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

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

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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。在美国，阿片类药物使用障碍（OUD）是一个重大的公共卫生问题。特别令人不安的是在过去十年内阿片类药物流行的快速演变，其特征是无意间过量激增涉及合成阿片类药物的死亡，例如芬太尼。这次激增的大贡献是增加频率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”。当前标准阿片类药物过量的护理是用阿片类拮抗剂纳洛酮治疗由于芬太尼的高效力和纳洛酮的半衰期而与芬太尼作战时。作为一种新颖的方法，针对芬太尼的治疗单克隆抗体（mAb）已设计为逆转药代动力学将药物从中枢神经系统中分配，避免过量并衰减阿片类药物诱导的呼吸抑郁。 TSRI的Janda Group最近披露了鼠mab的一代和使用能够逆转芬太尼诱导的行为并防止小鼠的过量致死性。最近，我们有具有高亲和力的芬太尼的人物mab，对其对其类似物的交叉反应性宽广可忽略不计与结构无关的药物（如丁丙诺啡和纳洛酮）结合。我们的铅mab可以逆转芬太尼在啮齿动物和恒河猕猴中的抗震荡作用，并显示了作用持续时间超过2周的非人类隐私。此外，mab可以从卡芬太尼引起的呼吸道抑郁症具有与纳洛酮相似的呼吸抑郁症，但效果更耐用。跟随我们重新设计为增强制造稳定性的努力，我们与Selexis SA签约，生产稳定的单元线。在我们的赠款的目的下过程开发和GMP制造业以建立制造过程，质量保证协议和我们抗体的稳定性概况。随后的CGMP材料的生产将使GLP毒理学研究在大鼠和狗中，最终进行I/IIA期临床试验。该材料也将用于最终阿片类药物诱导的小鼠和非人类素数的呼吸抑郁研究确认最终药物的治疗效率产品。总而言之，这些活动将使我们能够为我们的mab提出投资新药申请与FDA的候选人。