Development of Therapeutic Anti-Nicotine Monoclonal Antibodies through Trivalent Vaccine Design - Project Summary/Abstract.
Smoking is one of the leading causes of mortality worldwide and is the single greatest, preventable cause of
cancer and heart disease. Tobacco use is widespread (1.3 billion smokers worldwide) and current estimates
predict that it will contribute to 10 million deaths per year by 2020. The key psychoactive component in tobacco
is an alkaloid known as nicotine, which mediates the habit-forming effects of smoking tobacco. Smoking
cessation aids on the market consist of pharmacotherapies including nicotine replacement therapy (nicotine
patches and gum), bupropion (antidepressant) and varenicline (partial nicotinic receptor agonist). The primary
drawback to these currently available treatments is a lack of efficacy; only 20% of patients achieve nicotine
abstinence. Clearly, an unmet need exists for a more effective nicotine cessation therapy. In contrast to
small-molecule drugs, immunotherapy presents a promising option: nicotine-binding antibodies are
administered through active or passive immunization, which sequester nicotine in the blood, thus precluding
entry to the brain. Ample preclinical studies have shown that antibodies acting through this mechanism can
effectively attenuate nicotine’s addictive effects. Despite the therapeutic potential of anti-nicotine antibodies, no
antibodies have been tested in clinical trials as smoking cessation aids. As a possible explanation, previously
reported monoclonal antibodies show relatively weak affinity for nicotine, and therefore would not possess
sufficient potency for clinical testing. Our goals in this proposal are to produce high affinity anti-nicotine
antibodies through state of the art vaccine design. We plan to accomplish our goals of developing an effective
antibody through three specific aims: 1. Designing a novel trivalent nicotine conjugate vaccine formulated with
the most advanced known adjuvant system 2. Immunize mice with the trivalent nicotine vaccine for generation
of antibody-secreting hybridomas, which will be screened and selected based on nicotine affinity 3. In vivo
assessment of the selected antibody candidate in rats for mitigating nicotine pharmacology. Completion of the
grant aims is anticipated to generate valuable proof of concept data, enabling further development of novel
therapeutics for smoking cessation.
