A catalytic antibody against cocaine prevents cocaine's reinforcing and toxic effects in rats

Abstract

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.

Figure 1

Hydrolysis of cocaine at the benzoyl ester and the methyl ester (A). Presumed tetrahedral intermediate of benzoyl ester hydrolysis and the corresponding phosphonate monoester analog (B).

Figure 2

Log dose-response relationship for mAb 15A10 on rats’ survival after infusion of an LD₉₀ (16 mg/kg) cocaine. The effect of mAb 15A10 on survival was significant by a χ² test (P < 0.001).

Figure 3

Saturation of mAb 15A10 with cocaine. Mean cocaine dose at seizure and at death (A). Plasma concentration of ecgonine methyl ester (EME) and cocaine at death (B). A significant difference between the saline control group and the 15A10 group was determined using the Mann–Whitney U test for unpaired samples.

Figure 4

Pattern of intravenous cocaine (A), saline (B), or cocaine + mAb 15A10 (C) self-administration in a single rat. Each vertical line within the panels indicates a single injection, obtained on a fixed ratio 5 time-out 10 sec schedule of cocaine delivery. The three panels show infusion patterns from three consecutive sessions.

Figure 5

Comparison of the number of injections and response half-live (time required for 50% of the total injections to be taken) for responding maintained by cocaine, saline, or cocaine after administration of mAb 15A10. An asterisk indicates a significant difference from cocaine (P < 0.001; Tukey post hoc test).

Figure 6

Comparison of the response half-lives for milk reinforcer and milk reinforcer after administration of mAb 15A10 (A) and for responding maintained by bupropion, saline, or bupropion after administration of mAb 15A10 (B). ANOVA indicated a significant difference [F(2, 9) 70.28, P < 0.00001]. An asterisk indicates a significant difference from saline (P < 0.0001; Tukey post hoc test).