Citation

Baehr CA, Wu MM, Pandit SG, Arias-Umana J, AuCoin D, Pravetoni M. J. Pharmacol. Exp. Ther. 2022; ePub(ePub): ePub.

Copyright

(Copyright © 2022, American Society for Pharmacology and Experimental Therapeutics)

DOI

10.1124/jpet.121.001048

PMID

35153198

Abstract

The incidence of fatal drug overdoses in the United States is an alarming public health threat that has been exacerbated by the COVID-19 pandemic, resulting in over 100,000 deaths between April 2020 and April 2021. A significant portion of this is attributable to widespread access to fentanyl and other synthetic opioids, alone or in combination with heroin or psychostimulants such as cocaine or methamphetamine. Monoclonal antibodies (mAb) offer prophylactic and therapeutic interventions against opioid overdose by binding opioids in serum, reducing distribution of drug to the brain and other organs. Here, we investigated the efficacy of a lead anti-fentanyl mAb, clone HY6-F9, in reversal and prevention of fentanyl-induced toxicity compared to the opioid receptor antagonist naloxone (NLX) in rats. In post-exposure models, rats were challenged with fentanyl, followed by HY6-F9, NLX, or both. HY6-F9 reversed fentanyl-induced antinociception, respiratory depression, and bradycardia, and rats retained protection against additional challenges for at least 1 week. Although intravenous NLX reversed fentanyl-induced respiratory depression more rapidly than mAb alone, kinetics of reversal by intravenous mAb were similar to subcutaneous NLX. Co-administration of mAb and NLX provided greater protection than individual treatments against high doses of fentanyl. Prophylactic administration of mAb reduced the ED(50) of NLX approximately 2-fold against 2.25 mg/kg fentanyl. Finally, mAb sequestered fentanyl and its metabolite norfentanyl in serum, and reduced brain concentrations of fentanyl. These results support the translation of mAb as medical interventions alone or in combination with NLX to prevent and reverse fentanyl-related overdose. Significance Statement Fentanyl-related overdoses have increased dramatically in the US and worldwide. Currently, approved pharmacotherapies for treatment of opioid use disorder and reversal of overdose are not sufficient to curb the incidence of opioid-related deaths. Additionally, fentanyl and its potent analogs present a potential risk from use in deliberate poisoning or chemical attacks. This study demonstrates the use of mAb as a countermeasure to fentanyl-induced toxicity in pre- and post-exposure scenarios, supporting their use in combination with the opioid antagonist NLX.

Language: en

Keywords

opioids; Antibody; immunotherapy; monoclonal antibody