Tobacco use is the leading preventable cause of illness and death in the world today. Over 30 million Americans smoke tobacco. Nicotine is responsible for smokers becoming addicted to tobacco and keeps them addicted long-term. Currently available FDA-approved smoking cessation treatments have modest efficacy and no novel pharmacotherapies have been approved since 2006. Development of new and more effective medications are needed to reduce tobacco smoking, which despite dramatic progress, remains the single leading cause of addiction-related death and illness in the U.S. The focus of this project is advancing development of a first-inclass, nicotine-specific, human monoclonal antibody, ATI-1013, that has achieved pre-clinical proof-of-concept, as a treatment for nicotine addiction. ATI-1013’s development plan is aimed at smokers with an immediate medically recognized need to quit smoking to slow progression of their disease: the over 5 million smokers in the U.S. who having smoking-attributable diseases (e.g., cardiovascular disease, lung and other cancers, respiratory disease). ATI-1013’s MOA reduces nicotine exposure without acting on nicotinic receptors, offering a novel strategy compared to existing smoking cessation medications. The overarching objective of this proposal is to progress development of ATI-1013 from its current “mid” preclinical development stage to an approved IND for subsequent conduct of a first in human (FIH) Phase 1 clinical trial. The specific aims are focused on completing IND-enabling safety studies, manufacturing of clinical drug supply, and preparation/filing and approval of the IND with the FDA for the FIH clinical trial of ATI-1013 in healthy normal nonsmokers and smokers. Thus, the key goals are to complete all the requisite preclinical safety studies, assay development, CMC processes, production of high-quality drug product, and clinical trial requirements needed to initiate the Phase 1 study upon IND approval. Project Summary/Abstract