Tobacco smoke is the primary cause of lung cancer, cardiovascular disease and premature death, with nearly 5 million people dying each year. Treatments that prevent smoking will have a major impact on global health and are attractive products for commercial development. Nicotine vaccines and antibodies represent an important strategy for preventing nicotine from reaching the brain, although current clinical-stage vaccines are ineffective and for most people the antibody response is weak and short-lived. The challenge of inducing long- lasting antibodies titers requires a better method for presenting nicotine to the immune system. We hypothesize that targeted nicotine delivery to dendritic cells using agonistic mAbs to CD40 combined with a TLR4-based adjuvant will stimulate a superior antibody response. We will modify the rat anti-mouse CD40 mAb 1C10 for studies in mice and optimize its conjugation with derivatized nicotine. Mice will be vaccinated with ?CD40nic formulated with the TLR4-activating adjuvant GLA-SE. Anti-nicotine antibody titers will be benchmarked against mice vaccinated with a traditional vaccine, nicotine-KLH + alum. Vaccine potency will be determined using quantitative measures of antibody function including nicotine sequestration in blood and prevention of a nicotine abstinence response. Phase I SBIR funding will establish proof-of-concept in a relevant model and provide the justification for subsequent IND-enabling studies that will bring an innovative vaccine for smoking cessation into the clinic.
Public Health Relevance: Tobacco smoke is the primary cause of lung cancer, cardiovascular disease and premature death. There is a strong unmet need for an effective aid to smoking cessation. To halt the addictive effects of nicotine and increase the success rate for smoking cessation, we have designed a novel vaccine that will prevent nicotine from crossing the blood-brain barrier.
Public Health Relevance Statement: Tobacco smoke is the primary cause of lung cancer, cardiovascular disease and premature death. There is a strong unmet need for an effective aid to smoking cessation. To halt the addictive effects of nicotine and increase the success rate for smoking cessation, we have designed a novel vaccine that will prevent nicotine from crossing the blood-brain barrier.
NIH Spending Category: Biotechnology; Drug Abuse (NIDA only); Immunization; Prevention; Smoking and Health; Substance Abuse; Tobacco; Vaccine Related
Project Terms: Abstinence; Abstinence Syndrome; Adjuvant; Agonist; aluminum sulfate; Antibodies; Antibody Formation; Antigens; B-Cell Development; base; Benchmarking; Binding (Molecular Function); Blood; Blood - brain barrier anatomy; Brain; Cardiovascular Diseases; Carrier Proteins; Cellular biology; Cessation of life; Clinic; Clinical; commercialization; Coupled; Dendritic Cells; design; Development; Dose; experience; Funding; global health; Haptens; Humoral Immunities; Immune response; Immune system; immunogenicity; improved; innovation; Intellectual Property; Keyhole Limpet Hemocyanin; Lead; Life; Malignant neoplasm of lung; Marketing; Measures; Medical; Methods; Modeling; Modification; Monoclonal Antibodies; mouse model; Mus; Nicotine; Nicotine Dependence; novel vaccines; Outcome; Pathway interactions; Pharmaceutical Preparations; Phase; Plasma; premature; prevent; Prevention; Protocols documentation; Rattus; Relative (related person); response; Safety; safety testing; Small Business Innovation Research Grant; Smoking; smoking cessation; Staging; success; TNFRSF5 gene; Tobacco smoke; toll-like receptor 4; Toxic effect; Treatment Efficacy; Vaccinated; Vaccination; Vaccine Adjuvant; Vaccine Antigen; Vaccine Design; vaccine safety; Vaccines
