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Modulating cocaine vaccine potency through hapten fluorination.

ABSTRACT: Cocaine addiction is a long-lasting relapsing illness characterized by cycles of abuse, abstinence, and reinstatement, and antibody-based therapies could be a powerful therapeutic approach. Herein, we explored the possibility of using halogenated cocaine haptens to enhance the immunological properties of anti-cocaine vaccines. Three fluorine-containing cocaine haptens (GNF, GNCF and GN5F) and one chlorine-containing cocaine hapten (GNCl) were designed and synthesized, based upon the chemical scaffold of the only hapten that has reached clinical trials, succinyl norcocaine (SNC). Hapten GNF was found to retain potent cocaine affinity, and also elicit antibodies in a higher concentration than the parent structure SNC. Our data suggests that not only could strategic hapten fluorination be useful for improving upon the current cocaine vaccine undergoing clinical trials, but it may also be a valuable new approach, with application to any of the vaccines being developed for the treatment of drugs of abuse.

SUBMITTER: Cai X

PROVIDER: S-EPMC3637684 | biostudies-literature | 2013 Feb

REPOSITORIES: biostudies-literature

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Modulating cocaine vaccine potency through hapten fluorination.

Cai Xiaoqing X Tsuchikama Kyoji K Janda Kim D KD

Journal of the American Chemical Society 20130214 8

Cocaine addiction is a long-lasting relapsing illness characterized by cycles of abuse, abstinence, and reinstatement, and antibody-based therapies could be a powerful therapeutic approach. Herein, we explored the possibility of using halogenated cocaine haptens to enhance the immunological properties of anti-cocaine vaccines. Three fluorine-containing cocaine haptens (GNF, GNCF and GN5F) and one chlorine-containing cocaine hapten (GNCl) were designed and synthesized, based upon the chemical sca ...[more]

PMID: 23398531

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Project description:Since the demonstration of nicotine vaccines as a possible therapeutic intervention for the effects of tobacco smoke, extensive effort has been made to enhance nicotine specific immunity. Linker modifications of nicotine haptens have been a focal point for improving the immunogenicity of nicotine, in which the evaluation of these modifications usually relies on in vivo animal models, such as mice, rats or nonhuman primates. Here, we present two in vitro screening strategies to estimate and predict the immunogenic potential of our newly designed nicotine haptens. One utilizes a competition enzyme-linked immunoabsorbent assay (ELISA) to profile the interactions of nicotine haptens or hapten-protein conjugates with nicotine specific antibodies, both polyclonal and monoclonal. Another relies on computational modeling of the interactions between haptens and amino acid residues near the conjugation site of the carrier protein to infer linker-carrier protein conjugation effect on antinicotine antibody response. Using these two in vitro methods, we ranked the haptens with different linkers for their potential as viable vaccine candidates. The ELISA-based hapten ranking was in an agreement with the results obtained by in vivo nicotine pharmacokinetic analysis. A correlation was found between the average binding affinity (IC50) of the haptens to an anti-Nic monoclonal antibody and the average brain nicotine concentration in the immunized mice. The computational modeling of hapten and carrier protein interactions helps exclude conjugates with strong linker-carrier conjugation effects and low in vivo efficacy. The simplicity of these in vitro screening strategies should facilitate the selection and development of more effective nicotine conjugate vaccines. In addition, these data highlight a previously under-appreciated contribution of linkers and hapten-protein conjugations to conjugate vaccine immunogenicity by virtue of their inclusion in the epitope that binds and activates B cells.

Dataset Information

Modulating cocaine vaccine potency through hapten fluorination.

Publications

Modulating cocaine vaccine potency through hapten fluorination.

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