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

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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.