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.
For the United States, the epidemic of smoking-caused disease in the 20th century ranks among the greatest public health catastrophes of the century.- US Surgeon General's Report, 2014. The CDC estimates that smoking accounts for more than 480,000 deaths and costs more than $133 billion in direct US medical care annually. Current medications approved for treating nicotine-dependency have very modest efficacy: one-year abstinence rates range from 2-12% higher than placebo. Recently, an investigational nicotine vaccine did not demonstrate efficacy in late stage clinical trials. High levels of high-affinity nicotine-specific antibodies across the entire smoking population are thought to be needed for efficacy. Administration of a nicotine-specific monoclonal antibody (mAb) may be able to overcome these challenges. Three different labs have demonstrated pre-clinical proof of concept for the use of nicotine-specific mAbs in animal models of addiction. Building upon these laboratory findings we are developing human nicotine-specific mAbs to minimize the risk of potential adverse immunogenicity reactions in the clinic. We are conducting lead optimization using a variety of in vitro screens and animal models of nicotine dependence and withdrawal in order to select the best candidate(s) to enter pre-clinical development and provide the IND-enabling studies in preparation for clinical testing.