Development of Plant Derived Antibodies for Drugs Abuse

描述(由申请人提供)： 这一第一阶段/第二阶段STTR联合项目的目标是验证这样一个假设，即抗药单抗是治疗与苯环利定(PCP)滥用相关的医学问题的安全有效的方法。目前还没有治疗由急性或慢性滥用五氯苯酚引起的医疗问题的特效药。因此，迫切需要能够预防或减少PCP影响的长效药物，以及患者日常依从性的需要。我们推测，基于抗体的药物(在该STTR的第一阶段开发和生产)具有极其良好的药代动力学特性和独特的作用机制，可能为治疗五氯苯酚滥用提供新的希望。为该项目设计的药物是一种在植物中生产的嵌合单抗，它是由抗PCP鼠单抗的抗原结合可变区和人IgG2抗体的恒定区改造而成的。这种名为ch-mAb6B5的新药将结合已证实的鼠抗PCP单抗的有效性和人类单抗的安全性。该STTR的第一阶段应用集中在利用烟草植物的重组植物表达和制造系统中表达该抗体。该系统已经成功地将产品交付给临床进行人体测试，并已经存在强大的商业化制造系统。通过在表达和制造中使用这一新范式，该STTR的目标是为药物滥用治疗提供安全、有效和成本效益高的治疗方法。这种表达、制造和临床工作的结合需要证实这种方法的有效性。由于药物滥用的增加，对保健的长期影响的可能性可能非常大，并将成为公众的负担。在这一领域，可用的疗法很少，这些类型的行业/学术联盟对于推动这些疗法是必要的。 这一第二阶段STTR项目的目标是验证抗药物单抗是治疗与苯环利定(PCP)滥用相关的医学问题的安全有效疗法这一假设。目前还没有治疗由急性或慢性滥用五氯苯酚引起的医疗问题的特效药。因此，迫切需要能够预防或减少PCP影响的长效药物，以及患者日常依从性的需要。我们推测，基于抗体的药物(在该STTR的第一阶段开发和生产)具有极其良好的药代动力学特性和独特的作用机制，可能为治疗五氯苯酚滥用提供新的希望。为该项目设计的药物是一种在植物中生产的嵌合单抗，它是由抗PCP鼠单抗的抗原结合可变区和人IgG2抗体的恒定区改造而成的。这种名为ch-mAb6B5的新药将结合已证实的鼠抗PCP单抗的有效性和人类单抗的安全性。在这个第二阶段的STTR项目中，ch-mAb6B5将在人体临床试验中进行测试，以确定它在治疗五氯苯酚滥用方面是否安全有效。在这些研究中，将使用自愿的人类五氯苯酚滥用者的安全性和药代动力学测量来确定ch-mAb6B5的安全性、给药策略和生物剂量。然后，将在一组相似的患者中确定chmAb6B5的疗效和作用时间，这些患者正在接受门诊认知行为治疗，以治疗五氯苯酚滥用。从这些第一阶段和第二阶段临床试验中获得的客观知识将用于确定药物的安全性以及药物可能有效和有益的临床情景(例如，慢性滥用五氯苯酚)。

DESCRIPTION (provided by applicant): The goal of this combination Phase I / Phase II STTR project is to test the hypothesis that anti-drug monoclonal antibodies are a safe and effective therapy for the medical problems associated with phencyclidine (PCP) abuse. There are currently no specific medications for treating the medical problems caused by acute or chronic PCP abuse. Thus, long-lasting medications that could prevent or minimize PCP effects, and the need for day-to-day patient compliance are sorely needed. We hypothesize that antibody-based medications (developed and produced in Phase I of this STTR), with their extremely favorable pharmacokinetic properties and unique mechanisms of action might provide new hope as an innovative and novel medication for treating PCP abuse. The medication designed for this project is a chimeric monoclonal antibody produced in plants, which was engineered from the antigen binding variable regions of an anti-PCP mouse monoclonal antibody and the constant regions of a human IgG2 antibody. This new medication, called ch-mAb6B5, will have a combination of the proven effectiveness of the mouse anti-PCP monoclonal antibody combined with the safety of a human monoclonal antibody. The Phase I application of this STTR focuses on the expression of this antibody in a recombinant, plant based expression and manufacturing system using tobacco plants. This system has already successfully delivered products to the clinic for human testing and a strong commercialized manufacturing system already exists. By using this new paradigm in expression and manufacturing, the goal of this STTR is to provide safe, efficacious and cost effective therapies for drug abuse treatment. This combined expression, manufacturing and clinical effort is needed to confirm the utility of this approach. The potential for long term impact on health care due to increase in drug abuse could be very large and will be a public burden. Very few therapies are available in this area and these types of industry/academic consortia are necessary to bring these treatments forward. The goal of this Phase II STTR project is to test the hypothesis that anti-drug monoclonal antibodies are a safe and effective therapy for the medical problems associated with phencyclidine (PCP) abuse. There are currently no specific medications for treating the medical problems caused by acute or chronic PCP abuse. Thus, long-lasting medications that could prevent or minimize PCP effects, and the need for day-to-day patient compliance are sorely needed. We hypothesize that antibody-based medications (developed and produced in Phase I of this STTR), with their extremely favorable pharmacokinetic properties and unique mechanisms of action might provide new hope as an innovative and novel medication for treating PCP abuse. The medication designed for this project is a chimeric monoclonal antibody produced in plants, which was engineered from the antigen binding variable regions of an anti-PCP mouse monoclonal antibody and the constant regions of a human IgG2 antibody. This new medication, called ch-mAb6B5, will have a combination of the proven effectiveness of the mouse anti-PCP monoclonal antibody combined with the safety of a human monoclonal antibody. During this Phase II STTR project, ch-mAb6B5 will be tested in human clinical trials to determine if it is safe and effective in the treatment of PCP abuse. In these studies, safety and pharmacokinetic measurements in volunteer human PCP abusers will be used to determine the safety profile, dosing strategy, and biological dose of ch-mAb6B5. The efficacy and duration of action of chmAb6B5 will then be determined in a similar group of patients undergoing outpatient cognitive-behavioral therapy for their PCP abuse. The objective knowledge gained from these Phase I and II clinical trials will be used to determine safety of the medications and the clinical scenarios (e.g., chronic PCP abuse) in which the medications could be efficacious and beneficial.