A catalytic antibody against cocaine prevents cocaine's reinforcing and toxic effects in rats
A catalytic antibody against cocaine prevents cocaine's reinforcing and toxic effects in rats
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DOI：
10.1073/pnas.95.17.10176
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发表时间：
1998-08-18
影响因子：
11.1
通讯作者：
Landry, DW
中科院分区：
文献类型：
--
作者：
Mets, B;Winger, G;Landry, DW
长期以来，可卡因成瘾和过量服用一直无法得到特殊治疗。为了提供一种新的途径，利用过渡态类似物将可卡因水解为无毒、不成瘾的产物，引发了高活性的催化抗体mAb 15A10。在可卡因过量模型中，mAb 15A10以剂量依赖的方式保护大鼠免受可卡因诱导的癫痫发作和猝死；非催化抗可卡因抗体不降低毒性。与加速催化一致，在接受mAb 15A10和致死量可卡因的大鼠血浆中，水解产物ecgonine甲酯增加了10倍。在可卡因成瘾模型中，mAb 15A10完全阻断了可卡因对大鼠的强化作用。mAb 15A10特异性阻断可卡因，不影响牛奶或多巴胺再摄取抑制剂安非他酮维持的行为。该人工可卡因酯酶是一种设计合理的可卡因拮抗剂和具有药用潜力的催化抗体。
Cocaine addiction and overdose have long defied specific treatment. To provide a new approach, the high-activity catalytic antibody mAb 15A10 was elicited using a transition-state analog for the hydrolysis of cocaine to nontoxic, nouaddictive products. In a model of cocaine overdose, mAb 15A10 protected rats from cocaine-induced seizures and sudden death in a dose-dependent fashion; a noncatalytic anticocaine antibody did not reduce toxicity. Consistent with accelerated catalysis, the hydrolysis product ecgonine methyl ester was increased >10-fold in plasma of rats receiving mAb 15A10 and lethal amounts of cocaine. In a model of cocaine addiction, mAb 15A10 blocked completely the reinforcing effect of cocaine in rats. mAb 15A10 blocked cocaine specifically and did not affect behavior maintained by milk or by the dopamine reuptake inhibitor bupropion. This artificial cocaine esterase is a rationally designed cocaine antagonist and a catalytic antibody with potential for medicinal use.