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

项目摘要/摘要 我们的多学科翻译研究团队已经产生并开发了人性化的单克隆 对可卡因具有高亲和力(Kd=4 nM)且对非活性代谢物具有特异性的抗体(MAb) 可卡因。这种重组单抗是一种独特的新分子实体，临床前命名为h2E2。我们 研究表明，h2E2显著降低了小鼠和大鼠大脑中的可卡因浓度。此外，h2e2 拮抗可卡因对复吸大鼠模型的影响。这些研究预测h2e2将是一种有效的 人类可卡因滥用者的治疗。我们的行业合作伙伴Catalent Inc.建立了主细胞库 (MCB)，并可通过良好的制造规范(GMP)生产工业批量的精制h2E2。 从该MCB中提取的h2E2在体外与广泛的人体组织没有交叉反应。在动物身上 毒理学研究表明，在静脉注射剂量超过360毫克/公斤时，h2E2没有毒性迹象。这些IND- Enabling GLP研究预测，h2E2在人类身上使用将是安全的。在IND前的一次会议上，FDA 同意h2e2可以进行首个人体临床试验，以确定安全性，并测量 健康人体志愿者的药代动力学。然而，FDA将允许的剂量限制在40毫克/公斤。 而不是我们建议的120毫克/公斤。为了继续人类120毫克/公斤的剂量，更多的研究 在动物体内，需要在高出10倍的剂量(1,200毫克/公斤)下完成。FDA还要求进行以下研究 保持动物体内较高的h2E2水平，需要每周重复给药一个月，持续一段时间 接近预测的人体单次剂量的暴露时间。这些临床前研究将需要 H2e2配方的浓度是人体临床试验所需浓度的五倍。此外， FDA要求描述h2E2和可卡因的外周药理相互作用。因此， 我们将测量h2E2对可卡因诱导的大鼠心血管功能变化的影响。另外， 我们将使用以下方法确定可卡因在存在和不存在h2E2的情况下的毒理学和药代动力学 自我管理是慢性可卡因滥用的典范。顺利完成各项研究，以评估 在可卡因存在的情况下，h2e2的安全性，以及在反复给药后，将加速临床 通过启用所需的一系列Ia期和Ib期安全临床试验来开发h2E2。这将是 导致进行第二期临床试验，以确定h2E2是否可以降低患者复发的可能性 患有可卡因使用障碍。重要的是，临床试验的有效性是由可卡因的减少来定义的 消费量，通过尿液中可卡因和/或苯甲酰ecGonine(BE)浓度来衡量。我们有 最近有报道称，h2E2可显著减少大鼠尿中可卡因和BE的排泄量。它是 建议确定在h2E2存在的情况下可卡因的处置、代谢和排泄，以 了解应该如何适当地衡量可卡因的消费量。这些项目的顺利完成 临床开发里程碑将增加h2E2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.