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. 2025 Jul 22;16:100365. doi: 10.1016/j.dadr.2025.100365

A humanized monoclonal antibody attenuates carfentanil self-administration in nonhuman primates

Lindsey K Galbo-Thomma a,c, Carly Baehr d, Elaine A Gay e, Scott Runyon e, Marco Pravetoni f, Charles P France a,b,c,⁎
PMCID: PMC12332196  PMID: 40785734

Abstract

Approximately 70 % of fatal drug overdoses in the United States are attributed to fentanyl and fentanyl analogs. Current medications for reversing overdose and treating opioid use disorder might not be as effective against fentanyl and fentanyl analogs compared with other opioids, possibly due to their lipophilicity and high potency at the mu-opioid receptor (MOR). Hence, fentanyl and fentanyl analog-targeting monoclonal antibodies (mAb) could be an alternative treatment. The humanized (h) mAb hHY6-F9 has high relative affinity for fentanyl and decreases intravenous (i.v.) fentanyl self-administration in monkeys. hHY6-F9 has lower affinity for fentanyl analogs, including carfentanil; however, the effects of hHY6-F9 on fentanyl analogs in vivo have not been characterized. This study examined the effects of hHY6-F9 on i.v. carfentanil self-administration. hHY6-F9 was administered to two male rhesus monkeys self-administering carfentanil, heroin, cocaine, or fentanyl during twice daily sessions. Based on prior in vitro and in vivo findings, hHY6-F9 was hypothesized to attenuate fentanyl but not carfentanil, heroin, or cocaine self-administration. However, hHY6-F9 significantly decreased carfentanil self-administration for up to 5 weeks while having little or no effect on heroin, cocaine, or fentanyl self-administration. A cell-based pharmacological assay of carfentanil-induced MOR activation supported the carfentanil self-administration findings, showing that murine HY6-F9 reduced the effects of carfentanil. The ability of hHY6-F9 to attenuate the effects of an ultra-potent fentanyl analog could be advantageous for treating opioid use disorder or overdose given the unpredictability of the unregulated opioid supply.

Keywords: Monoclonal antibody, Fentanyl analog, Fentanyl, Carfentanil, Opioid use disorder, Nonhuman primate

Highlights

  • •

    A humanized mAb reduced carfentanil self-administration in nonhuman primates.

  • •

    The effects of a single administration of the mAb were evident for 5–6 weeks.

  • •

    The mAb reduced mu-opioid receptor activation by carfentanil in a cell-based assay.

1. Introduction

The number of drug overdose fatalities in the U.S. remains high, having peaked at ~111,000 in 2022 and decreasing to ~108,000 in 2023; an estimated 70 % of those deaths were attributed to fentanyl and fentanyl analogs (Centers for Disease Control and Prevention, 2024, Garnett and Miniño, 2024). Fentanyl and many fentanyl analogs, including carfentanil, that are detected in the unregulated opioid supply are highly potent mu-opioid receptor (MOR) agonists, presenting challenges in treating opioid use disorder (OUD) and overdose (Chambers et al., 2023, Suzuki and El-Haddad, 2017). For example, repeated administration or larger doses of naloxone can be necessary to reverse an overdose involving carfentanil (Kang et al., 2022, Moss and Carlo, 2019). Fentanyl- and fentanyl analog-targeting monoclonal antibodies (mAbs) could be effective alternatives to currently available medications (France et al., 2021, Martinez et al., 2023, Townsend et al., 2021). mAbs alter the distribution of their target ligand(s) with a rapid onset and long duration of action, and fentanyl and fentanyl analog-targeting mAbs can reverse and prevent the cardiorespiratory effects and self-administration of their target ligands in rats and monkeys (Baehr et al., 2022, Bremer et al., 2023, Galbo-Thomma et al., 2025). CSX-100, a mAb targeting fentanyl, carfentanil, and other analogs, has progressed to clinical trials (Bremer et al., 2023, Cessation Therapeutics, 2024). A humanized (h) mAb, hHY6-F9, has nanomolar relative affinity for fentanyl (~3 nM) and cross-reactivity for other opioids and fentanyl analogs, including carfentanil, albeit with lower (e.g., micromolar) affinity (Hicks et al., 2022, Hoppe et al., 2025). In rhesus macaques, hHY6-F9 decreased intravenous (i.v.) fentanyl but not heroin or cocaine self-administration (Galbo-Thomma et al., 2025); however, the effects of hHY6-F9 on fentanyl analogs are unknown. This proof-of-concept study examined the effects of hHY6-F9 in two male monkeys self-administering carfentanil, heroin, cocaine, and fentanyl. Based on prior findings (Galbo-Thomma et al., 2025, Hicks et al., 2022, Hoppe et al., 2025), hHY6-F9 was hypothesized to attenuate self-administration of fentanyl but not carfentanil, heroin, or cocaine. The effects of murine HY6-F9 (from which hHY6-F9 was derived) on carfentanil-induced MOR signaling were also examined using a cell-based assay.

