid ofundesirable effects. Thus, several studies have evaluatedthe behavioral and physiological effects of pBChEadministered alone as well as prior to nerve agent248