Chemical Strategies for Developing Improved Vaccines against Phenethylamines

描述(由申请人提供)：取代苯乙胺(SPA)，如甲基苯丙胺(MA)和甲氧麻黄酮(MD)，对人类健康具有破坏性，并存在严重的滥用倾向。自20世纪60年代以来，尽管各国政府试图控制这种药物，但非法使用和生产MA的现象一直很猖獗。另一方面，MD在本世纪初之前几乎是未知的，但近年来MD的使用和生产以惊人的速度增长，特别是在英国。目前还没有FDA批准的疗法来治疗SPA成瘾。免疫药物疗法，即滥用药物疫苗(DoAVs)是治疗药物成瘾的一种有吸引力的选择，因为它的副作用低，易于给药和长期有效。滥用药物疫苗背后的概念是，它们诱导针对目标药物化合物的高度特异的体液免疫反应。抗药物抗体在外围与药物结合，从而阻止药物越过血脑屏障。因此，这种药物不能作用于大脑中的感受器，产生有益的心理效果。这项拟议的研究项目的目标是创造和测试一种治疗SPA成瘾的改进疫苗。以前报道的SPA疫苗(特别是MA)还没有显示出任何阻止大鼠自我给药的能力，这是有望治疗成瘾的疫苗的重要基准。此外，文献中没有关于有效的MD疫苗的报道。增加免疫原的表位密度是提高疫苗性能的有力策略。这一策略在DoAVs领域尚未被探索，它将被用于通过与载体蛋白相连的聚合物和树枝状大分子创造新型SPA疫苗。开发SPA疫苗的具体目的是：(1)设计和合成新的MA和MD半抗原，并将其作为疫苗进行免疫化学检测和行为检测。用新型半抗原蛋白偶联物免疫小鼠，可诱导出对MA和MD的高滴度抗体，用放射免疫法测定对药物的高亲和力。免疫的小鼠也应该表现出钝化MA/MD诱导的过度运动活动。新的半抗原被认为比以前报道的半抗原更具免疫原性，因为它们以最自然的形式呈现出药物样的部分。(2)将AIM-1半抗原引入新型多触觉支架。作为疫苗，这些支架具有更高的表位密度，这可能会提高传统单价疫苗的效力。(3)在大鼠模型上对改良疫苗进行评价。这些新型疫苗可能有望在模拟人类吸毒成瘾的大鼠自我给药模型中减轻MA/MD的成瘾效应。

DESCRIPTION (provided by applicant): Substituted phenethylamines (SPA) such as methamphetamine (MA) and mephedrone (MD) are destructive to human health and present a significant abuse liability. Since the 1960s illicit use and production of MA has been rampant despite governments attempting to control the drug. MD on the other hand was virtually unknown before the early 2000s, but in recent years use and production of MD has increased at an alarming rate especially in the UK. No FDA approved therapies currently exist to treat SPA addiction. Immunopharmacotherapy i.e. drugs of abuse vaccines (DoAVs) is an attractive option for the treatment of drug addiction because of its low side-effect profile, ease of administration and its long-lived potency. The concept behind drugs of abuse vaccines is that they elicit highly specific humoral immune responses against a target drug compound. Anti-drug antibodies bind to the drug in the periphery, thus preventing the drug from crossing the blood brain barrier. As a result the drug cannot act on receptors in the brain to produce its rewarding, psychological effects. The goal of the proposed research project is to create and test an improved vaccine for treatment of SPA addiction. Previously reported SPA vaccines (specifically MA) have not shown any ability to block self- administration in rat which is an important benchmark for vaccines that hold promise in treating addiction. Furthermore, no report of a working MD vaccine exists in the literature. Increasing epitope density of immunogens is a robust strategy for increasing vaccine performance. This strategy, unexplored in the realm of DoAVs, will be used to create novel SPA vaccines via polymers and dendrimers linked to carrier proteins. The specific aims for developing SPA vaccines are: (1) Design and synthesize novel MA and MD haptens and test them as vaccines in immunochemical assays and behavioral assays. Mice immunized with the novel hapten-protein conjugates should elicit high titer IgG antibody responses to MA and MD as measured by ELISA and high affinity for drug in radioimmunoassay. Immunized mice should also display a blunting of MA/MD induced hyperlocomotor activity. The novel haptens are hypothesized to be more immunogenic than previously reported haptens since they present the drug-like moiety in its most natural form. (2) Incorporate Aim 1 haptens into novel multihaptenic scaffolds. As vaccines, these scaffolds possess increased epitope density which may boost potency over traditional monovalent vaccines. (3) Evaluate the improved vaccines in rat models. The novel vaccines may hold promise in mitigating the addictive effects of MA/MD in rat self- administration models which are designed to mimic the human condition of drug addiction.