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) 等替代苯乙胺 (SPA) 对人类健康具有破坏性，并且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该药物，但 MA 的非法使用和生产仍然猖獗。另一方面，MD 在 2000 年代初之前几乎不为人所知，但近年来，MD 的使用和生产以惊人的速度增长，尤其是在英国。目前尚无 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) 是治疗药物成瘾的一种有吸引力的选择，因为它副作用低、易于给药且效力持久。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。抗药物抗体与外周的药物结合，从而阻止药物穿过血脑屏障。因此，该药物无法作用于大脑中的受体以产生有益的心理作用。拟议研究项目的目标是创造并测试一种改进的疫苗，用于治疗 SPA 成瘾。之前报道的 SPA 疫苗（特别是 MA）没有表现出任何阻止​​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效策略。这种在 DoAV 领域尚未探索的策略将用于通过与载体蛋白连接的聚合物和树枝状聚合物来制造新型 SPA 疫苗。开发SPA疫苗的具体目标是：（1）设计和合成新型MA和MD半抗原，并在免疫化学测定和行为测定中将它们作为疫苗进行测试。用新型半抗原-蛋白缀合物免疫的小鼠应引发针对MA和MD的高滴度IgG抗体反应（通过ELISA测量）以及放射免疫测定中对药物的高亲和力。免疫小鼠还应表现出 MA/MD 诱导的运动过度活动减弱。假设新型半抗原比先前报道的半抗原更具免疫原性，因为它们以最天然的形式呈现药物样部分。 (2) 将 Aim 1 半抗原纳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，这可能比传统单价疫苗增强效力。 (3)在大鼠模型中评价改良疫苗。在旨在模拟人类药物成瘾状况的大鼠自我给药模型中，新型疫苗可能有望减轻 MA/MD 的成瘾作用。