Lead Optimization and Preclinical Development of Human Nicotine-Specific mAbs

描述(由申请人提供)：在美国，吸烟每年导致48万人死亡。美国疾病控制与预防中心估计，每年因治疗吸烟及与吸烟相关的疾病而产生的直接医疗费用为1330亿美元。只有1：5的吸烟者使用标准护理药物疗法实现长期戒烟，让大多数人仍然吸烟并寻找替代方案。我们正在开发尼古丁特异性高亲和力人类单抗(MAbbs)，作为戒烟治疗的辅助手段。尼古丁特异性单抗(NIC-mAbbs)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。临床前的概念验证已经用小鼠NIC-mAbs和人类NIC-mAb导联得到了很好的证明。NIC-mAbs可以消除尼古丁疫苗在临床上观察到的免疫反应(数量和质量)的高度个体间差异。NIC-mAbs可以提供对个体间可变性的急需控制，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。该联盟致力于开发临床使用的NIC-mAbb。目前正在采取几种方法来提供NIC-mAb导联系列，用于导联优化和临床前开发。这些计划处于不同的开发阶段，包括使用常规基因工程技术使小鼠NIC-mAb人性化，从表达先前接种过疫苗的人的高亲和力NIC-mAbs的人类b细胞中进行选择，以及筛选高亲和力Fab的人噬菌体展示文库。这些并行的努力，使用不同的来源和方法，将提高我们选择具有所需特征的开发候选对象进入IND使能研究的成功几率。给定的NIC-mAb系列中的每一种铅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良好的体内研究来进行。我们的目标是在为人类临床研究做准备的IND使能研究方面取得进展。

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.