Catalytic cocaine antibody

Use of a catalytic cocaine antibody may bypass this potential downfall of the active immunization approach. The enzymatically active catalytic cocaine antibody cleaves cocaine into two inactive metabolites ecognine methyl ester and benzoic acid. The two metabolites are released from the catalytic antibody rendering the antibody free to degrade more cocaine. Because the... 

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). 

Basmadjian G., Singh S., Sastrodjojo B. et al. Generation of polyclonal catalytic antibodies against cocaine using transition state analogs of cocaine conjugated to diphtheria toxoid. Chem. Pharm. Bull. 43 1902, 1995. 

Berkman C., Underiner G., Cahsman J. Synthesis of an immunogenic template for the generation of catalytic antibodies for (-) cocaine hydrolysis. J. Org. Chem. 61 5686, 1996. 

Mets B., Winger G., Cabrera C. et al. A catalytic antibody against cocaine prevents cocaine s reinforcing and toxic effects in rats. Proc. Natl. Acad. Sci. U.S.A. 95 10176, 1998. 

Catalytic antibodies generally do not approach the catalytic efficiency of enzymes, but medical and industrial uses for them are nevertheless emerging. For example, catalytic antibodies designed to degrade cocaine are being investigated as a potential aid in the treatment of cocaine addiction. 

Invention Significance Catalytic antibodies used to degrade cocaine,... 

The blocking action could also be implemented by administration of an enzyme or a catalytic antibody (regarded as an artificial enzyme) that not only binds but also accelerates cocaine metabolism and thereby frees itself for further binding [16-25]. Usually, a pharmacokinetic agent would not be expected to across the blood-brain barrier and thus would itself have no direct pharmacodynamic action, such as abuse liability [5]. 

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... 

Cashman JR, Berkman CE, Underiner GE. Catalytic antibodies that hydrolyze (—)-cocaine obtained by a high-throughput procedure. J. Pharmacol. Exp. Ther. 2000 293(3) 952-961. 

Matsushita M, Hoffman TZ, Ashley JA, Zhou B, Wirsching P, Janda KD. Cocaine catalytic antibodies the primary importance of linker effects. Bioorg. Med. Chem. Lett. 2001 ll(2) 87-90. 

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). 

Typical antibody-catalyzed reaction rates are several hundredfold to 100,000-fold faster than the uncatalyzed reaction of the substrate. Several fundamental postulates have been proposed to explain the rate enhancements that nevertheless fall short of the enormous rate accelerations of enzymes. Is activity truly due solely to transition state stabilization by antibody-binding interactions Can additional binding interactions be built into the combining site or into the substrate molecule itself to increase the overall rate of the reaction Can new screening methods and immunological methods be developed to uncover novel catalysts with diverse activities Most important, can novel esterolytic catalysts be developed based on currently available catalytic antibody technology to efficiently hydrolyze and detoxicate cocaine ... 

Tawfik et al. 1990). While the cocaine catalytic antibodies reported... 

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... 

As another minor point, the use of catalytic antibodies with esterase activity could theoretically lead to autoimmunity against endogenous enzymes. This problem could be partially overcome if Fab fragments were used, or perhaps completely overcome if humanized antibodies or their fragments w ere used. Also, it is not currently known if endogenous ligands will be substrates for these catalytic enzymes this could potentially decrease the effective rate for cocaine metabolism or lead to other medical problems. 

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