IND-Enabling Pre-Clinical Studies to Accelerate the Clinical Development of a Humanized Anti-Cocaine Monoclonal Antibody

项目总结/摘要 我们的多学科翻译研究团队已经产生并开发了一种人源化单克隆抗体， 对可卡因具有高亲和力（Kd = 4 nM）并对可卡因的非活性代谢物具有特异性的抗体（mAb） 可卡因该重组mAb是一种独特的新分子实体，临床前名称为h2 E2。我们 已经表明，h2 E2显着降低大脑可卡因浓度在小鼠和大鼠。此外，H2 E2 在复发的大鼠模型中拮抗可卡因的作用。这些研究预测h2 e2将是一种有效的 治疗人类可卡因滥用者我们的行业合作伙伴Catalent Inc.建立主细胞库 (MCB)并且可以通过良好生产规范（GMP）生产工业量的纯化H2 E2。 来自该MCB的h2 E2在体外与大量人体组织无交叉反应性。在动物 在毒理学研究中，h2 E2在高达360 mg/kg的静脉内剂量下没有显示毒性。这些IND- 使得GLP研究预测h2 E2用于人类是安全的。在一次IND前会议上，FDA 同意h2 E2可以进行首次人体临床试验，以确定安全性，并测量 在健康志愿者中的药代动力学。然而，FDA将允许剂量限制为40 mg/kg， 而不是我们建议的120 mg/kg。为了继续进行120 mg/kg剂量的人体试验， 在动物中，需要以10倍高的剂量（1，200 mg/kg）完成。FDA还要求进行研究， 在动物中维持高的h2 E2水平，需要每周间隔重复给药一个月，持续时间 接近人体单剂量的预测暴露时间。这些临床前研究将需要 h2 E2制剂的浓度比人体临床试验所需的浓度高五倍。此外该 FDA要求表征h2 E2和可卡因的外周药理学相互作用。因此，我们认为， 我们将测量h2 E2对可卡因诱导的大鼠心血管功能变化的影响。此外，本发明还 我们将确定可卡因的毒理学和药代动力学在存在和不存在h2 E2的情况下， 自我管理作为慢性可卡因滥用的模型。顺利完成研究，以评估 h2 E2在可卡因存在下的安全性，以及重复给药后，将加速临床 通过实现所需的一系列Ia期和Ib期安全性临床试验来开发h2 E2。这将 导致II期临床试验，以确定h2 E2是否可以降低患者复发的可能性 可卡因使用障碍重要的是，临床试验中的疗效是由可卡因的减少来定义的。 消费量，这是衡量可卡因和/或苯甲酰芽子碱（BE）在尿液中的浓度。我们有 最近报道，h2 E2显著降低大鼠中可卡因和BE的尿排泄。是 建议在h2 E2存在下测定可卡因的处置、代谢和排泄， 了解应如何适当衡量可卡因消费量。成功完成这些 临床开发里程碑将增加h2 E2的价值并促进商业化。

PROJECT SUMMARY/ABSTRACT Our multidisciplinary translational research team has generated and developed a humanized monoclonal antibody (mAb) with a high affinity (Kd = 4 nM) for cocaine and specificity over the inactive metabolites of cocaine. This recombinant mAb is a unique new molecular entity with a preclinical designation of h2E2. We have shown that h2E2 dramatically lowers brain cocaine concentrations in mice and rats. Furthermore, h2E2 antagonizes the effect of cocaine in a rat model of relapse. These studies predict h2E2 will be an effective treatment for human cocaine abusers. Our industry collaborator, Catalent Inc., established a Master Cell Bank (MCB) and can produce industrial quantities of purified h2E2 through good manufacturing practices (GMP). The h2E2 from this MCB shows no cross-reactivity in vitro with an extensive panel of human tissues. In animal toxicology studies, h2E2 gave no indications of toxicity at intravenous doses up to 360 mg/kg. These IND- enabling GLP studies predict that h2E2 will be safe for use in humans. During a pre-IND meeting, the FDA agreed that h2E2 could proceed to first-in-human clinical trials to establish safety, and measure the pharmacokinetics, in healthy human volunteers. However, the FDA limited the allowed dose to 40 mg/kg in humans instead of our proposed 120 mg/kg. To proceed to the 120 mg/kg dose in humans, additional studies in animals need to be completed at a 10-fold higher dose (1,200 mg/kg). The FDA also requested studies that maintain high h2E2 levels in animals, requiring repeated dosing at weekly intervals for a month, a duration approximating the predicted exposure time of a single dose in humans. These pre-clinical studies will require a formulation of h2E2 five-fold more concentrated than that required for the human clinical trials. In addition, the FDA requested characterization of peripheral pharmacological interactions of h2E2 and cocaine. Therefore, we will measure the effect of h2E2 on cocaine-induced changes in cardiovascular function in rats. Additionally, we will determine the toxicology and pharmacokinetics of cocaine in the presence and absence of h2E2 using self-administration as a model of chronic cocaine abuse. The successful completion of the studies to assess the safety of h2E2 in the presence of cocaine, and after repeated administrations, will accelerate the clinical development of h2E2 by enabling the required series of Phase Ia and Phase Ib safety clinical trials. This will lead to a Phase II clinical trial to determine whether h2E2 can decrease the probability of relapse in patients with cocaine use disorder. Importantly, efficacy in clinical trials is defined by reductions in cocaine consumption, which is measured by cocaine and/or benzoylecgonine (BE) concentrations in urine. We have recently reported that h2E2 dramatically decreases the urinary excretion of both cocaine and BE in rats. It is proposed to determine the disposition, metabolism, and excretion of cocaine in the presence of h2E2 to understand how cocaine consumption should be appropriately measured. The successful completion of these clinical development milestones will add value to h2E2 and facilitate commercialization.