Active Immunization for Treating Methamphetamine Abuse

治疗甲基苯丙胺滥用的主动免疫

• 批准号: 7502083
• 负责人: Samuel Michael Owens
• 金额: $ 95.73万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-30 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7502083
• 关键词: Active Immunization; Address; Adverse effects; Affect; Affinity; Amphetamines; Animal Model; Animals; Antibodies; Antibody Affinity; Antigens; Area; Autopsy; Behavior Therapy; Behavioral; Behavioral Assay; Blood Chemical Analysis; Brain; Chemicals; Chronic; Clinical Drug Development; Clinical Trials; Cocaine; Cocaine Dependence; Collaborations; Combined Modality Therapy; Compatible; Condition; Conjugate Vaccines; Counseling; Data; Data Analyses; Data Set; Dependence; Development; Drug Formulations; Drug Kinetics; Epitopes; Funding; Future; Goals; Haptens; Health; Histology; Human; Immune response; Immunization; In Vitro; Industry; Injection of therapeutic agent; Interdisciplinary Study; Investigational New Drug Application; Knowledge; Ligand Binding; Measures; Medical; Methamphetamine; Modeling; Monitor; Monoclonal Antibodies; Mus; National Institute of Drug Abuse; Neurologic; Nicotine; Patients; Penetration; Pharmaceutical Preparations; Phencyclidine; Positioning Attribute; Preclinical Testing; Preparation; Production; Program Development; Proteins; Protocols documentation; Psychological reinforcement; Public Health; Rate; Rattus; Relapse; Research; Research Design; Research Personnel; Research Project Grants; Safety; Self Administration; Serum; Site; Specificity; Staging; Testing; Therapeutic; Tissues; Translating; Treatment Efficacy; United States Food and Drug Administration; Vaccination; Vaccine Design; Vaccines; Vision; Withdrawal; Work; addiction; animal data; animal tissue; base; cigarette smoking; cross reactivity; density; design; ecstasy; ecstasy abuse; experience; in vivo; innovation; multidisciplinary; novel; pre-clinical; preclinical study; prevent; programs; recidivism; research clinical testing; response; scale up; therapeutic effectiveness; vaccine development; vaccine efficacy; vaccine safety

DESCRIPTION (provided by applicant): Although vaccines to treat nicotine and cocaine addiction are currently in clinical trials, no specific medications exist to treat dependence on (+)-methamphetamine ((+)METH)-like drugs. To address this need, these preclinical studies will facilitate the medical discovery and development of new (+)METH- conjugate vaccines (MCVs) to help patients stop using (+)METH-like drugs. These important new MCVs are expected to block or reduce (+)METH effects in patients. The discovery of medically effective MCVs will be accomplished through our well-integrated, multidisciplinary research program designed to manufacture and test MCVs. In previous preclinical studies, our group showed that 1) titer and affinity of antibodies generated against MCV are not adversely affected by continuous (+)METH use, 2) a single MCV might be used to generate high-affinity antibodies against (+)METH and (+)-amphetamine ((+)AMP), and 3) anti-(+)METH monoclonal antibodies generated from a novel MCV can be used to reduce brain (+)METH concentrations and reduce (+)METH or (+)AMP self-administration. These accomplishments substantially enhanced our scientific vision, clearly defined the project's research aims, and identified a premier MCV candidate for the for use in active immunization. Our ultimate goal is to have one or more safe, effective MCV in a human- compatible formulation ready for clinical trials within five years. To accomplish this, we have four aims. In Aim 1, we will design, synthesize, and manufacture innovative new MCVs and carefully optimize the immunological conditions needed to achieve the best combination of antibody titer, affinity, specificity of response, and duration of action (i.e., therapeutic effectiveness). In Aim 2, we will test the best of these MCVs in pharmacokinetic and behavioral studies designed to select MCVs that decrease penetration of (+)METH into the brain and reduce or block drug self-administration without adversely influencing withdrawal effects. In Aim 3, safety will be determined by monitoring general animal health, measuring blood chemistries, and examining animal tissues during and after chronic vaccination. In Aim 4, a data monitoring program based on data sets collected in Aims 1-3 will be developed and enacted with industry partner InterveXion Therapeutics to maximize the potential for expedient FDA approval. The decision to take an MCV candidate to the FDA will be made in collaboration with external advisors and NIDA, then our ongoing programmatic approach will facilitate rapid transition through clinical testing, including IND application. Achieving our goal will address the major public health problem of (+)METH dependence by blocking or reducing its effects even under challenges of binge and relapse.

描述（由申请人提供）：虽然治疗尼古丁和可卡因成瘾的疫苗目前正处于临床试验阶段，但尚无特定药物可治疗对 (+)-甲基苯丙胺 ((+)METH) 类药物的依赖。为了满足这一需求，这些临床前研究将促进新型 (+)METH 结合疫苗 (MCV) 的医学发现和开发，以帮助患者停止使用 (+)METH 类药物。这些重要的新型 MCV 预计将阻止或减少 (+)METH 对患者的影响。医学上有效的 MCV 的发现将通过我们旨在制造和测试 MCV 的综合性多学科研究计划来完成。在之前的临床前研究中，我们的小组表明：1) 连续使用 (+)METH 不会对针对 MCV 产生的抗体的滴度和亲和力产生不利影响，2) 单个 MCV 可能用于产生针对 (+)METH 的高亲和力抗体和 (+)-安非他明 ((+)AMP)，以及 3) 由新型 MCV 产生的抗 (+)METH 单克隆抗体可用于降低脑内 (+)METH 浓度并减少(+)METH 或 (+)AMP 自我给药。这些成就极大地增强了我们的科学视野，明确了该项目的研究目标，并确定了用于主动免疫的首要 MCV 候选者。我们的最终目标是在五年内以人体相容的配方制备出一种或多种安全、有效的 MCV，准备好进行临床试验。为了实现这一目标，我们有四个目标。在目标 1 中，我们将设计、合成和制造创新的新型 MCV，并仔细优化实现抗体滴度、亲和力、反应特异性和作用持续时间（即治疗效果）最佳组合所需的免疫条件。在目标 2 中，我们将在药代动力学和行为研究中测试这些 MCV 中最好的部分，旨在选择能够减少 (+)METH 渗透到大脑中并减少或阻止药物自我给药而不会对戒断效果产生不利影响的 MCV。在目标 3 中，将通过监测一般动物健康、测量血液化学成分以及在长期疫苗接种期间和之后检查动物组织来确定安全性。在目标 4 中，将与行业合作伙伴 InterveXion Therapeutics 一起开发和制定基于目标 1-3 中收集的数据集的数据监测计划，以最大限度地发挥 FDA 迅速批准的潜力。将 MCV 候选药物提交 FDA 的决定将与外部顾问和 NIDA 合作做出，然后我们正在进行的程序化方法将促进通过临床测试（包括 IND 申请）的快速过渡。实现我们的目标将通过阻止或减少（+）冰毒依赖的影响来解决（+）冰毒依赖的主要公共卫生问题，即使在暴饮暴食和复发的挑战下也是如此。