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Monoclonal Antibodies against Fentanyl and Fentanyl Analogs for Prevention of Opioid Overdose

Anti‐opioid vaccines and antibodies have been proposed as a therapeutic agent to treat opioid use disorder and prevent opioid intoxication and overdose. In contrast to receptor‐targeting small molecule pharmacotherapy (e.g. naloxone) for opioid use disorder and overdose, antibody‐based therapeutics operate through sequestration of the target molecule in the serum, preventing access through the blood‐brain barrier. Monoclonal antibodies (mAb) offer several benefits as therapeutic agents, including long serum half‐life, high specificity for the target compound, and minimal side effects. Using a magnetic enrichment strategy to isolate opioid‐specific B cells, we have developed hybridomas expressing mAb against oxycodone, morphine, or fentanyl, that protect from opioid toxicity by preventing distribution of the target opioid to the brain. Passive immunization of mice with these mAbs significantly reduced both the antinociceptive effects and the concentration in the brain of each target opioid. Importantly, passive immunization of mice and rats with anti‐fentanyl mAb prevented fentanyl‐induced respiratory depression and bradycardia, two primary risk factors for opioid overdose‐related death. These anti‐fentanyl mAbs exhibited low nanomolar affinities in vitro, as measured by both competitive ELISA and biolayer interferometry. Finally, sequencing of opioid‐specific mAb identified recurring sequence motifs in antigen‐binding regions, which can inform rational design of mAbs to target structural variation in fentanyl analogs and related compounds. Overall, these results indicate passive immunization as a promising strategy to prevent toxic effects of opioids and other compounds of interest.