PRE-CLINICAL ANIMAL TESTING

该项目中提出的对大鼠的研究将建立以下证据： 概念，并将有助于选择人源抗可卡因的单抗 最有希望最终进展到阶段的抗体 1人体临床试验。将用于 确定领先候选人将是人类单抗可卡因 在最低浓度下消除自身抗体的抗体 由大鼠注射先前加强剂量的可卡因。一个 关于临床需要的抗体剂量的关键问题 有效的将通过这个项目来解决。银杏叶提取物的临床疗效观察 被动免疫疗法被认为是由于抗体诱导的 减少进入大脑的可卡因。基于以下条件的计算 关于免疫治疗作用机制的假说表明 预期的抗可卡因单抗的性质和剂量 临床上应该是有效的。然而，之前发表的一项研究 报道称，一种剂量低10倍的抗可卡因单抗 在可卡因成瘾动物模型上是有效的。剂量为 免疫治疗所需的单抗将决定免疫治疗的剂量 将生产抗体，从而决定成本和 整个SPIRCAP计划的时间框架。市面上可以买到的鼠标 鲍尔博士对抗可卡因的单抗进行了表征 (项目1)。该抗体对可卡因具有较高的亲和力和特异性。 并被预测为代表人类单抗的标准 可卡因抗体的疗效将进行比较。作为人类的单克隆 具有适当特异性和亲和力的抗可卡因抗体是 从项目1产生的领先候选抗体将经历 在大鼠身上进行测试以确定：1)人的药代动力学 抗可卡因的单抗。2)所需的抗体剂量 废除可卡因的自我给药，并减轻 可卡因对运动行为和刻板印象的影响。3)药代动力学研究 可卡因和可卡因进入大脑的情况 抗体。抗体水平和可卡因血浆水平的测定 浓度将由临床化学核心(科学)提供 核心2)。药代动力学数据将在#年生成和分析 与药代动力学小组合作(科学核心4)。这些 数据将决定所需的抗体数量和哪种抗体 将在扩大生产和良好制造方面处于领先地位 实践(GMP)认证设施，然后进行动物毒性测试 由NIDA药物开发司赞助。

The studies in rats proposed in this project will establish proof-of- concept and will aid in the selection of the human monoclonal anti-cocaine antibody which is the most promising for the eventual advancement to phase 1 clinical trials in human subjects. The criteria which will be used to define the leading candidate will be that human monoclonal anti-cocaine antibody which at the lowest concentration abolishes the self- administration by rats of a previously reinforcing dose of cocaine. A pivotal issue regarding the dose of antibody required to be clinically effective will be addressed by this project. The clinical effectiveness of passive immunotherapy is hypothesized to be due to the antibody-induced reduction of cocaine entry into the brain. Calculations based on hypothesis of the mechanism of action of immunotherapy indicate the expected properties and doses of monoclonal anti-cocaine antibodies which should be clinically effective. However, a previously published study reported that 10 fold lower doses of a monoclonal anti-cocaine antibody were effective in animal models of cocaine addiction. The dose of monoclonal antibody required for immunotherapy will determine how much antibody will be manufactured and thereby will determine the cost and the time frame of the entire SPIRCAP program. A commercially available mouse monoclonal anti-cocaine antibody has been characterized by Dr. Ball (Project 1). This antibody has high affinity and specificity for cocaine and is predicted to represent the standard by which human monoclonal anti- cocaine antibodies will be compared for efficacy. As human monoclonal anti-cocaine antibodies of appropriate specificity and affinity are generated from project 1, the leading candidate antibodies will undergo testing in rats to determine: 1) The pharmacokinetics of the human monoclonal anti-cocaine antibodies. 2) The dose of antibody required to abolish the self-administration of cocaine and to attenuate the effects of cocaine on locomotor behavior and stereotype. 3) The pharmacokinetics of cocaine and the entry of cocaine into the brain in the presence of the antibody. Measurements of antibody levels and cocaine plasma concentrations will be provided by the clinical chemistry Core (Scientific Core 2). The pharmacokinetic data will be generated and analyzed in collaboration with the pharmacokinetics group (Scientific Core 4). These data will determine the quantity of antibody required and which antibody will be advanced for scale-up production and in good manufacturing practice (GMP) certified facility and then to animal toxicity testing under the auspices of the Medications Development Division of NIDA.