Development of fentanyl-specific monoclonal antibody (mAb) to antagonize the pharmacological effects of fentanyl

Chen, Xiao-Yi; Wang, Li; Ma, Xiao; Yang, Fan; Wang, Xiao; Xu, Peng; Xu, Li-Li; Di, Bin

doi:10.1016/j.taap.2024.116918

Toxicology and Applied Pharmacology

2024

DOI: 10.1016/j.taap.2024.116918

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Development of fentanyl-specific monoclonal antibody (mAb) to antagonize the pharmacological effects of fentanyl

Xiao-Yi Chen,

Li Wang,

Xiao Ma

et al.

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2024

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Cited by 3 publications

References 77 publications

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Establishment of Broad-Specificity Monoclonal Antibody-Based Immunoassay for Rapid Detection of Indole-Type and Indazole-Type Synthetic Cannabinoids and Metabolites

Chen,

Ma,

Wang

et al. 2024

Anal. Chem.

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Synthetic cannabinoids (SCs) have emerged as one of the most severely abused categories of new psychoactive substances (NPS), exacerbating the global drug problem and posing significant threats to public health. Presently, a class of new amide-type SCs featuring an indazole or indole core has been identified in numerous cases of illegal drug use, but there is still a lack of comprehensive analysis methods of SC detection. Herein, monoclonal antibodies (mAbs) 2E4 and AE6 targeting 36 indoletype and indazole-type SCs and their metabolites with IC 50 ranging from 0.14 to 85.28 ng/mL were prepared and the molecular mechanism of antibody recognition was elaborated. We established the indirect competitive enzyme-linked immunosorbent assay (ic-ELISA) and gold immunochromatography assay (GICA) based on mAbs 2E4 and AE6 to detect indazole-type and indole-type SCs in urine and hair samples. Under optimal conditions, the proposed method detected ADB-BUTINACA (an indazole-type SC) with limits of detection (LODs) of 0.11 ng/mL for urine and 0.024 ng/ mg for hair by ic-ELISA, and 1.02 ng/mL for urine and 0.046 ng/mg for hair by GICA; the LODs of 4F-MDMB-BUTICA (an indole-type SC) detection was 0.036 ng/mL for urine and 0.012 ng/mg for hair by ic-ELISA, and 0.54 ng/mL for urine and 0.03 ng/ mg for hair by GICA. Collectively, our study provides a comprehensive foundation for the rapid screening and quantitation of SC derivatives in biological samples.

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Establishment of Broad-Specificity Monoclonal Antibody-Based Immunoassay for Rapid Detection of Indole-Type and Indazole-Type Synthetic Cannabinoids and Metabolites

Chen,

Ma,

Wang

et al. 2024

Anal. Chem.

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Structure-Based Engineering of Monoclonal Antibodies for Improved Binding to Counteract the Effects of Fentanyl and Carfentanil

Rodarte,

Baehr,

Hicks

et al. 2024

ACS Omega

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The opioid overdose epidemic is a growing and evolving public health crisis fueled by the widespread presence of fentanyl and fentanyl analogues (F/FAs) in both street mixtures and counterfeit pills. To expand current treatment options, drugtargeting monoclonal antibodies (mAbs) offer a viable therapeutic for both pre-and postexposure clinical scenarios. This study reports the isolation, in vitro characterization, and in vivo efficacy of two murine mAb families targeting fentanyl, carfentanil, or both. Because humanization of the mAbs by CDR grafting negatively impacted affinity for both fentanyl and carfentanil, crystal structures of mAbs in complex with fentanyl or carfentanil were analyzed to identify key residues involved in ligand binding in murine versus humanized structures, and site-directed mutagenesis was used to verify their functional importance. The structural analysis identified a framework residue, Tyr36, present in the murine germline sequence of two mAbs, which was critical for binding to fentanyl and carfentanil. These studies emphasize the importance of structural considerations in mAb engineering to optimize mAbs targeting small molecules including opioids and other drugs of public health interest.

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Fentanyl Overdose Causes Prolonged Cardiopulmonary Dysregulation in Male SKH1 Mice

Newman,

Connery,

Kannan

et al. 2024

Pharmaceuticals

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Fentanyl overdose is a survivable condition that commonly resolves without chronic overt changes in phenotype. While the acute physiological effects of fentanyl overdose, such as opioid-induced respiratory depression (OIRD) and Wooden Chest Syndrome, represent immediate risks of lethality, little is known about longer-term systemic or organ-level impacts for survivors. In this study, we investigated the effects of a single, bolus fentanyl overdose on components of the cardiopulmonary system up to one week post. SKH1 mice were administered subcutaneous fentanyl at the highest non-lethal dose (62 mg/kg), LD10 (110 mg/kg), or LD50 (135 mg/kg), before euthanasia at 40 min, 6 h, 24 h, or 7 d post-exposure. The cerebral cortex, heart, lungs, and plasma were assayed using an immune monitoring 48-plex panel. The results showed significantly dysregulated cytokine, chemokine, and growth factor concentrations compared to time-matched controls, principally in hearts, then lungs and plasma to a lesser extent, for the length of the study, with the cortex largely unaffected. Major significant analytes contributing to variance included eotaxin-1, IL-33, and betacellulin, which were generally downregulated across time. The results of this study suggest that cardiopulmonary toxicity may persist from a single fentanyl overdose and have wide implications for the endurance of the expanding population of survivors.

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Development of fentanyl-specific monoclonal antibody (mAb) to antagonize the pharmacological effects of fentanyl

Cited by 3 publications

References 77 publications

Establishment of Broad-Specificity Monoclonal Antibody-Based Immunoassay for Rapid Detection of Indole-Type and Indazole-Type Synthetic Cannabinoids and Metabolites

Establishment of Broad-Specificity Monoclonal Antibody-Based Immunoassay for Rapid Detection of Indole-Type and Indazole-Type Synthetic Cannabinoids and Metabolites

Structure-Based Engineering of Monoclonal Antibodies for Improved Binding to Counteract the Effects of Fentanyl and Carfentanil

Fentanyl Overdose Causes Prolonged Cardiopulmonary Dysregulation in Male SKH1 Mice

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