Development of Therapeutic Anti-Nicotine Monoclonal Antibodies through Trivalent Vaccine Design

Project Summary AbstractSmoking is one of the leading causes of mortality worldwide and is the single greatestpreventable cause of cancer and heart diseaseTobacco use is widespreadbillion smokers worldwideand current estimates predict that it will contribute tomillion deaths per year byThe key psychoactive component in tobacco is an alkaloid known as nicotinewhich mediates the habit forming effects of smoking tobaccoSmoking cessation aids on the market consist of pharmacotherapies including nicotine replacement therapynicotine patches and gumbupropionantidepressantand vareniclinepartial nicotinic receptor agonistThe primary drawback to these currently available treatments is a lack of efficacyonlyof patients achieve nicotine abstinenceClearlyan unmet need exists for a more effective nicotine cessation therapyIn contrast to small molecule drugsimmunotherapy presents a promising optionnicotine binding antibodies are administered through active or passive immunizationwhich sequester nicotine in the bloodthus precluding entry to the brainAmple preclinical studies have shown that antibodies acting through this mechanism can effectively attenuate nicotine s addictive effectsDespite the therapeutic potential of anti nicotine antibodiesno antibodies have been tested in clinical trials as smoking cessation aidsAs a possible explanationpreviously reported monoclonal antibodies show relatively weak affinity for nicotineand therefore would not possess sufficient potency for clinical testingOur goals in this proposal are to produce high affinity anti nicotine antibodies through state of the art vaccine designWe plan to accomplish our goals of developing an effective antibody through three specific aimsDesigning a novel trivalent nicotine conjugate vaccine formulated with the most advanced known adjuvant systemImmunize mice with the trivalent nicotine vaccine for generation of antibody secreting hybridomaswhich will be screened and selected based on nicotine affinityIn vivo assessment of the selected antibody candidate in rats for mitigating nicotine pharmacologyCompletion of the grant aims is anticipated to generate valuable proof of concept dataenabling further development of novel therapeutics for smoking cessation Project NarrativeNicotine dependence is responsible for compulsive tobacco smokingwhich incurs a large detriment to public health worldwide by increasing the incidence of cancer and cardiovascular diseaseCurrently available pharmacological smoking cessation aids have been inadequate at mitigating the addictive effects of nicotineAs an alternativewe propose the development of therapeutic antibodies which can directly neutralize nicotine in the bloodthus blocking nicotine from exerting its rewarding effects on the brain