Monoclonal antibodies (mAbs) and vaccines have been proposed as medical countermeasures to treat opioid use disorder (OUD) and prevent opioid overdose. In contrast to current pharmacotherapies (e.g., methadone, buprenorphine, naltrexone, and naloxone) for OUD and overdose, which target brain opioid receptors, mAbs and vaccine-generated polyclonal antibodies sequester the target opioid in the serum and reduce drug distribution to the brain. Furthermore, mAbs offer several potential clinical benefits over approved medications, such as longer serum half-life, higher selectivity, reduced side effects, and no abuse liability. Using magnetic enrichment to isolate opioid-specific B cell lymphocytes prior to fusion with myeloma partners, this study identified a series of murine hybridoma cell lines expressing mAbs with high affinity for opioids of clinical interest, including oxycodone, heroin and its active metabolites, and fentanyl. In mice, passive immunization with lead mAbs against oxycodone, heroin, and fentanyl reduced drug-induced antinociception and the distribution of the target opioid to the brain. In mice and rats, mAb pretreatment reduced fentanyl-induced respiratory depression and bradycardia, two risk factors for opioid-related overdose fatality. Overall, these results support use of mAbs to counteract toxic effects of opioids and other chemical threats. SIGNIFICANCE STATEMENT The incidence of fatal overdoses due to the widespread access to heroin, prescription opioids, and fentanyl suggests that current Food and Drug Administration–approved countermeasures are not sufficient to mitigate the opioid epidemic. Monoclonal antibodies (mAbs) may provide acute protection from overdose by binding to circulating opioids in serum. Use of mAbs prophylactically, or after exposure in combination with naloxone, may reduce hospitalization and increase survival.
|Number of pages
|Journal of Pharmacology and Experimental Therapeutics
|Published - Dec 2020
Bibliographical noteFunding Information:
This work was supported by the National Institute on Drug Abuse, National Institute of Allergy and Infectious Diseases, and the Office of The Director of the National Institutes of Health under CounterACT Administrative Supplement to award number [U01DA038876] and under award number [U01DA051658] (to M.P.); and by the National Institutes of Health under [T32DA007097] (to C.B.) and [T32DA037183] (to A.H.K.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Dynamic light scattering analysis was conducted in the Minnesota Nano Center, which is supported by the National Science Foundation through the National Nano Coordinated Infrastructure Network (NNCI) [Award Number ECCS-1542202]. Disclosures of interest: MP and CB are inventors of PCT application “Anti-opioid compounds and methods of making and using same." All other authors have no conflicts of interest. https://doi.org/10.1124/jpet.120.000124. s This article has supplemental material available at jpet.aspetjournals.org.
Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics.