First-In-Human Study 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)且对可卡因的非活性代谢物具有特异性的抗体(MAb)。 这种独特的新分子实体(临床前命名，h2E2)由一个人类伽马1(1)重组体组成 链和人/鼠嵌合Lamda()轻链，与 完全是人类的免疫球蛋白1。这种抗可卡因的单抗已经达到或超过了所有必要的临床前开发 作为治疗可卡因使用障碍的里程碑。抗可卡因单抗结合和隔离可卡因 外周循环，我们已经表明，h2E2显著降低了脑部可卡因浓度。 小鼠和大鼠体内。此外，在复发的大鼠模型中，h2E2拮抗可卡因的作用。这些 研究预测了人类可卡因滥用者的疗效。我们的行业合作伙伴Catalent Inc.已经建立了一个 GLP主细胞库(MCB)，具有作为GMP生产平台的选定细胞系 工业大批量纯化重组h2E2。从该MCB中获得的重组h2E2没有交叉反应。 在体外与广泛的人体组织发生反应，并且没有迹象表明在高剂量下有毒性 动物毒理学研究。这些支持IND的GLP研究预测，h2E2在人类身上使用将是安全的。 在与NIDA的协调下，我们已安排在2018年9月初与FDA举行IND前会议 准备提交IND，然后进行第一次人体临床试验，以确定安全性。这个 还将建立h2e2在人体内的药代动力学，并开发任何抗h2e2抗体。 将会受到监控。这些具体目标的成功完成将允许并指导未来的设计 在可卡因存在的情况下评估h2E2安全性的临床试验和重复使用h2e2的安全性 行政部门。然后，临床开发将进入第二阶段临床疗效试验。鉴于其 主要是人体结构，h2e2对患者重复治疗应该是安全的，其预期的缓慢 在人体内清除应该会带来长期疗效。这些临床开发的积极结果 里程碑将增加产品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 cocaine's inactive metabolites. This unique new molecular entity (preclinical designation, h2E2) consists of a human gamma 1 (1) heavy chain and a human/mouse chimeric lamda () light chain and has approximately 95% sequence identity with a fully human IgG1. This anti-cocaine mAb has met or exceeded all the necessary pre-clinical development milestones as a therapeutic to treat cocaine use disorders. Anti-cocaine mAbs bind and sequester cocaine in the peripheral circulation and we have shown that h2E2 dramatically lowers brain cocaine concentrations in mice and in rats. Furthermore, h2E2 antagonizes the effect of cocaine in a rat model of relapse. These studies predict efficacy in human cocaine abusers. Our industry collaborator, Catalent Inc., has established a GLP Master Cell Bank (MCB) with a selected cell line that serves as the platform for the GMP manufacture of industrial quantities of purified recombinant h2E2. The recombinant h2E2 from this MCB shows no cross- reactivity in vitro with an extensive panel of human tissues, and no indications of toxicity at high doses in animal toxicology studies. These IND-enabling GLP studies predict that h2E2 will be safe for use in humans. In coordination with NIDA we have scheduled a pre-IND meeting with the FDA for early September of 2018 in preparation for the filing of an IND and then proceeding to first-in-human clinical trials to establish safety. The pharmacokinetics of h2E2 in humans will also be established and the development of any anti-h2E2 antibodies will be monitored. The successful completion of these Specific Aims will permit and inform the design of future clinical trials to assess the safety of h2E2 in the presence of cocaine and the safety of h2E2 after repeated administrations. The clinical development would then proceed to Phase II clinical efficacy trials. Given its mostly human structure, h2E2 should be safe for repeated treatments in patients and its anticipated slow clearance in humans should confer long-term efficacy. Positive outcomes of these clinical development milestones will add value to the product and facilitate commercialization.