First Human Studies of a Chimeric Anti-Methamphetamine Monoclonal Antibody

描述（由申请人提供）：甲基苯丙胺（METH）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，迄今为止，没有药物被批准用于治疗METH成瘾。该项目的可实现目标是在人类中首次研究一种新药，一种新型抗METH单克隆抗体（mAb），可以选择性地快速结合血液中的METH，并防止其进入大脑，从而导致成瘾。这种基于抗体的药物，命名为ch-mAb 7 F9，已经被设计成人类-小鼠嵌合形式（METH的KD = 9 nM），对人类使用应该是安全的。研究人员认为，抗METH ch-mAb 7 F9将通过提供第一种可以长时间降低METH增强特性的药物来改变成瘾的临床治疗。与使用甲氧苯丙胺有关的累犯率很高。通过使用长效抗体拮抗剂提供全天候保护，使患者不受METH作用的影响，患者将不太容易复发METH使用，从而显着提高成功恢复的机会。抗药物mAb药物对于成瘾治疗具有主要优势，因为即使在免疫受损的患者中也可以容易地实现稳态浓度和精确控制剂量，并且因为它们不会与其他药物相互作用。对于研究和测试计划，ch-mAb 7 F9将在美国食品和药物管理局（FDA）批准的试验中进行人体安全性测试。一个经验丰富、跨学科的学术和行业团队将实现以下具体目标：1）通过获得FDA批准执行既定的监管策略，以进行ch-mAb 7 F9在人体中的1a期安全性试验，并完成ch-mAb 7 F9与METH相互作用的1b期研究的开发计划; 2）完成支持1a期研究所需的分析和制造过程;和3）在首次人体研究中确定ch-mAb 7 F9在人体中的安全性和药代动力学。Ch-mAb 7 F9正在生产中，并将在本提案资助时配制用于给药。此外，成功的研究性新药申请所需的生产和检测过程已经通过之前成功的IND前会议进行了验证，用于类似的抗苯环利定成瘾mAb。该安全性研究对于确定有效的人类给药方案以用于ch-mAb 7 F9与METH组合的安全性的后续Ib期相互作用研究和ch-mAb 7 F9的II期功效试验将是至关重要的。治疗学的愿景是，这种可用于启动和继续药物治疗的药物将与高质量的行为矫正计划结合使用，以显着改善患者的预后。

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.