Lead Optimization and Preclinical Development of Human Nicotine-Specific mAbs

人烟碱特异性单克隆抗体的先导化合物优化和临床前开发

• 批准号: 8828430
• 负责人: Matthew W Kalnik
• 金额: $ 255.3万
• 依托单位: ANTIDOTE THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-30 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8828430
• 关键词: Abstinence; Accounting; Affinity; Animal Model; Animals; Antibodies; Antidotes; B-Lymphocytes; Bacteriophages; Biologic Development; Biological Assay; Brain; Caring; Cell Line; Cells; Centers for Disease Control and Prevention (U.S.); Cessation of life; Characteristics; Clinic; Clinical; Clinical Trials; Cloning; Cost-Benefit Data; Dependency; Development; Development Plans; Disease; Epidemic; Failure; Funding; Generations; Genetic Engineering; Genetic Recombination; Goals; Half-Life; Haptens; Health; Health Care Costs; Human; Human Development; Immune; Immune response; In Vitro; Individual; Intravenous infusion procedures; Laboratory Finding; Lead; Left; Libraries; Medical; Methods; Mission; Monoclonal Antibodies; Mus; National Institute of Drug Abuse; Nicotine; Nicotine Dependence; Nicotine Withdrawal; Phage Display; Pharmaceutical Preparations; Pharmacotherapy; Placebos; Population; Preparation; Private Sector; Probability; Process; Production; Property; Public Health; Qualifying; Reaction; Reporting; Research Contracts; Risk; Running; Safety; Sales; Series; Shotguns; Smoker; Smoking; Source; Specificity; Staging; Substance Use Disorder; Surgeon; Techniques; Technology; Testing; Therapeutic; United States; Vaccinated; Vaccines; Withdrawal; Withholding Treatment; Work; addiction; advanced system; cigarette smoking; cost; drug candidate; drug development; experience; feeding; human monoclonal antibodies; immunogenicity; improved; in vitro Assay; in vivo; lead series; man; medical specialties; meetings; pre-clinical; programs; research clinical testing; screening; smoking cessation; standard of care; success; varenicline

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.

描述（由申请人提供）：在美国，吸烟每年导致> 480，000人死亡。CDC估计，治疗吸烟和吸烟相关疾病的直接医疗费用超过1330亿美元/年。只有1：5的吸烟者使用标准药物治疗实现长期戒烟，大多数人仍然吸烟并寻求替代品。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手段。尼古丁特异性单克隆抗体（nic-mAbs）减少尼古丁向大脑的分布，并在尼古丁依赖和戒断的动物模型中显示出疗效。临床前概念验证已经用小鼠nic-mAb和人nic-mAb先导化合物进行了充分记录。Nic-mAb可以消除临床上观察到的尼古丁疫苗免疫应答（数量和质量）的高度个体间变异性。Nic-mAbs可以提供对个体间变异性的急需控制，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。该联盟致力于开发用于临床的nic-mAb。正在采取几种方法来提供nic-mAb电极导线系列，用于电极导线优化和临床前开发。这些程序处于不同的开发阶段，包括使用常规基因工程技术对小鼠nic-mAbs进行人源化，从先前接种疫苗的个体中表达高亲和力nic-mAbs的人b细胞中进行选择，以及筛选人噬菌体展示文库中的高亲和力Fab。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人进入IND使能研究的几率。给定nic-mAb系列中的每种先导化合物将通过各种标准化体外试验和尼古丁依赖和戒断动物模型中成熟的体内研究进行。我们的目标是将开发候选药物进展为IND使能研究，为人体临床研究做准备。