Monoclonal Antibodies Counteract Opioid-Induced Behavioral and Toxic Effects in Mice and Rats

被引:41
作者
Baehr, Carly [1 ,2 ]
Kelcher, April Huseby [1 ,3 ]
Khaimraj, Aaron [1 ]
Reed, Dana E. [4 ]
Pandit, Sujata G. [4 ]
AuCoin, David [4 ]
Averick, Saadyah [5 ]
Pravetoni, Marco [1 ,6 ]
机构
[1] Univ Minnesota, Sch Med, Dept Pharmacol, Minneapolis, MN 55455 USA
[2] Univ Minnesota, Sch Med, Dept Vet Populat Med, Minneapolis, MN 55455 USA
[3] Univ Minnesota, Sch Med, Dept Psychiat & Behav Sci, Minneapolis, MN 55455 USA
[4] Univ Nevada, Reno Sch Med, Reno, NV 89557 USA
[5] Allegheny Hlth Network, Pittsburgh, PA USA
[6] Univ Minnesota, Ctr Immunol, Minneapolis, MN 55455 USA
基金
美国国家卫生研究院; 美国国家科学基金会;
关键词
CONJUGATE VACCINE; COCAINE DEPENDENCE; USE DISORDERS; DOUBLE-BLIND; EFFICACY; OXYCODONE; HEROIN; HAPTEN; GENERATION; BRAIN;
D O I
10.1124/jpet.120.000124
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
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. Inmice 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.
引用
收藏
页码:469 / 477
页数:9
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