2. Methods

2.1. Self-administration procedure

Two adult male rhesus monkeys (KI, MA; mean age ± 1 standard deviation [SD], 14.2 ± 6.0 years) with experimental histories (e.g., opioid self-administration) underwent surgical implantation of a chronic indwelling i.v. catheter, allowing monkeys to self-administer drug in the home cage twice daily (sessions beginning at 1000 and 1400 h; see Supplemental methods). Monkeys were individually housed in a temperature- and humidity-controlled room with a 14/10-h light/dark cycle and were maintained in accordance with the University of Texas Health Science Center at San Antonio Institutional Animal Care and Use Committee and the 2011 Guide for the Care and Use of Laboratory Animals (National Research Council, 2010). Monkeys received daily rations of primate chow (Harlan Teklad, Madison, WI) and fresh fruit to maintain healthy weights (10.6–11.0 kg) and water was available ad libitum.

Details of the self-administration procedure are in Supplemental methods. Briefly, in the presence of a distinctive visual stimulus, 30 consecutive responses on the active lever resulted in an infusion, followed by a 180-s timeout period. Monkeys could obtain a maximum of 30 infusions per 90-min session, including a noncontingent priming infusion delivered at the outset of a session. Baseline carfentanil dose-effect curves (0.0001–0.01 μg/kg/infusion) were generated with the unit dose at the peak of the curve available in subsequent sessions. Self-administration was redetermined for 3.2 μg/kg/infusion heroin, 32 μg/kg/infusion cocaine, and 0.32 μg/kg/infusion fentanyl, which monkeys previously self-administered (see Supplemental results; Galbo-Thomma et al., 2025). Before hHY6-F9 was tested, vehicle was administered (i.v.) 15 min before a morning session and the effects on carfentanil, heroin, and cocaine self-administration were examined for 2 days. Next, a single infusion of 10 mg/kg hHY6-F9 was administered 15 min before a morning session; to determine the effects of hHY6-F9 on self-administration of each drug, carfentanil was available in morning sessions while heroin and cocaine were alternatively available in afternoon sessions. Every 7th day saline was substituted for carfentanil in the morning session and fentanyl was substituted for heroin or cocaine in the afternoon session. The effects of hHY6-F9 were examined for at least 4 weeks because 10 mg/kg hHY6-F9 previously modified fentanyl self-administration for 16–30 days in these monkeys (Galbo-Thomma et al., 2025); there were 92 (monkey KI) and 118 (monkey MA) days between hHY6-F9 administrations and fentanyl self-administration in both monkeys returned to baseline (Galbo-Thomma et al., 2025) prior to starting the present study. Because hHY6-F9 decreased carfentanil self-administration for at least 4 weeks (see 3.1. Self-administration), the carfentanil dose increased by 0.5 log units for 3 days to determine if the effects of hHY6-F9 were maintained (from 0.00032 to 0.001 μg/kg/infusion in KI during week 5; from 0.0032 to 0.01 μg/kg/infusion in MA during week 6). To determine if hHY6-F9 significantly modified carfentanil, heroin, or cocaine self-administration, a linear mixed model with an autocorrelation of order 1 was utilized; a Dunnett’s multiple comparisons post hoc analysis compared baseline infusions to the mean number of infusions obtained 1–4 weeks after treatment. Results were analyzed using R Studio (Posit Software, PBC, Boston, MA).

