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用于治疗对（+）-甲基苯丙胺（（+）METH）样药物的依赖。为了满足这一需求，这些临床前研究将促进新的（+）METH-缀合物疫苗（MCV）的医学发现和开发，以帮助患者停止使用（+）METH-样药物。这些重要的新MCV预计将阻断或减少（+）METH对患者的影响。医学上有效的MCV的发现将通过我们设计用于制造和测试MCV的综合性多学科研究计划来完成。在先前的临床前研究中，我们的小组表明：1）针对MCV产生的抗体的滴度和亲和力不受连续（+）METH使用的不利影响，2）单个MCV可用于产生针对（+）METH和（+）-安非他明（（+）AMP）的高亲和力抗体，和3）由新MCV产生的抗（+）METH单克隆抗体可用于降低脑（+）METH浓度和减少（+）METH或（+）AMP自身给药。这些成就大大增强了我们的科学视野，明确了项目的研究目标，并确定了用于主动免疫的首选MCV候选者。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MCV，并将其制成与人体相容的制剂，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，并仔细优化实现抗体滴度、亲和力、反应特异性和作用持续时间的最佳组合所需的免疫学条件（即，治疗效果）。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MCV，这些研究旨在选择减少（+）METH渗透到大脑中并减少或阻断药物自我给药而不会对戒断作用产生不利影响的MCV。在目标3中，将通过在慢性疫苗接种期间和之后监测一般动物健康、测量血液化学和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一起开发并实施基于目标1-3中收集的数据集的数据监测计划，以最大限度地提高FDA批准的可能性。将MCV候选人提交给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计划方法将通过临床试验（包括IND申请）促进快速过渡。实现我们的目标将解决主要的公共卫生问题（+）METH的依赖，通过阻断或减少其影响，即使在狂欢和复发的挑战。

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.