Chemical Strategies for Developing Improved Vaccines against Phenethylamines

开发改进的苯乙胺疫苗的化学策略

• 批准号: 8717454
• 负责人: Paul T Bremer
• 金额: $ 2.97万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-15 至 2016-04-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8717454
• 关键词: Adjuvant; Adverse effects; Affinity; Agonist; Aluminum; Amphetamines; Antibodies; Antibody Affinity; Antibody Formation; Antigens; Bathing; Behavioral; Behavioral Assay; Benchmarking; Binding; Biological Assay; Blood - brain barrier anatomy; Brain; Carrier Proteins; Chemicals; Data; Dendrimers; Dependence; Dose; Drug Addiction; Drug Compounding; Drug Controls; Drug Targeting; Enzyme-Linked Immunosorbent Assay; Epitopes; Evaluation; FDA approved; Future; Goals; Government; Haptens; Health; Human; Immune response; Immunization; Immunoconjugates; Immunoglobulin G; Intoxication; Intravenous; Isomerism; Keyhole Limpet Hemocyanin; Life; Link; Literature; Measures; Methamphetamine; Modeling; Motor Activity; Mus; Performance; Pharmaceutical Preparations; Pharmacodynamics; Phenethylamines; Polymers; Positioning Attribute; Production; Proteins; Protocols documentation; Psychotropic Drugs; Radioimmunoassay; Rattus; Reporting; Research; Research Project Grants; Rewards; Risk; Salts; Self Administration; Serum; Site; Societies; Specificity; Testing; Therapeutic; Toll-like receptors; Vaccinated; Vaccine Design; Vaccines; Work; addiction; aluminum sulfate; cathinone; density; design; drug of abuse; effective therapy; enantiomer; immunogenic; immunogenicity; improved; meetings; novel; novel vaccines; polyclonal antibody; prevent; psychologic; public health relevance; receptor; response; scaffold; success; theories; vaccine development

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.

描述（由申请人提供）：甲基苯丙胺（MA）和甲氧麻黄酮（MD）等取代苯乙胺（SPA）对人体健康具有破坏性，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MA的非法使用和生产仍然猖獗。另一方面，MD在21世纪初之前几乎不为人知，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。目前没有FDA批准的治疗SPA成瘾的疗法。免疫药物疗法，即药物滥用疫苗（DoAV）是治疗药物成瘾的一个有吸引力的选择，因为它的副作用低，易于管理和长期效力。滥用药物疫苗背后的概念是，它们引发针对靶药物化合物的高度特异性体液免疫应答。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，从而产生奖励性的心理效应。拟议研究项目的目标是创建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）没有显示出任何阻断大鼠自我施用的能力，这是有希望治疗成瘾的疫苗的重要基准。此外，文献中没有关于有效MD疫苗的报告。增加免疫原的表位密度是增加疫苗性能的稳健策略。这种策略在DoAV领域尚未探索，将用于通过连接到载体蛋白的聚合物和树枝状聚合物来创建新型SPA疫苗。SPA疫苗的具体目标是：（1）设计合成新型MA和MD半抗原，并将其作为疫苗进行免疫化学和行为学试验。用新的半抗原-蛋白质缀合物免疫的小鼠应引起对MA和MD的高滴度IgG抗体应答（如通过ELISA测量的）和对放射免疫测定中的药物的高亲和力。免疫小鼠还应显示MA/MD诱导的过度运动活性的钝化。假设新的半抗原比以前报道的半抗原更具免疫原性，因为它们以其最天然的形式呈现药物样部分。(2)将Aim 1半抗原并入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，这可以增强传统单价疫苗的效力。(3)在大鼠模型中评价改良疫苗。新型疫苗可能有望减轻MA/MD在大鼠自我给药模型中的成瘾作用，该模型旨在模拟人类药物成瘾状况。