First Human Studies of a Chimeric Anti-Methamphetamine Monoclonal Antibody

描述(申请人提供)：甲基苯丙胺(冰毒)滥用在美国和世界造成严重的医疗、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的抗冰毒单抗(MAb)，可以选择性地快速结合血液中的冰毒，并防止它进入导致成瘾的大脑。这种以抗体为基础的药物，命名为ch-mAb7F9，已经被改造成一种人-鼠嵌合形式(Kd=9 NM)，对人类使用应该是安全的。研究人员认为，抗冰毒单抗Ab7F9将通过提供第一种药物来改变成瘾的临床治疗，这种药物可以长时间减少冰毒的增强特性。与使用冰毒相关的再犯罪率很高。通过使用一种长效抗体拮抗剂来提供24小时不受冰毒影响的保护，患者将不太容易再次使用冰毒，从而显著提高成功康复的机会。抗药物单抗药物在成瘾治疗方面具有重大优势，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-mAb7F9将在食品和药物管理局(FDA)批准的试验中进行人体安全性测试。一支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)通过获得FDA的批准，执行既定的监管策略，以进行ch-mAb7F9在人体上的1a阶段安全性试验，并完成ch-mAb7F9与冰毒相互作用的1b阶段研究的开发计划；2)完成支持1a阶段研究所需的分析和制造过程；以及3)在首个人体试验中确定ch-mAb7F9在人体的安全性和药代动力学。CH-mAb7F9正在生产中，将在为本提案提供资金时制定供管理之用。此外，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成功的抗苯环利定成瘾单抗的IND前会议进行了验证。这项安全性研究将对确定有效的人体剂量方案至关重要，以用于后续的1b期联合应用ch-mAb7F9和冰毒的安全性交互研究，以及ch-mAb7F9的2期疗效试验。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调整计划结合使用，以显著改善患者的结果。

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.