Active Immunization for Treating Methamphetamine Abuse

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在临床试验中，但没有特定的药物可以治疗对(+)-甲基苯丙胺(+)-甲基苯丙胺类药物的依赖。为了满足这一需求，这些临床前研究将促进新的（+）甲基苯丙胺结合疫苗（mcv）的医学发现和开发，以帮助患者停止使用（+）甲基苯丙胺类药物。这些重要的新型mcv有望阻断或减少（+）甲基苯丙胺对患者的影响。医学上有效的mcv的发现将通过我们精心设计的制造和测试mcv的综合多学科研究计划来完成。在之前的临床前研究中，我们的研究小组发现：1)抗MCV抗体的效价和亲和力不受持续使用甲基安非他明的不利影响；2)单个MCV可用于产生抗（+）甲基安非他明和（+）安非他明（AMP）的高亲和力抗体；3)由新型MCV产生的抗（+）甲基安非他明单克隆抗体可用于降低脑（+）甲基安非他明浓度，减少（+）甲基安非他明或（+）AMP的自我给药。这些成就大大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选MCV候选物。我们的最终目标是在五年内研制出一种或多种安全有效的人体兼容MCV制剂，用于临床试验。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，并仔细优化所需的免疫学条件，以实现抗体滴度、亲和力、反应特异性和作用时间（即治疗效果）的最佳组合。在Aim 2中，我们将在药代动力学和行为研究中测试这些mcv中的最佳mcv，这些mcv旨在选择减少（+）冰毒进入大脑的渗透，减少或阻止药物自我给药而不会对戒断效应产生不利影响的mcv。在目标3中，将通过监测一般动物健康、测量血液化学物质以及在慢性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，基于目标1-3中收集的数据集的数据监测程序将与行业合作伙伴InterveXion Therapeutics一起开发和制定，以最大限度地提高获得FDA批准的可能性。将MCV候选药物提交给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通过临床测试（包括IND申请）促进快速过渡。实现我们的目标将通过阻止或减少其影响来解决（+）冰毒依赖的主要公共卫生问题，即使在酗酒和复发的挑战下也是如此。

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.