Immunization to Block the Effects of Nicotine

免疫阻断尼古丁的影响

• 批准号: 7925112
• 负责人: PAUL R PENTEL
• 金额: $ 6.75万
• 依托单位: HENNEPIN HEALTHCARE RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2010-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7925112
• 关键词: Active Immunization; Acute; Address; Affinity; Animal Model; Animals; Antibodies; Antibody Formation; Antigens; Attenuated; Behavior; Behavioral; Behavioral Assay; Brain; Carrier Proteins; Clinical; Clinical Treatment; Clinical Trials; Data; Development; Disadvantaged; Discrimination; Dose; Drug Kinetics; Experimental Designs; Goals; Human; Immunization; Immunologics; Immunotherapy; Individual; Methods; Monoclonal Antibodies; Nicotine; Nicotine Dependence; Passive Immunization; Phase; Psychological reinforcement; Rattus; Rewards; Schedule; Self Administration; Series; Serum; Supplementation; Tobacco Dependence; Translations; Vaccinated; Vaccination; Vaccines; Work; addiction; attenuation; base; clinical efficacy; cost; craving; immunogenicity; novel strategies; novel therapeutics; response; smoking cessation; vaccine efficacy; varenicline

DESCRIPTION (provided by applicant): The goal of this work is to study mechanism-based strategies for enhancing the efficacy of immunotherapy against nicotine as a treatment for nicotine dependence in rats. Vaccination against nicotine has substantial efficacy in animal models for attenuating the behavioral effects of nicotine, and early clinical trials show increases in smoking cessation rates. While these data are encouraging, vaccines are not effective in all individuals. A major limitation of nicotine vaccines is their inability to consistently produce high serum antibody levels, and the large individual variability in these levels, which results in many non-responders. Passive immunization with nicotine-specific monoclonal antibodies, an alternative to vaccination, is highly effective in animals and can reliably produce high antibody levels, but is more costly than vaccination. Preliminary data in rats suggest that a combination of vaccination and passive immunization is more effective than vaccination alone. Aim 1 of this study will confirm and expand these studies using a target antibody concentration strategy (individualized supplementation of vaccinated rats with monoclonal antibody to achieve an effective serum antibody concentration) that could be applied clinically to exploit the advantages of both approaches while conserving monoclonal antibody. Aim 2 will examine whether the efficacy of immunotherapy can be enhanced by using a polyvalent nicotine vaccine. Preliminary studies have identified 2 nicotine immunogens that produce non cross-reacting antibodies and so are immunologically distinct. Their combined use is predicted to produce additive serum antibody levels and might also reduce the individual variability in response, resulting in fewer non-responders. This aim will evaluate the efficacy of 2 or 3 distinct nicotine immunogens combined into bi- or trivalent vaccines to determine whether they are more effective than a single immunogen. A second limitation of immunotherapy is that it likely blocks the direct effects of nicotine (reward and reinforcement) to a greater extent than subsequent effects that occur when nicotine is no longer present (craving). Aim 3 will examine the efficacy of immunotherapy combined with varenicline. Immunotherapy and varenicline have complementary but compatible mechanisms of action and effects, suggesting that their combination would be more effective than either one alone. For all 3 Aims, an integrated set of immunologic, pharmacokinetic and behavioral assays (nicotine self-administration, locomotor sensitization, discrimination) will be used to study mechanisms and assess efficacy. These Aims explore novel approaches to increasing nicotine vaccine efficacy using strategies with strong preliminary indications of usefulness and high potential for translation into clinical use. They address the principal limitations of a new therapeutic strategy which already appears to have clinical efficacy.

描述（由申请人提供）：这项工作的目标是研究基于机制的策略，以增强针对尼古丁的免疫疗法作为大鼠尼古丁依赖性治疗的功效。在动物模型中，尼古丁疫苗对于减轻尼古丁的行为影响具有显着功效，早期临床试验表明戒烟率有所提高。尽管这些数据令人鼓舞，但疫苗并非对所有个体都有效。尼古丁疫苗的一个主要限制是它们无法持续产生高血清抗体水平，并且这些水平的个体差异很大，这导致许多无反应者。使用尼古丁特异性单克隆抗体进行被动免疫是疫苗接种的替代方案，对动物非常有效，并且可以可靠地产生高抗体水平，但比疫苗接种成本更高。大鼠的初步数据表明，疫苗接种和被动免疫的结合比单独接种疫苗更有效。本研究的目标 1 将使用目标抗体浓度策略（对接种的大鼠个体化补充单克隆抗体以达到有效的血清抗体浓度）来确认和扩展这些研究，该策略可应用于临床以利用两种方法的优点，同时保留单克隆抗体。目标 2 将研究是否可以通过使用多价尼古丁疫苗来增强免疫疗法的功效。初步研究已鉴定出 2 种尼古丁免疫原，它们能产生非交叉反应抗体，因此在免疫学上是不同的。预计它们的联合使用会产生额外的血清抗体水平，并且还可能减少反应的个体差异，从而减少无反应的人数。该目标将评估 2 或 3 种不同的尼古丁免疫原组合成二价或三价疫苗的功效，以确定它们是否比单一免疫原更有效。免疫疗法的第二个局限性是，它可能比尼古丁不再存在时产生的后续影响（渴望）更大程度地阻止尼古丁的直接影响（奖励和强化）。目标 3 将检查免疫疗法联合伐尼克兰的疗效。免疫疗法和伐尼克兰具有互补但兼容的作用机制和效果，表明它们的组合比单独使用任何一种都更有效。对于所有 3 个目标，将使用一套综合的免疫学、药代动力学和行为测定（尼古丁自我给药、运动敏化、辨别）来研究机制和评估功效。这些目标探索了提高尼古丁疫苗功效的新方法，使用的策略具有强有力的初步有用性和转化为临床应用的巨大潜力。他们解决了新治疗策略的主要局限性，该策略似乎已经具有临床疗效。