Norman Andrew B, Gooden Felicia C T, Tabet Michael R, Ball William J
Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, Ohio
Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, Ohio.
Drug Metab Dispos. 2014 Jul;42(7):1125-31. doi: 10.1124/dmd.114.057034. Epub 2014 Apr 14.
The monoclonal antibody (mAb), h2E2, is a humanized version of the chimeric human/murine anti-cocaine mAb 2E2. The recombinant h2E2 protein was produced in vitro from a transfected mammalian cell line and retained high affinity (4 nM Kd) and specificity for cocaine over its inactive metabolites benzoylecgonine (BE) and ecgonine methyl ester. In rats, pharmacokinetic studies of h2E2 (120 mg/kg i.v.) showed a long terminal elimination half-life of 9.0 days and a low volume of distribution at steady state (Vdss) of 0.3 l/kg. Pretreatment with h2E2 produced a dramatic 8.8-fold increase in the area under the plasma cocaine concentration-time curve (AUC) and in brain a concomitant decrease of 68% of cocaine's AUC following an i.v. injection of an equimolar cocaine dose. Sequestration of cocaine in plasma by h2E2, shown via reduction of cocaine's Vdss, indicates potential clinical efficacy. Although the binding of cocaine to h2E2 in plasma should inhibit distribution and metabolism, the elimination of cocaine remained multicompartmental and was still rapidly eliminated from plasma despite the presence of h2E2. BE was the major cocaine metabolite, and brain BE concentrations were sixfold higher than in plasma, indicating that cocaine is normally metabolized in the brain. In the presence of h2E2, brain BE concentrations were decreased and plasma BE was increased, consistent with the observed h2E2-induced changes in cocaine disposition. The inhibition of cocaine distribution to the brain confirms the humanized mAb, h2E2, as a lead candidate for development as an immunotherapy for cocaine abuse.
单克隆抗体（mAb）h2E2是嵌合型人/鼠抗可卡因单克隆抗体2E2的人源化版本。重组h2E2蛋白由转染的哺乳动物细胞系在体外产生，对可卡因保持高亲和力（解离常数Kd为4 nM），且对其无活性代谢物苯甲酰芽子碱（BE）和芽子碱甲酯具有特异性。在大鼠中，h2E2（静脉注射120 mg/kg）的药代动力学研究显示，其终末消除半衰期较长，为9.0天，稳态分布容积较低，为0.3 l/kg。用h2E2进行预处理后，静脉注射等摩尔剂量可卡因后，血浆可卡因浓度-时间曲线下面积（AUC）显著增加了8.8倍，而大脑中可卡因的AUC则相应降低了68%。h2E2使血浆中可卡因的分布容积减小，表明其可将可卡因隔离在血浆中，这显示了潜在的临床疗效。尽管血浆中可卡因与h2E2的结合应会抑制其分布和代谢，但可卡因的消除仍呈多室模型，且尽管存在h2E2，其仍能从血浆中快速消除。BE是主要的可卡因代谢物，大脑中BE的浓度比血浆中高六倍，表明可卡因通常在大脑中代谢。在存在h2E2的情况下，大脑中BE的浓度降低，血浆中BE的浓度升高，这与观察到的h2E2引起的可卡因处置变化一致。可卡因向大脑分布的抑制证实了人源化单克隆抗体h2E2作为可卡因滥用免疫疗法开发的主要候选药物。
