Cigarette smoking is responsible for >480,000 deaths per year in the United States. The CDC estimates direct healthcare costs due to treating smoking and smoking-related illness is >$133 billion/yr. Only 1:5 smokers achieve long-term abstinence using standard of care pharmacotherapies leaving the majority still smoking and seeking alternatives. We are developing nicotine-specific high-affinity human monoclonal antibodies (mAbs) as aids to smoking cessation treatment. Nicotine-specific mAbs (nic-mAbs) reduce nicotine distribution to the brain and demonstrate efficacy in animal models of nicotine dependence and withdrawal. The preclinical proof-of-concept has been well-documented with mouse nic-mAbs and human nic-mAb leads. Nic-mAbs can eliminate the high degree of inter-individual variability in immune response observed clinically for nicotine vaccines (quantity and quality). Nic-mAbs can provide the much needed control over inter-individual variability necessary to achieve clinical proof-of-concept of the PK mechanism of treating nicotine addiction. This Alliance is dedicated to developing nic-mAbs for clinical use. Several approaches are being undertaken to provide nic-mAb lead series for lead optimization and pre-clinical development. The programs are at various stages of development and encompass humanization of mouse nic-mAbs using routine genetic engineering techniques, selection from human b-cells that express high-affinity nic-mAbs from prior-vaccinated individuals, and screening a human phage display library for high-affinity Fab's. These parallel efforts, using different sources and methods, will improve our odds of success in selecting a development candidate with the desired characteristics to move ahead into IND-enabling studies. Each lead in a given nic-mAb series will be progressed through a variety of standardized in vitro assays and well-established in vivo studies in animal models of nicotine dependency and withdrawal. Our goal is to progress a development candidate to IND enabling studies in preparation for clinical investigational studies in man.