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

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.