Preclinical Testing of Antibody Therapy for METH Abuse

这个跨学科项目的目标是促进新药物的快速发展，以治疗与(+)-甲基苯丙胺[（+）冰毒]滥用有关的医学问题。这将通过一个整合良好、高度集中的研究项目来完成，该项目旨在制造和测试针对甲基苯丙胺滥用和/或成瘾的基于单克隆抗体的疗法。项目1（核心单位）将提供强有力的领导，重要的供应和支持服务，包括大规模单克隆抗体生产，免疫化学和药代动力学研究的LC/MS/MS分析，以及研究结果的综合数据分析。项目2将使用人类药物依赖的大鼠和猴子模型来测试药物在减少（+）冰毒成瘾特性方面的有效性。这些研究将包括抗体在自我给药和药物歧视范例中的测试。项目3将确定药物在急性和慢性用药疾病模型中的疗效、作用时间和安全性。三个动物模型将涵盖一系列人类使用模式，从不频繁使用到危险的“暴”使用（+）冰毒。运动活动和血流动力学影响的测量，以及动物总体健康状况的变化，将被用来确定药物减少影响的能力，即使在过量使用（+）冰毒的情况下。该项目将包括通过发展先进的农业医药制造技术，开发最大限度地大规模、低成本生产抗体的技术。编码抗（+）甲基安非他明抗体的DNA将被引入植物中，从而能够以可接受的成本大规模地表达和积累药物级单克隆抗体。这个多方面项目的研究结果将作为这些重要的新药物的初步临床前测试，用于治疗（+）冰毒依赖和滥用的破坏性后果。

The goal of this transdisciplinary program project is to facilitate the rapid development of new medications for the treatment of medical problems associated with (+) -methamphetamine [(+)METH]abuse. This will be accomplished through a well-integrated and highly focused research program, designed to manufacture and test monoclonal antibody-based therapy for METH abuse and/or addiction. Project 1 (the core unit) will provide strong leadership, vital supply and support services that include large scale monoclonal antibody production, immunochemical and LC/MS/MS analysis for pharmacokinetic studies, and integrated data analysis of the research findings. Project 2 will use rat and monkey models of human drug dependencies to test the effectiveness of the medications in reducing the addictive properties of (+)METH. These studies will include testing of the antibodies in self-administration and drug discrimination paradigms. Project 3 will determine the efficacy, duration of action and safety of the medications in disease models of acute and chronic drug use. Thee animal models will span a range of human use patterns from infrequent usages to dangerous "binge" usage of (+)METH. Measures of locomotor activity and hemodynamic effects, along with changes in the general health status of the animals, will be used to determine the ability of the medications to reduce effects even in the presence of binge use of (+)METH. Project will involve developing the technology for maximizing large scale, low cost production of the antibodies through the development of advanced agrimedicine manufacturing technology. DNA that codes for anti-(+)METH antibody will be introduced into plants enabling the expression and accumulation of pharmaceutical grade monoclonal antibodies on a very large scale and at an acceptable cost. The results of the studies in this multifaceted program project will serve as the initial preclinical testing of these important new medications for the treatment of the devastating consequences of the (+)METH dependence and abuse.