Process Development, Manufacturing, and Preclinical Evaluation of a Monoclonal Antibody for Fentanyl Overdose

抽象的。 阿片类药物使用障碍（OUD）是美国一个重要的公共卫生问题。特别令人不安的是， 在过去十年中，阿片类药物流行病迅速演变，其特征是无意过量用药激增 涉及合成阿片类药物的死亡，如芬太尼。这种激增的一个主要原因是频率增加 海洛因和其他非法阿片类药物被芬太尼及其类似物污染或“切割”。现行标准 阿片类药物过量的治疗方法是使用阿片类药物拮抗剂纳洛酮治疗， 由于芬太尼的高效力和纳洛酮的短半衰期，作为一种新颖的方法， 已经设计了抗芬太尼的治疗性单克隆抗体（mAbs）来逆转药物动力学 药物在中枢神经系统外的分布，避免过量和减弱阿片类药物诱导的 呼吸抑制TSRI的Janda小组最近公开了鼠mAb的产生和使用， 能够逆转芬太尼诱导的行为并防止小鼠过量致死。最近我们 产生了对芬太尼具有高亲和力的人单克隆抗体，并与其类似物具有广泛的交叉反应性， 与结构无关的药物如丁丙诺啡和纳洛酮结合。我们的单抗可以逆转 芬太尼在啮齿类动物和恒河猴中的抗伤害作用， 超过两周的非人类灵长类动物。此外，mAb可以从卡芬太尼诱导的小鼠中拯救小鼠。 呼吸抑制，疗效与纳洛酮相似，但效果更持久。遵循我们 为了提高生产的稳定性，我们与Selexis SA签订了合同， 稳定细胞系根据我们的资助目标，Selexis SA的合作伙伴KBI Bioproma将承担以下任务： 工艺开发和GMP生产，以建立生产工艺、质量保证方案 和抗体的稳定性cGMP材料的后续生产将使GLP毒理学研究成为可能 在大鼠和狗中进行，并最终进行I/IIa期临床试验。这种材料也将用于最终的阿片类药物诱导 在小鼠和非人灵长类动物中进行呼吸抑制研究，以确认最终药物的疗效 产品总之，这些活动将使我们能够为mAb提交研究性新药申请 FDA的候选人

Abstract. Opioid use disorder (OUD) is a significant public health problem in the United States. Particularly troubling is the rapid evolution of an opioid epidemic within the past decade, characterized by a surge in unintentional overdose deaths involving synthetic opioids, such as fentanyl. A large contributor to this surge is the increased frequency of heroin and other illicit opioid being contaminated or “cut” with fentanyl and its analogs. The current standard of care for opioid overdose is treatment with opioid antagonist naloxone, which is considerably less effective when combating fentanyl due to fentanyl’s high potency and the short half-life of naloxone. As a novel approach, therapeutic monoclonal antibodies (mAbs) against fentanyl have been designed to reverse the pharmacokinetic distribution of the drug out of the central nervous system, averting overdose and attenuating opioid-induced respiratory depression. The Janda group at TSRI recently disclosed the generation and use of murine mAbs that were able to reverse fentanyl-induced behavior and prevent overdose lethality in mice. Recently, we have generated human mAbs with high-affinity for fentanyl and broad cross-reactivity to its analogs with negligible binding to structurally-unrelated medications such as buprenorphine and naloxone. Our lead mAb can reverse the antinociceptive effects of fentanyl in rodents and rhesus macaques and has shown a duration of action in non-human primates of over 2 weeks. Furthermore, the mAb can rescue mice from carfentanil-induced respiratory depression with similar efficacy to naloxone, but with a much more durable effect. Following our reengineering efforts to enhance stability for manufacturing, we have contracted with Selexis SA to produce a stable cell line. Under the aims of our grant, KBI Biopharma, a partner of Selexis SA, will undertake tasks in process development and GMP manufacturing to establish a manufacturing process, quality assurance protocol and stability profile for our antibody. Subsequent production of cGMP material will enable GLP toxicology studies in rats and dogs and eventually a Phase I/IIa clinical trial. This material will also be used in final opioid-induced respiratory depression studies in mice and non-human primates to confirm therapeutic efficacy of final drug product. In sum, these activities will enable us to file for an investigational new drug application for our mAb candidate with the FDA.