RÉSUMÉ
Fentanyl and other synthetic opioids are the leading cause of drug-related deaths in the United States. mAbs that selectively target fentanyl and fentanyl analogues offer a promising strategy for treating both opioid-related overdoses and opioid use disorders. To increase the duration of efficacy of a candidate mAb against fentanyl, we selected three sets of mutations in the Fc region of an IgG1 anti-fentanyl mAb (HY6-F9DF215, HY6-F9DHS, HY6-F9YTE) to increase binding to the neonatal Fc receptor (FcRn). The mAb mutants were compared against unmodified (wild-type [WT], HY6-F9WT) anti-fentanyl mAb for fentanyl binding, thermal stability, and FcRn affinity in vitro, and for efficacy against fentanyl and mAb half-life in vivo in mice. Biolayer interferometry showed a >10-fold increase in the affinity for recombinant FcRn of the three mutant mAbs compared with HY6-F9WT. During an acute fentanyl challenge in mice, all FcRn-mutated mAbs provided equal protection against fentanyl-induced effects, and all mAbs reduced brain fentanyl levels compared with the saline group. Serum persistence of the mutant mAbs was tested in Tg276 transgenic mice expressing human FcRn. After administration of 40 mg/kg HY6-F9WT, HY6-F9DF215, HY6-F9DHS, and HY6-F9YTE, the mAbs showed half-lives of 6.3, 26.4, 14.7, and 6.9 d, respectively. These data suggest that modification of mAbs against fentanyl to bind to FcRn with higher affinity can increase their half-life relative to WT mAbs while maintaining efficacy against the toxic effects of fentanyl, further supporting their potential role as a therapeutic treatment option for opioid use disorder and overdose.