Modulating Cocaine Vaccine Potency through Hapten Fluorination

Cai, Xiaoqing; Tsuchikama, Kyoji; Janda, Kim D.

doi:10.1021/ja400356g

Cited by 38 publications

(32 citation statements)

References 27 publications

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“…Fluorination of drugs, in which a hydrogen is replaced by the sterically similar but more electronegative fluorine, is a common method of enhancing drug–receptor binding and might also affect the binding of haptens to BCRs. Fluorination of a cocaine hapten did not alter the affinity for cocaine of the antibodies produced by vaccination of mice, but modestly increased the mean cocaine-specific serum antibody level (Cai, Tsuchikama, & Janda, 2013). Because ligand fluorination is a general method, it may be useful for other haptens as well.…”

Section: Strategies For Improving Vaccine Efficacymentioning

confidence: 98%

New Directions in Nicotine Vaccine Design and Use

Pentel

LeSage

2014

Advances in Pharmacology

127

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Clinical trials of nicotine vaccines suggest that they can enhance smoking cessation rates but do not reliably produce the consistently high serum antibody concentrations required. A wide array of next-generation strategies are being evaluated to enhance vaccine efficacy or provide antibody through other mechanisms. Protein conjugate vaccines may be improved by modifications of hapten or linker design or by optimizing hapten density. Conjugating hapten to viruslike particles or disrupted virus may allow exploitation of naturally occurring viral features associated with high immunogenicity. Conjugates that utilize different linker positions on nicotine can function as independent immunogens, so that using them in combination generates higher antibody concentrations than can be produced by a single immunogen. Nanoparticle vaccines, consisting of hapten, T cell help peptides, and adjuvants attached to a liposome or synthetic scaffold, are in the early stages of development. Nanoparticle vaccines offer the possibility of obtaining precise and consistent control of vaccine component stoichiometry and spacing and immunogen size and shape. Passive transfer of nicotine-specific monoclonal antibodies offers a greater control of antibody dose, the ability to give very high doses, and an immediate onset of action but is expensive and has a shorter duration of action than vaccines. Viral vector-mediated transfer of genes for antibody production can elicit high levels of antibody expression in animals and may present an alternative to vaccination or passive immunization if the long-term safety of this approach is confirmed. Next-generation immunotherapies are likely to be substantially more effective than first-generation vaccines.

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Section: Strategies For Improving Vaccine Efficacymentioning

confidence: 98%

New Directions in Nicotine Vaccine Design and Use

Pentel

LeSage

2014

Advances in Pharmacology

127

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“…SAS has been effectively used in previous campaigns to evaluate drugs of abuse vaccines. 27, 32-34 Once formulated, the efficacies of the four vaccines were determined by vaccination of Swiss Webster mice (n=6). Antibody titers of mouse serum samples were determined by ELISA using 1 -BSA 22 as the coating antigen (Figure 2a).…”

Section: Resultsmentioning

confidence: 99%

Methamphetamine Vaccines: Improvement through Hapten Design

et al. 2016

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Methamphetamine (MA) addiction is a serious public health problem, and current methods to abate addiction and relapse are currently ineffective for mitigating this growing global epidemic. Development of a vaccine targeting MA would provide a complimentary strategy to existing behavioral therapies, but this has proven challenging. Herein, we describe optimization of both hapten design and formulation, identifying a vaccine that elicited a robust anti-MA immune response in mice, decreasing methamphetamine-induced locomotor activity.

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“…μg/ml) of cocaine binding antibodies and understand its binding kinetic parameters to cocaine. Currently, this issue has been widely addressed using equilibrium dialysis experiments with radioactive cocaine (23, 27, 28), however, these experiments still need to be validated. Since cocaine is a weak base with pKa of 8.6, it converts to BE even in regular phosphate buffer and its half-life in normal plasma is only 154 min (29).…”

Section: Discussionmentioning

confidence: 99%

Hapten Optimization for Cocaine Vaccine with Improved Cocaine Recognition

et al. 2014

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In the absence of any effective pharmacotherapy for cocaine addiction, immunotherapy is being actively pursued as a therapeutic intervention. While several different cocaine haptens have been explored to develop anti-cocaine antibodies, none of the hapten was successfully designed which had a protonated tropane nitrogen as is found in native cocaine under physiological conditions, including the succinyl norcocaine (SNC) hapten that has been tested in phase II clinical trials. Herein, we discuss three different cocaine haptens: hexyl-norcocaine (HNC), bromoacetamido butyl- norcocaine (BNC), and succinyl-butyl- norcocaine (SBNC), each with a tertiary nitrogen structure mimicking that of native cocaine which could optimize the specificity of anti-cocaine antibodies for better cocaine recognition. Mice immunized with these haptens conjugated to immunogenic proteins produced high titer anti-cocaine antibodies. However, during chemical conjugation of HNC and BNC haptens to carrier proteins, the 2β methyl ester group is hydrolyzed and immunizing mice with these conjugate vaccines in mice produced antibodies that bound both cocaine and the inactive benzoylecgonine metabolite. While in the case of the SBNC conjugate vaccine hydrolysis of the methyl ester did not appear to occur, leading to antibodies with high specificity to cocaine over BE. Though we observed similar specificity with a SNC hapten, the striking difference is that SBNC carries a positive charge on the tropane nitrogen atom, and therefore it is expected to have better binding of cocaine. The 50% cocaine inhibitory concentration (IC50) value for SBNC antibodies (2.8 μM) was significantly better than the SNC antibodies (9.4 μM) when respective hapten-BSA was used as a substrate. In addition, antibodies from both sera had no inhibitory effect from BE. In contrast to BNC and HNC, the SBNC conjugate was also found to be highly stable without any noticeable hydrolysis for several months at 4°C and 2-3 days in pH 10 buffer at 37°C.

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Modulating Cocaine Vaccine Potency through Hapten Fluorination

Cited by 38 publications

References 27 publications

New Directions in Nicotine Vaccine Design and Use

New Directions in Nicotine Vaccine Design and Use

Methamphetamine Vaccines: Improvement through Hapten Design

Hapten Optimization for Cocaine Vaccine with Improved Cocaine Recognition

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