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, nonaddictive 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.Cocaine is presently abused in the United States by Ϸ2 million hardcore addicts and Ͼ4 million regular users (1). The acute toxicity of cocaine overdose frequently complicates abuse and the potential medical consequences of this syndrome include convulsions and death (1). Despite decades of effort, however, no useful antagonists of cocaine's reinforcing or toxic effects have been identified. This failure is due, in part, to the drug's mechanism of action as a competitive blocker of neurotransmitter reuptake (2). Cocaine's blockade of a dopamine reuptake transporter in the central nervous system is hypothesized to be the basis of its reinforcing effect (3), and the difficulties inherent in blocking a blocker appear to have hindered the development of antagonists for addiction. Further, dopamine appears to play such a general role in many types of behavior that dopamine receptor agonists and antagonists that might be expected to modify cocaine's actions do not act selectively (4). For cocaine overdose, this problem is compounded by the binding of cocaine at high concentrations to multiple receptors in the central nervous system and the cardiovascular system. For example, blockade of serotonin reuptake transporters contributes to cocaine-induced convulsions (5); dopamine reuptake blockade (5, 6), and dopamine D 1 receptor binding (6) contribute to lethality; and blockade of norepinephrine-reuptake transporters, as well as blockade of cardiac myocyte Na ϩ channels and other ion transporters, contribute to arrhythmias and sudden death (7). Thus, cocaine abuse and toxicity may well pose insurmountable problems for the classical receptor-antagonist approach.These difficulties in developing antagonists for cocaine led us to embark on an alternative approach-to intercept cocaine with a circulating agent, thereby rendering it unavailable for receptor binding. An antibody is a natural choice for a circulating interceptor, and, in 1974, antiheroin antibodies were shown to block heroin-induced reinforcement in a rhesus monkey (8). However...

Zn2+ > Ni 2+ , related to the first hydrolysis equilibrium constant. The metal removal efficacy was strongly dependent on pH, and to a lesser extent on metal/zeolite ratio.

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