Immunization to Block the Effects of Nicotine

描述（由申请方提供）：本研究的目的是研究基于机制的策略，用于增强尼古丁免疫疗法作为大鼠尼古丁依赖治疗的有效性。在动物模型中，针对尼古丁的疫苗接种对于减弱尼古丁的行为影响具有显著的功效，并且早期临床试验显示戒烟率增加。虽然这些数据令人鼓舞，但疫苗并不是对所有人都有效。尼古丁疫苗的一个主要限制是它们不能持续产生高血清抗体水平，以及这些水平的较大个体差异，这导致许多无应答者。尼古丁特异性单克隆抗体的被动免疫是疫苗接种的一种替代方法，在动物中非常有效，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组合比单独接种更有效。本研究的目的1将使用靶抗体浓度策略（个体化补充单克隆抗体接种大鼠以达到有效的血清抗体浓度）确认和扩展这些研究，该策略可在临床上应用，以利用两种方法的优势，同时保留单克隆抗体。目标2将检验是否可以通过使用多价尼古丁疫苗来增强免疫治疗的功效。初步研究已经确定了两种尼古丁免疫原，它们产生非交叉反应抗体，因此在免疫学上是不同的。它们的联合使用预计会产生相加的血清抗体水平，也可能减少个体反应的变异性，从而减少无应答者。该目的将评价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，它可能在更大程度上阻断尼古丁的直接作用（奖励和强化），而不是尼古丁不再存在时发生的后续作用（渴望）。目的3将检验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相容的作用和效果机制，这表明它们的组合比单独使用更有效。对于所有3个目的，将使用一套完整的免疫学、药代动力学和行为试验（尼古丁自我给药、运动致敏、辨别）来研究机制和评估疗效。这些目标探索了使用具有强初步有用性和转化为临床使用的高潜力的策略来增加尼古丁疫苗功效的新方法。他们解决了一种新的治疗策略的主要局限性，这种策略似乎已经具有临床疗效。

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.