2.2. Calcium mobilization assay

Carfentanil-induced activation of human MOR (hMOR) was measured in a calcium mobilization assay as described previously (Raleigh et al., 2017). Briefly, stable Gα16-CHO-hMOR cells overexpressing the hMOR and promiscuous Gα16 protein were cultured in 96-well black-walled assay plates at 30,000 cells/well in Ham’s F12 medium (supplemented with 10 % fetal bovine serum, 100 units of penicillin/streptomycin, and 100 μg/mL Normocin). Cells were washed and loaded with Calcium 5 dye (Molecular Devices LLC, San Jose, CA) in prewarmed (37 °C) assay buffer (1x HBSS, 20 mM HEPES, 2.5 mM probenecid, pH 7.4) for 1 h. Carfentanil and murine HY6-F9 were pre-incubated for 30 min at room temperature at 5x their final assay concentrations. Calcium 5 fluorescence signal was monitored on a FLIPR Penta (Molecular Devices LLC) for 90 s with carfentanil and HY6-F9 dilutions added to cells at 10 s. Peak fluorescence was calculated, and data were normalized to the signal from carfentanil alone and expressed as percent relative response. Statistical significance was determined by performing a one-way ANOVA with a Dunnett’s multiple comparisons post hoc analysis using GraphPad Prism (GraphPad Software LLC, San Diego, CA).

2.3. Monoclonal antibody and drugs

Purified hHY6-F9 in phosphate buffered saline was generated by Celltheon Corporation (Union City, CA; see Supplemental methods; Galbo-Thomma et al., 2025; Hicks et al., 2022) and used in the self-administration study. Drugs were provided by the National Institute on Drug Abuse Drug Supply Program (Rockville, MD) and dissolved in sterile saline. hHY6-F9 and all drugs were drawn through a sterile polyethersulfone syringe filter (0.22 µm, 25 mm; ThermoFisher Scientific, Waltham, MA) before i.v. administration. Murine HY6-F9 used for the calcium mobilization assay was expressed from hybridoma and Protein A and purified as described previously (Baehr et al., 2022). hHY6-F9 and murine HY6-F9 were shown to have comparable affinities for carfentanil in multiple assays (Hicks et al., 2022, Hoppe et al., 2025).

3. Results

3.1. Self-administration

Fig. 1 shows results for the self-administration of carfentanil, heroin, cocaine, and fentanyl under control conditions (baseline [BL]) and after administration of hHY6-F9. At baseline, monkeys obtained >20 infusions of carfentanil (KI, 0.00032 μg/kg/infusion; MA, 0.0032 μg/kg/infusion), heroin, cocaine, and fentanyl (see Supplemental results and Fig. 1). hHY6-F9 significantly decreased carfentanil self-administration for at least 5 weeks (F(4, 4)= 18.37, p = 0.008). On the day of treatment, monkey KI obtained 46.9 % fewer carfentanil infusions (11) compared with baseline (20.7 ± 3.1), whereas, in monkey MA, hHY6-F9 progressively decreased carfentanil self-administration over 3 days to an average of 10 infusions (compared to 26.7 ± 0.6 with baseline). Carfentanil self-administration remained significantly reduced in both monkeys, compared with baseline, by ~70 % for 2–4 weeks after treatment (p < 0.05 each week). Because the number of carfentanil infusions obtained by monkey MA decreased from week 3–4 (from 7.8 ± 5.7 to 2.3 ± 0.8), the effects of hHY6-F9 were examined for a 5th week when MA received an average of 5.0 ± 5.5 infusions. Increasing the carfentanil dose in week 6 to 0.01 μg/kg/infusion in MA modestly increased the number of infusions obtained to 11.3+ 4.2. Increasing the carfentanil dose in week 5 to 0.001 μg/kg/infusion in KI had little effect on the number of infusions obtained (from 6.7 ± 2.1 to 7.7 ± 4.5). hHY6-F9 did not markedly affect self-administration of heroin or cocaine during the 4 weeks after treatment. However, in monkey MA the number of cocaine infusions obtained was reduced (~28 %) 3–5 weeks after treatment and the number of heroin infusions received decreased when the carfentanil dose was increased (from ~ 27 in week 5 to ~10 in week 6; half-filled circle, upper right panel, Fig. 1). hHY6-F9 had no effect on fentanyl self-administration in monkey MA; monkey KI obtained 4 fentanyl infusions 6 days after hHY6-F9 treatment but obtained ≥17 fentanyl infusions in subsequent weeks. Vehicle (VEH, Fig. 1) did not markedly affect self-administration of carfentanil, heroin, or cocaine.

