Abstract

Monoclonal antibodies (mAb) and vaccines have been proposed as medical countermeasures to treat opioid use disorder (OUD) and prevent opioid overdose. In contrast to current pharmacotherapies (e.g., methadone, buprenorphine, naltrexone, and naloxone) for OUD and overdose, which target brain opioid receptors, mAb and vaccine-generated polyclonal antibodies sequester the target opioid in the serum and reduce drug distribution to the brain. Further, mAb offer several potential clinical benefits over approved medications, such as longer serum half-life, high selectivity, reduced side effects, and low abuse liability. Using magnetic enrichment to isolate opioid-specific B cell lymphocytes prior to fusion with myeloma partners, this study identified a series of murine hybridoma cell lines expressing mAb with high affinity for opioids of clinical interest, including oxycodone, heroin and its active metabolites, and fentanyl. In mice, passive immunization with lead mAb against oxycodone, heroin, and fentanyl reduced drug-induced antinociception and the distribution of the target opioid to the brain. In mice and rats, mAb pre-treatment reduced fentanyl-induced respiratory depression and bradycardia, two risk factors for opioid-related overdose fatality. Overall, these results support use of mAb to counteract toxic effects of opioids and other chemical threats.

Significance Statement The incidence of fatal overdoses due to the widespread access to heroin, prescription opioids, and fentanyl suggests that current FDA-approved countermeasures are not sufficient to mitigate the opioid epidemic. Monoclonal antibodies (mAb) may provide acute protection from overdose by binding to circulating opioids in serum. Use of mAb prophylactically, or post-exposure in combination with naloxone, may reduce hospitalization and increase survival.