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

治疗芬太尼过量的单克隆抗体的工艺开发、生产和临床前评估

基本信息

批准号：
10269936
负责人：
Paul T Bremer
金额：
$ 102.26万
依托单位：
CESSATION THERAPEUTICS, LLC
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-30 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10269936
关键词：
Affinity Animal Model Antibodies Attenuated Behavior Behavioral Binding Biological Assay Canis familiaris Carbohydrates Cell Line Cells Clinic Clinical Clinical Trials Consult Contracts Data Development Dose Drug Kinetics Engineering Evolution Fentanyl Formulation Frequencies Generations Grant Half-Life Heroin Human Intervention Intoxication Investigational Drugs Investigational New Drug Application Lead Macaca mulatta Maximum Tolerated Dose Methods Monoclonal Antibodies Mus Naloxone Neuraxis Opioid Opioid Antagonist Overdose Pharmaceutical Preparations Pharmacologic Substance Pharmacopoeias Phase Plethysmography Poison Process Property Proteomics Protocols documentation Public Health Quality Control Rattus Reference Standards Research Rodent Running Safety Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization Stream Structure Suboxone Sum Testing Therapeutic Therapeutic Monoclonal Antibodies Toxic effect Toxicology Treatment Efficacy United States Ventilatory Depression Viral analog analytical method animal rule base cGMP production cardiovascular effects carfentanil cell bank cross reactivity design drug distribution drug production efficacy study efficacy testing experience fentanyl overdose human monoclonal antibodies illicit opioid immunogenicity improved manufacturing process medication safety meetings method development murine monoclonal antibody nonhuman primate novel strategies opioid epidemic opioid overdose opioid use disorder overdose death preclinical development preclinical efficacy preclinical evaluation prevent quality assurance respiratory response safety testing stability testing stable cell line standard of care success synthetic opioid technology development

项目摘要

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.

抽象的。阿片类药物使用障碍（OUD）是美国的一个重大公共卫生问题。过去十年阿片类药物流行病的迅速演变，其特点是意外过量用药激增涉及合成阿片类药物（例如芬太尼）的死亡人数激增的一个重要原因是频率的增加。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”的现行标准。阿片类药物过量的护理方法是使用阿片类药物拮抗剂纳洛酮进行治疗，但其效果要差得多由于芬太尼的高效力和纳洛酮的半衰期短，因此在对抗芬太尼时，作为一种新颖的方法，针对芬太尼的治疗性单克隆抗体 (mAb) 旨在逆转药代动力学将药物分布到中枢神经系统之外，避免服用过量并减弱阿片类药物引起的 TSRI 的 Janda 小组最近披露了鼠类单克隆抗体的产生和使用。最近，我们能够逆转芬太尼诱导的行为并防止小鼠过量致死。生成的人单克隆抗体对芬太尼具有高亲和力，与其类似物具有广泛的交叉反应性，可忽略不计我们的先导单克隆抗体与结构无关的药物（例如丁丙诺啡和纳洛酮）的结合可以逆转。芬太尼对啮齿动物和恒河猴的镇痛作用，并显示出持续的作用此外，mAb 还可以拯救卡芬太尼诱导的小鼠。呼吸抑制与纳洛酮具有相似的功效，但效果更持久。为了提高制造的稳定性，我们与 Selexis SA 签订了合同，生产根据我们资助的目标，Selexis SA 的合作伙伴 KBI Biopharma 将承担以下任务：工艺开发和 GMP 制造，建立制造工艺、质量保证协议我们抗体的后续生产将使 GLP 毒理学研究成为可能。在大鼠和狗中，最终进行 I/IIa 期临床试验，该材料也将用于最终的阿片类药物诱导。对小鼠和非人类灵长类动物进行呼吸抑制研究，以确认最终药物的治疗效果总之，这些活动将使我们能够为我们的单克隆抗体申请新药研究申请。 FDA 的候选人。