Lead Optimization and Preclinical Development of Human Nicotine-Specific mAbs

描述（由申请人提供）：在美国，吸烟每年造成48万人死亡。美国疾病控制与预防中心估计，每年用于治疗吸烟和吸烟相关疾病的直接医疗费用为1330亿美元。只有1:5的吸烟者通过标准的药物治疗实现了长期的戒烟，剩下的大多数人仍在吸烟并寻求其他选择。我们正在开发尼古丁特异性高亲和力人单克隆抗体（mab）作为戒烟治疗的辅助药物。尼古丁特异性单克隆抗体（nic- mab）减少尼古丁在大脑中的分布，并在尼古丁依赖和戒断的动物模型中显示出有效性。临床前概念验证已被小鼠nic-mAb和人类nic-mAb引线充分证明。nic - mab可以消除临床观察到的尼古丁疫苗免疫反应的高度个体间差异（数量和质量）。nic - mab可以提供对个体间变异性的控制，这是实现治疗尼古丁成瘾的“PK机制”的临床概念验证所必需的。该联盟致力于开发用于临床的nici - mab抗体。目前正在采取几种方法来提供nic-mAb先导系列，用于先导优化和临床前开发。这些项目处于不同的发展阶段，包括使用常规基因工程技术对小鼠nic-mAbs进行人源化，从先前接种过疫苗的个体中选择表达高亲和力nic-mAbs的人b细胞，以及筛选高亲和力Fab的人噬菌体展示库。这些平行的努力，使用不同的来源和方法，将提高我们成功选择具有所需特征的开发候选药物的几率，从而推进IND-enabling研究。在给定的nic-mAb系列中，每个先导都将通过各种标准化的体外分析和在尼古丁依赖和戒断的动物模型中建立的体内研究进行进展。我们的目标是推进一种开发候选药物，使其能够进行IND研究，为人体临床研究做准备。

DESCRIPTION (provided by applicant): 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.