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）对人体健康具有破坏性，并且存在严重的滥用风险。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仍然猖獗。另一方面，在21世纪初之前，MD几乎不为人所知，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批准的治疗SPA成瘾的疗法。免疫药物疗法，即滥用药物疫苗（doav）是治疗吸毒成瘾的一种有吸引力的选择，因为其副作用低、易于施用和效力长。滥用药物疫苗背后的概念是，它们引发针对目标药物化合物的高度特异性体液免疫反应。抗药物抗体在外周与药物结合，从而阻止药物穿过血脑屏障。因此，这种药物不能作用于大脑中的受体，从而产生有益的心理效果。拟议的研究项目的目标是创造和测试一种用于治疗SPA成瘾的改进疫苗。先前报道的SPA疫苗（特别是MA）在大鼠身上没有显示出任何阻断自我给药的能力，这是疫苗治疗成瘾的一个重要基准。此外，文献中没有关于有效的MD疫苗的报道。增加免疫原表位密度是提高疫苗性能的有力策略。这一策略在doav领域尚未被探索过，它将通过与载体蛋白连接的聚合物和树突分子来制造新型SPA疫苗。SPA疫苗开发的具体目标是：(1)设计合成新的MA和MD半抗原，并将其作为疫苗进行免疫化学试验和行为试验。用这种新型半抗原蛋白偶联物免疫小鼠后，ELISA检测小鼠对MA和MD产生高滴度IgG抗体反应，放射免疫测定小鼠对药物具有高亲和力。免疫小鼠也应表现出MA/MD诱导的过度运动活动减弱。假设这种新型半抗原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药物样部分。(2)将Aim 1半抗原整合到新型多半抗原支架中。作为疫苗，这些支架具有增加的表位密度，这可能比传统的单价疫苗提高效力。(3)改良疫苗在大鼠模型上的评价。这种新型疫苗有望在大鼠自我给药模型中减轻MA/MD的成瘾性，这种模型旨在模仿人类药物成瘾的情况。

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.