Immunization to Block the Effects of Nicotine

免疫阻断尼古丁的影响

• 批准号: 7121330
• 负责人: PAUL R PENTEL
• 金额: $ 6.02万
• 依托单位: HENNEPIN HEALTHCARE RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-02-01 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7121330
• 关键词: antibody titering; antigen antibody reaction; antigens; behavior test; drug metabolism; drug screening /evaluation; immunochemistry; immunoglobulin G; immunologic assay /test; immunopharmacology; laboratory rat; monoclonal antibody; nicotine; passive immunization; pharmacokinetics; smoking cessation; substance abuse related behavior; tobacco abuse; vaccine development; vaccines

DESCRIPTION (provided by applicant): The aim of this proposal is to study mechanism-based strategies for enhancing the efficacy of vaccination for the treatment of nicotine dependence in rats. Vaccination of rats against nicotine binds and sequesters nicotine in serum, reduces nicotine distribution to brain, and blocks or attenuates a variety of nicotine-induced behaviors that are relevant to nicotine dependence. These results suggest that vaccination may be useful in the treatment or prevention of nicotine dependence, and a phase I clinical trial has been initiated. However, there are potential limitations to vaccine efficacy, and some effects of vaccination are incomplete. This may be due to the finite amount of antibody that can be elicited by vaccination (and the variability in response among subjects), inability to control the affinity of antibodies elicited by vaccination, or the spectrum of action of vaccination which may target some aspects of nicotine dependence (e.g. reinforcement) better than others (e.g. ongoing withdrawal). This study will examine two general approaches to enhancing the efficacy of immunization; (a) the use of passive immunization with monoclonal nicotine-specific antibodies to investigate the relationship of affinity and dose to efficacy, and to determine whether passive immunization (administration of exogenous antibody) may have therapeutic application of its own as an alternative or supplement to vaccination, and (b) combining vaccination with other interventions that act via complementary mechanisms. Specific hypotheses to be tested are that 1) The efficacy of immunization can be enhanced by optimizing antibody affinity for nicotine, 2) Efficacy can be enhanced by using passive immunization to provide higher doses of antibody than can be achieved with vaccination, 3) Passive immunization with therapeutically effective antibody doses is well tolerated, 4) Vaccine efficacy can be enhanced by combining it with the nicotinic receptor antagonist mecamylamine, or nicotine infusion (simulating nicotine replacement therapy), and 5) Efficacy can be enhanced by combining vaccination with passive immunization, a strategy that could exploit the potential clinical advantages of each. These questions will be studied using a variety of pharmacokinetic and behavioral models including nicotine distribution to brain after acute and chronic nicotine dosing, nicotine self-administration, reinstatement of nicotine responding, nicotine abstinence, and relief of nicotine abstinence by nicotine. These data will expand our understanding of the mechanisms, limitations and clinical potential of both vaccination and passive immunization for the treatment or prevention of nicotine dependence.

描述（由申请方提供）：本提案的目的是研究基于机制的策略，以增强疫苗接种治疗大鼠尼古丁依赖的有效性。对大鼠接种尼古丁疫苗可结合并隔离血清中的尼古丁，减少尼古丁向大脑的分布，并阻断或减弱与尼古丁依赖相关的多种尼古丁诱导行为。这些结果表明，疫苗接种可能有助于治疗或预防尼古丁依赖，并已启动I期临床试验。然而，疫苗效力存在潜在的局限性，疫苗接种的一些效果是不完全的。这可能是由于疫苗接种可引发的抗体量有限（以及受试者之间应答的变异性），无法控制疫苗接种引发的抗体亲和力，或疫苗接种的作用谱可能比其他方面（例如持续戒断）更好地靶向尼古丁依赖的某些方面（例如强化）。这项研究将审查提高免疫效力的两种一般办法;（a）使用尼古丁特异性单克隆抗体进行被动免疫，以研究亲和力和剂量与功效的关系，并确定被动免疫是否（外源性抗体的施用）可以具有其自身作为疫苗接种的替代或补充的治疗应用，和（B）将疫苗接种与通过互补机制起作用的其他干预相结合。待测试的具体假设是：1）免疫的功效可以通过优化抗体对尼古丁的亲和力来增强，2）功效可以通过使用被动免疫来增强，以提供比用疫苗接种可以实现的更高剂量的抗体，3）用治疗有效抗体剂量的被动免疫耐受良好，4）疫苗效力可以通过与烟碱受体拮抗剂美加明或尼古丁输注液组合来增强（模拟尼古丁替代疗法），和5）可以通过将疫苗接种与被动免疫结合来增强功效，这是一种可以利用每种药物潜在临床优势的策略。将使用各种药代动力学和行为模型研究这些问题，包括急性和慢性尼古丁给药后尼古丁向大脑的分布、尼古丁自我给药、尼古丁反应恢复、尼古丁戒断和尼古丁缓解尼古丁戒断。这些数据将扩大我们对疫苗接种和被动免疫治疗或预防尼古丁依赖的机制、局限性和临床潜力的理解。