Fig. 1.

Fig. 1

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The mean (±1 SD) number of carfentanil (A), heroin (B), cocaine (C), and fentanyl (D) infusions obtained by each of two monkeys (KI, squares; MA, circles) at baseline (BL, mean of 3 sessions) and each week after a single treatment with 10 mg/kg hHY6-F9 (mAb). The unit dose of each drug that was self-administered is indicated in each panel. Carfentanil was available in morning sessions (each open symbol is the mean of 6 sessions per week) and heroin and cocaine (each symbol is the mean of 3 sessions per week) were alternatively available in afternoon sessions, except the last day of each week when saline was available in the morning (data not shown) and fentanyl (each symbol is from a single session per week) was available in the afternoon. Half-filled symbols connected by a dashed line represent the mean number of infusions (an average of 3 sessions for carfentanil and an average of 2 sessions each for heroin and data from a single session for cocaine) obtained the week that the carfentanil dose was increased (from 0.00032 to 0.001 μg/kg/infusion in KI, week 5; from 0.0032 to 0.01 μg/kg/infusion in MA, week 6). Asterisks indicate the grouped mean number of infusions obtained that week was significantly different from BL (p < 0.05).

3.2. hMOR activation

Fig. 2 shows the effects of murine HY6-F9 on carfentanil-induced MOR activation. HY6-F9 alone did not activate MOR above baseline, and carfentanil pre-incubated with an equimolar concentration of HY6-F9 activated MOR similarly to carfentanil alone. Concentrations of 50 and 500 nM HY6-F9 (100 nM binding sites and 1000 nM binding sites, respectively) significantly reduced, but did not eliminate, carfentanil-induced MOR activation (F(6, 14)= 74.02, p < 0.0001).

Fig. 2.

Fig. 2

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Carfentanil-induced MOR activation measured using a calcium mobilization assay; data are expressed as percent relative response from 1 nM carfentanil in the presence of 0.5–500 nM HY6-F9. Bars represent the mean (±1 SEM) of three determinations of each condition; asterisks (**p < 0.01, ***p < 0.001) indicate a significant difference compared with 1 nM of carfentanil alone.

4. Discussion

A single administration of hHY6-F9 decreased carfentanil self-administration in monkeys for at least 5 weeks. This finding was unexpected since murine HY6-F9 (from which hHY6-F9 was derived) has a relative affinity of ~3 nM for fentanyl, but only ~3 µM for carfentanil (by competitive ELISA; Hicks et al., 2022) and does not affect the distribution of 20 µg/kg carfentanil to the brain in mice (Rodarte et al., 2024). However, the maximum possible carfentanil intake in one session in this study was 200- to 2000-fold lower (MA and KI, respectively) than 20 µg/kg carfentanil, suggesting that hHY6-F9 can alter carfentanil distribution when there is a large excess of hHY6-F9 to carfentanil. The in vitro data reported herein show that a 100-fold excess of HY6-F9 was required to significantly reduce MOR activation by 1 nM carfentanil. Notably, the maximum concentration of HY6-F9 used here (500 nM or 1 µM binding sites) is within an order of magnitude of the reported 3  µM relative affinity of HY6-F9 for carfentanil (Hicks et al., 2022). Therefore, HY6-F9 would be predicted to sequester at least 50 % of carfentanil in vivo so long as the serum HY6-F9 concentration is maintained above 100 nM-1 µM. Moreover, Galbo-Thomma et al. (2025) reported that 20  mg/kg hHY6-F9 produced an average initial concentration (C0) of 662 µg/mL and a half-life of ~7.5 days in rhesus monkeys. Assuming 10 mg/kg hHY6-F9 produces a C0 of approximately 331 µg/mL (~4.4 µM binding sites) with a similar half-life to the prior study, hHY6-F9 levels sufficient to affect carfentanil distribution could be maintained for at least 3 weeks (predicting ~50 µg/mL mAb or ~650 nM binding sites remaining on day 21).

