PT  - JOURNAL ARTICLE
AU  - Carly Baehr
AU  - April Huseby Kelcher
AU  - Aaron Khaimraj
AU  - Dana E. Reed
AU  - Sujata G. Pandit
AU  - David AuCoin
AU  - Saadyah Averick
AU  - Marco Pravetoni
TI  - Monoclonal Antibodies Counteract Opioid-Induced Behavioral and Toxic Effects in Mice and Rats
AID  - 10.1124/jpet.120.000124
DP  - 2020 Dec 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 469--477
VI  - 375
IP  - 3
4099  - http://jpet.aspetjournals.org/content/375/3/469.short
4100  - http://jpet.aspetjournals.org/content/375/3/469.full
SO  - J Pharmacol Exp Ther2020 Dec 01; 375
AB  - Monoclonal antibodies (mAbs) 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, mAbs and vaccine-generated polyclonal antibodies sequester the target opioid in the serum and reduce drug distribution to the brain. Furthermore, mAbs offer several potential clinical benefits over approved medications, such as longer serum half-life, higher selectivity, reduced side effects, and no 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 mAbs with high affinity for opioids of clinical interest, including oxycodone, heroin and its active metabolites, and fentanyl. In mice, passive immunization with lead mAbs against oxycodone, heroin, and fentanyl reduced drug-induced antinociception and the distribution of the target opioid to the brain. In mice and rats, mAb pretreatment reduced fentanyl-induced respiratory depression and bradycardia, two risk factors for opioid-related overdose fatality. Overall, these results support use of mAbs 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 Food and Drug Administration–approved countermeasures are not sufficient to mitigate the opioid epidemic. Monoclonal antibodies (mAbs) may provide acute protection from overdose by binding to circulating opioids in serum. Use of mAbs prophylactically, or after exposure in combination with naloxone, may reduce hospitalization and increase survival.