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: 9113552
• 负责人: Matthew W Kalnik
• 金额: $ 293.97万
• 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 2018-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9113552
• 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; 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.



项目成果

Attenuating nicotine's effects with high affinity human anti-nicotine monoclonal antibodies.

• DOI: 10.1371/journal.pone.0254247
• 发表时间: 2021
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Raleigh MD;Beltraminelli N;Fallot S;LeSage MG;Saykao A;Pentel PR;Fuller S;Thisted T;Biesova Z;Horrigan S;Sampey D;Zhou B;Kalnik MW
• 通讯作者: Kalnik MW

The nicotine-degrading enzyme NicA2 reduces nicotine levels in blood, nicotine distribution to brain, and nicotine discrimination and reinforcement in rats.

• DOI: 10.1186/s12896-018-0457-7
• 发表时间: 2018-07-24
• 期刊: BMC biotechnology
• 影响因子: 3.5
• 作者: Pentel PR;Raleigh MD;LeSage MG;Thisted T;Horrigan S;Biesova Z;Kalnik MW
• 通讯作者: Kalnik MW