In a prior study (Galbo-Thomma et al., 2025), the first fentanyl self-administration session occurred 15  min after treatment with 10 mg/kg hHY6-F6, whereas in the current study fentanyl was not available until 6 days after treatment with hHY6-F9. Given an estimated half-life of 7.5 days, the hHY6-F9 serum concentration on day 6 is estimated to have been ~60 % of C0, potentially reducing the ability of hHY6-F9 to sequester fentanyl during the first fentanyl session (note that fentanyl self-administration was markedly reduced in monkey KI in the first week; Fig. 1). At this predicted serum concentration, hHY6-F9 would be at a 2.5-fold molar excess of the maximum fentanyl intake on day 6, but fentanyl would exceed available hHY6-F9 binding sites by day 20 (third fentanyl session). Meanwhile, because the carfentanil doses were 100- or 1000-fold (MA and KI, respectively) smaller than the fentanyl dose, the available hHY6-F9 binding sites would be expected to be in excess of the carfentanil dose for the duration of the study.

Carfentanil-related overdose deaths increased rapidly in 2016, then declined and remained very low for several years (<80 deaths; Jalal and Burke, 2021); however, provisional overdose death statistics from 2024 indicate that the prevalence of carfentanil could be increasing (~450 deaths; Tanz et al., 2024). Given the unpredictability of the unregulated opioid supply, the ability of hHY6-F9 to sequester ultra-potent fentanyl analogs could be advantageous for treating individuals exposed to potent opioids. Future studies including a larger sample of male and female subjects should investigate whether hHY6-F9 attenuates other effects of carfentanil, such as ventilatory depression, as well as the effects of other fentanyl analogs.

CRediT authorship contribution statement

Lindsey K. Galbo-Thomma: Conceptualization, Data curation, Formal analysis, Investigation, Writing – original draft, Writing – review & editing. Carly Baehr: Conceptualization, Data curation, Visualization, Writing – review & editing. Elaine A:A. Gay: Data curation, Writing – review & editing. Scott Runyon: Data curation, Writing – review & editing. Marco Pravetoni: Conceptualization, Funding acquisition, Writing – review & editing. Charles P. France: Conceptualization, Funding acquisition, Writing – review & editing.

Funding

This work was supported by USPHS awards U01DA51658 (Pravetoni), UG3DA057850 (Pravetoni), T32DA031115 (France), F32DA063281 (Galbo-Thomma), and L70DA061529 (Galbo-Thomma), as well as the Rick L. Seaver Endowed Professorship in Brain Wellness from the University of Washington Garvey Institute for Brain Solutions (Pravetoni) and the Welch Foundation Grant AQ-0039 (France).

Declaration of Competing Interest

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The mAb described in this work is the subject of patent applications (inventors: Pravetoni and Baehr). M. Pravetoni is the founder of CounterX Therapeutics, Inc. The other authors have no financial conflicts or competing interests to declare.

Acknowledgments

The authors thank Dr. Wouter Koek for expert statistical assistance and K. Fernandez de Lara, S. Hopper, J. Martinez, M. Parra, G. Vicuna, and B. Vrana for excellent technical assistance.

Footnotes

Appendix A

Supplementary data associated with this article can be found in the online version at doi:10.1016/j.dadr.2025.100365.

Appendix A. Supplementary material

Supplementary material

mmc1.docx (76.8KB, docx)

Data availability

Source data for all figures in the current study are available from the corresponding author upon reasonable request.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplementary material

mmc1.docx (76.8KB, docx)

Data Availability Statement

Source data for all figures in the current study are available from the corresponding author upon reasonable request.

Articles from Drug and Alcohol Dependence Reports are provided here courtesy of Elsevier

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