Preclinical Testing of Antibody Therapy for METH Abuse

这个跨学科项目的目标是促进新药的快速开发，以治疗与(+)-甲基苯丙胺[(+)冰毒]滥用相关的医疗问题。这将通过一个整合良好和高度集中的研究计划来实现，该计划旨在制造和测试基于单抗的治疗冰毒滥用和/或成瘾的方法。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，包括大规模的单抗生产、用于药代动力学研究的免疫化学和LC/MS/MS分析，以及研究结果的综合数据分析。项目2将使用大鼠和猴子的人类药物依赖模型来测试药物在减少(+)冰毒成瘾特性方面的有效性。这些研究将包括对自我管理和药物歧视范例中的抗体进行测试。项目3将确定这些药物在急性和慢性药物使用的疾病模型中的有效性、作用持续时间和安全性。动物模型将跨越一系列人类使用模式，从不频繁使用到危险的(+)冰毒的“狂欢”使用。运动活动和血流动力学效应的测量，以及动物总体健康状况的变化，将被用来确定即使在大量使用(+)冰毒的情况下，药物降低效果的能力。该项目将涉及通过开发先进的农用药物制造技术来最大限度地大规模、低成本地生产抗体的技术。编码抗(+)冰毒抗体的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用级别的单抗。这一多方面计划项目的研究结果将作为这些治疗(+)冰毒依赖和滥用的破坏性后果的重要新药的初步临床前测试。

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.