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Research ArticleDrug Discovery and Translational Medicine

Pharmacological Profiling of Antifentanyl Monoclonal Antibodies in Combination with Naloxone in Pre- and Postexposure Models of Fentanyl Toxicity

Carly A. Baehr, Mariah M. Wu, Sujata G. Pandit, Jose Arias-Umana, David AuCoin and Marco Pravetoni
Journal of Pharmacology and Experimental Therapeutics May 2022, 381 (2) 129-136; DOI: https://doi.org/10.1124/jpet.121.001048
Carly A. Baehr
Department of Pharmacology, University of Minnesota Medical School, Minneapolis, Minnesota (C.A.B., M.M.W., M.P.); Department of Veterinary Population Medicine, University of Minnesota, Minneapolis, Minnesota (M.M.W.); Reno School of Medicine, University of Nevada, Reno, Nevada (S.G.P., J.A.-U., D.A.); University of Minnesota Center for Immunology, Minneapolis, Minnesota (M.P.); and Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, Washington (M.P.)
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Mariah M. Wu
Department of Pharmacology, University of Minnesota Medical School, Minneapolis, Minnesota (C.A.B., M.M.W., M.P.); Department of Veterinary Population Medicine, University of Minnesota, Minneapolis, Minnesota (M.M.W.); Reno School of Medicine, University of Nevada, Reno, Nevada (S.G.P., J.A.-U., D.A.); University of Minnesota Center for Immunology, Minneapolis, Minnesota (M.P.); and Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, Washington (M.P.)
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Sujata G. Pandit
Department of Pharmacology, University of Minnesota Medical School, Minneapolis, Minnesota (C.A.B., M.M.W., M.P.); Department of Veterinary Population Medicine, University of Minnesota, Minneapolis, Minnesota (M.M.W.); Reno School of Medicine, University of Nevada, Reno, Nevada (S.G.P., J.A.-U., D.A.); University of Minnesota Center for Immunology, Minneapolis, Minnesota (M.P.); and Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, Washington (M.P.)
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Jose Arias-Umana
Department of Pharmacology, University of Minnesota Medical School, Minneapolis, Minnesota (C.A.B., M.M.W., M.P.); Department of Veterinary Population Medicine, University of Minnesota, Minneapolis, Minnesota (M.M.W.); Reno School of Medicine, University of Nevada, Reno, Nevada (S.G.P., J.A.-U., D.A.); University of Minnesota Center for Immunology, Minneapolis, Minnesota (M.P.); and Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, Washington (M.P.)
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David AuCoin
Department of Pharmacology, University of Minnesota Medical School, Minneapolis, Minnesota (C.A.B., M.M.W., M.P.); Department of Veterinary Population Medicine, University of Minnesota, Minneapolis, Minnesota (M.M.W.); Reno School of Medicine, University of Nevada, Reno, Nevada (S.G.P., J.A.-U., D.A.); University of Minnesota Center for Immunology, Minneapolis, Minnesota (M.P.); and Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, Washington (M.P.)
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Marco Pravetoni
Department of Pharmacology, University of Minnesota Medical School, Minneapolis, Minnesota (C.A.B., M.M.W., M.P.); Department of Veterinary Population Medicine, University of Minnesota, Minneapolis, Minnesota (M.M.W.); Reno School of Medicine, University of Nevada, Reno, Nevada (S.G.P., J.A.-U., D.A.); University of Minnesota Center for Immunology, Minneapolis, Minnesota (M.P.); and Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, Washington (M.P.)
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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 leading antifentanyl mAb, clone HY6-F9, in reversal and prevention of fentanyl-induced toxicity compared with the opioid receptor antagonist naloxone (NLX) in rats. In postexposure 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. Coadministration of mAb and NLX provided greater protection than individual treatments against high doses of fentanyl. Prophylactic administration of mAb reduced the ED50 of NLX approximately twofold against 2.25 mg/kg of 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 monoclonal antibodies as a countermeasure to fentanyl-induced toxicity in pre- and postexposure scenarios, supporting their use in combination with the opioid antagonist naloxone.

Footnotes

    • Received December 6, 2021.
    • Accepted February 2, 2022.
  • 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 award number [Grant U01-DA051658] (to M.P.); and by the National Institutes of Health under [Grant T32-DA007097] (to M.M.W.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

  • M.P. and C.B. are inventors of a patent application “Anti-opioid compounds and methods of making and using same.” All other authors declare no conflicts of interest.

  • https://doi.org/10.1124/jpet.121.001048.

  • ↵Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • Copyright © 2022 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 381 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 381, Issue 2
1 May 2022
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Research ArticleDrug Discovery and Translational Medicine

Pharmacology of Antifentanyl mAb with Naloxone in Rats

Carly A. Baehr, Mariah M. Wu, Sujata G. Pandit, Jose Arias-Umana, David AuCoin and Marco Pravetoni
Journal of Pharmacology and Experimental Therapeutics May 1, 2022, 381 (2) 129-136; DOI: https://doi.org/10.1124/jpet.121.001048

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Research ArticleDrug Discovery and Translational Medicine

Pharmacology of Antifentanyl mAb with Naloxone in Rats

Carly A. Baehr, Mariah M. Wu, Sujata G. Pandit, Jose Arias-Umana, David AuCoin and Marco Pravetoni
Journal of Pharmacology and Experimental Therapeutics May 1, 2022, 381 (2) 129-136; DOI: https://doi.org/10.1124/jpet.121.001048
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