Catalytic antibody, anti-cocaine

For the second step of the cocaine methyl ester hydrolysis involving the water-assisted proton transfer, the calculated energy barrier, 4.8 kcal/mol, associated with transition state TS2dW-Me, is also lower than the corresponding first step. So, with the direct participation of the solvent water molecule in the proton transfer process, the first step of the hydrolysis in aqueous solution should be rate-determining, whether for the cocaine benzoyl ester hydrolysis or for the cocaine methyl ester hydrolysis. This conclusion provides theoretical support for the design of analogs of the first transition state for the cocaine benzoyl ester hydrolysis to elicit anti-cocaine catalytic antibodies [22,25]. 

The first anti-cocaine catalytic antibody was reported by Landry and associates in 1993 [22]. The transition-state analog used to ehdt the first anticocaine catalytic antibody was a stable structure of the transition state for the benzoyl ester hydrolysis of chair cocaine [22,25]. Based on the computational analysis discussed above, the new TSA structure depicted in Fig. 4 was synthesized and 85 cocaine esterases out of 450 anti-analog antibodies... 

Powerful selective antidotes or antagonists to treat cocaine abuse are necessary to offset the increased cocaine toxicity currently observed in the United States. The use of catalytic antibodies in the creation of selective binding agents and detoxication catalysts of cocaine could represent a novel approach that may result in significant advances in the field of detoxication of drugs of abuse. An anti-cocaine catalytic antibody directed to hydrolyze the benzoyl ester could in principle catalyze the formation of ecgonine and benzoic acid, hydrolysis products of cocaine that do not possess the reinforcing or CNS stimulation properties of cocaine (Spealman et al. 1989). 

E.C. Sherer, G. Yang, G.M. Turner, G.C. Shields, and D.W. Landry, Comparison of experimental and theoretical structures of a transition state analogue used for the induction of anti-cocaine catalytic antibodies, J. Phys. Chem. A 101 (1997), pp. 8526-8529. 

Sudden death is a major factor in cocaine-related fatalities. The mechanism for the cardiotoxicity is not fully understood, but it appears to be poorly predicted from patient to patient. Nevertheless, a rapid immuno-therapeutic response would be essential in treating cocaine-related toxicity, and even catalytic antibodies with low micromolar (M) Michaelis-Menton constant (K ) values may not be fast-acting enough. By comparison, high-affinity anti-drug antibodies typically have dissociation constant (K ) values in the low nanomolar (nM) to high picomolar (pM) range. Therefore, to test the usefulness of catalytic antibodies, it will be important to conduct full dose-response curves with the cocaine catalytic antibodies and to... 

The safety of the cocaine vaccine TC-CD in former cocaine abusers has been evaluated in a Phase I clinical trial, and it was determined that the vaccine was well tolerated with dose-related increases in antibody levels.65 Two Phase II clinical trials have now been conducted.66,67 The vaccine was again well tolerated and subjects reported a reduction in cocaine s reinforcing effects. The antibody levels were detectable after the second dose, peaked at 8 to 12 weeks, and remained elevated for up to 6 months preliminary findings indicated a negative association between antibody level and cocaine use. Other anti-cocaine vaccines in development include a blocking antibody (ITAC-cocaine) and a monoclonal catalytic antibody (15A10). 

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