First Human Studies of a Chimeric Anti-Methamphetamine Monoclonal Antibody

描述（由申请人提供）：甲基苯丙胺（冰毒）滥用在美国和世界范围内造成严重的医疗、社会和经济危害。然而，到目前为止，还没有药物被批准用于治疗冰毒成瘾。该项目的可实现目标是对一种新药进行首次人体研究，这种新药是一种新型抗甲基安非他明单克隆抗体（mAb），可以选择性地快速结合血液中的甲基安非他明，并防止其进入大脑，从而导致成瘾。这种以抗体为基础的药物被命名为ch-mAb7F9，已经被改造成人鼠嵌合形式（甲基安非他明的KD = 9 nM），应该可以安全用于人类。研究人员认为抗甲基安非他明的ch-mAb7F9将通过提供第一种可以长期减少甲基安非他明强化特性的药物来改变成瘾的临床治疗。使用冰毒有很高的再犯率。通过使用长效抗体拮抗剂全天候保护患者免受甲基苯丙胺的影响，患者复发的可能性将大大降低，从而大大提高了成功康复的机会。抗单抗药物在成瘾治疗方面具有主要优势，因为即使在免疫功能低下的患者中，也很容易实现稳定的浓度和精确的剂量控制，而且它们不会与其他药物相互作用。在研究和测试项目中，ch-mAb7F9将在美国食品和药物管理局（FDA）批准的一项试验中进行人体安全性测试。一个经验丰富的跨学科学术和行业团队将实现以下具体目标：1)执行既定的监管策略，获得FDA批准进行ch-mAb7F9在人体中的1a期安全性试验，并完成ch-mAb7F9与冰毒相互作用的1b期研究的开发计划；2)完成支持第1a期研究所需的分析和制造流程；3)在首次人体研究中确定ch-mAb7F9在人体中的安全性和药代动力学。Ch-mAb7F9正在生产中，并将在本提案获得资金时制定用于管理。此外，一个成功的研究性新药申请所需的生产和测试过程已经通过之前一个成功的抗苯环利定成瘾单抗的ind前会议得到了验证。这项安全性研究对于确定ch-mAb7F9与甲基安非他明联合安全性的1b期相互作用研究以及ch-mAb7F9的2期疗效试验的有效人体给药方案至关重要。治疗学的愿景是，这种药物可以用于启动和继续药物治疗，将与高质量的行为矫正项目结合使用，以显著改善患者的治疗效果。

DESCRIPTION (provided by applicant): Methamphetamine (METH) abuse causes serious medical, social, and economic harm in the USA and the world. However, to date, no medications are approved to treat METH addiction. The achievable goal of this project is to perform the first studies in humans of a new medicine, a novel anti-METH monoclonal antibody (mAb) that can selectively and quickly bind METH in the blood and prevent it from entering the brain where it causes addiction. This antibody-based medicine, designated ch-mAb7F9, is already engineered into a human-mouse chimeric form (KD for METH = 9 nM) that should be safe for human use. The investigators think anti-METH ch-mAb7F9 will transform the clinical treatment of addiction by providing the first medication that can reduce METH's reinforcing properties for prolonged periods of time. There is a high rate of recidivism associated with METH use. By using a long-acting antibody antagonist to provide around-the-clock protection from METH effects, patients will be much less vulnerable to relapse to METH use and thereby have significantly improved chances at succeeding with recovery. Anti-drug mAb medications have major advantages for addiction therapy given that steady-state concentrations and precise control of dosing are readily achievable even in immune-compromised patients, and because they will not interact with other medicines. For the research and testing program, ch-mAb7F9 will be tested in humans for safety in a Food and Drug Administration (FDA)-approved trial. A highly experienced, transdisciplinary academic and industry team will accomplish the following Specific Aims: 1) execute an established regulatory strategy by obtaining FDA approval to perform a Phase 1a safety trial of ch-mAb7F9 in humans, and complete the development plan for Phase 1b studies of the interaction of ch-mAb7F9 with METH; 2) complete the analytical and manufacturing processes necessary to support the Phase 1a study; and 3) determine the safety and pharmacokinetics of ch-mAb7F9 in humans in a first-in- human study. Ch-mAb7F9 is in production and will be formulated for administration at the time of funding of this proposal. Furthermore, the production and testing processes required for a successful Investigational New Drug application are already validated through a previous successful pre-IND meeting for a similar anti-phencyclidine addiction mAb. This safety study will be crucial for determining effective human dosing regimens for follow up Phase 1b interaction studies of the safety of ch-mAb7F9 in combination with METH, and Phase 2 efficacy trials of ch-mAb7F9. The therapeutics vision is that this medication, which can be used to initiate and continue pharmacologic treatment, will be used in combination with high quality behavioral modification programs to dramatically improve patient outcomes. PUBLIC HEALTH RELEVANCE: This project is designed to conduct the first studies in humans of an innovative, new antibody medicine designed to block methamphetamine effects while patients undergo the long process of recovery from methamphetamine addiction. In this project, an anti-methamphetamine monoclonal antibody will be tested to determine its safety and its potential for effectiveness. This innovative medication: i) could provide an essential missing component of standard drug-abuse treatment programs; ii) has the potential to reduce the devastating behavioral and societal effects of methamphetamine abuse; and iii) therefore should improve public health.