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An Engineered Human-Antibody Fragment with Fentanyl Pan-Specificity that Reverses Carfentanil-Induced Respiratory Depression.

ABSTRACT: The opioid overdose crisis primarily driven by potent synthetic opioids resulted in more than 500,000 deaths in the US over the last 20 years. Though naloxone, a short acting medication, remains the primary treatment option for temporarily reversing opioid overdose effects, alternative countermeasures are needed. Monoclonal antibodies present a versatile therapeutic opportunity that can be tailored for synthetic opioids and that can help prevent post-treatment renarcotization. The ultrapotent analog carfentanil, is especially concerning due to its unique pharmacological properties. With this in mind, we generated a fully human antibody through a drug-specific B cell sorting strategy with a combination of carfentanil and fentanyl probes. The resulting pan-specific antibody was further optimized through scFv phage display. This antibody, C10-S66K, displays high affinity to carfentanil, fentanyl, and other analogs, and reversed carfentanil-induced respiratory depression. Additionally, x-ray crystal structures with carfentanil and fentanyl bound provided structural insight into key drug:antibody interactions.

SUBMITTER: Eubanks LM

PROVIDER: S-EPMC10349930 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature

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An Engineered Human-Antibody Fragment with Fentanyl Pan-Specificity that Reverses Carfentanil-Induced Respiratory Depression.

Eubanks Lisa M LM Pholcharee Tossapol T Oyen David D Natori Yoshihiro Y Zhou Bin B Wilson Ian A IA Janda Kim D KD

bioRxiv : the preprint server for biology 20230704

The opioid overdose crisis primarily driven by potent synthetic opioids resulted in more than 500,000 deaths in the US over the last 20 years. Though naloxone, a short acting medication, remains the primary treatment option for temporarily reversing opioid overdose effects, alternative countermeasures are needed. Monoclonal antibodies present a versatile therapeutic opportunity that can be tailored for synthetic opioids and that can help prevent post-treatment renarcotization. The ultrapotent an ...[more]

PMID: 37461607

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Project description:Introduction: Overdose fatalities associated with the opioid epidemic are predictably attributable to drug-induced respiratory depression. In terms of illicit opioid abuse, fentanyl is the synthetic opioid responsible for the largest number of overdose deaths. There is, therefore, an urgent need to identify safe and effective therapeutics that can attenuate fentanyl-induced respiratory depression. Identification of effective alternate analgesic strategies that lessen the respiratory depression associated with narcotics would also help improve current strategies for pain management. Our laboratory recently reported that the G protein-biased CB2 cannabinoid receptor agonist LY2828360 suppressed chemotherapy-induced neuropathic nociception and attenuated both morphine tolerance and physical dependence in paclitaxel-treated mice. However, the impact of LY2828360 on other undesirable side effects of opioids, such as opioid-induced respiratory depression, remains unknown. Materials and Methods: We used whole-body plethysmography to assess the impact of the CB2 cannabinoid agonist LY2828360 on fentanyl-induced respiratory depression using wild-type (WT) and CB2 knockout (CB2KO) mice. Results: Fentanyl reduced minute ventilation and respiratory frequency without altering tidal volume in both WT and CB2KO mice. In WT mice, the high dose of fentanyl (0.2 mg/kg intraperitoneal [i.p.]) produced a greater suppression of respiratory parameters compared with the low dose of fentanyl (0.1 mg/kg i.p.). Coadministration of a behaviorally active dose of LY2828360 (3 mg/kg i.p.) with fentanyl (0.2 mg/kg i.p.) attenuated fentanyl-induced respiratory depression in WT mice. Notably, LY2828360 (3 mg/kg i.p.) did not attenuate fentanyl-induced respiratory depression in CB2KO mice, consistent with mediation by CB2 receptors. Moreover, LY2828360 (3 mg/kg i.p.) alone lacked intrinsic effects on respiratory parameters in either WT or CB2KO mice. Conclusion: The combination of a CB2 agonist with fentanyl may represent a safer adjunctive therapeutic strategy compared with a narcotic analgesic alone by attenuating the development of opioid-induced respiratory depression. Moreover, the CB2 agonist, administered alone, did not alter respiration. Our findings suggest that the CB2 cannabinoid agonist LY2828360 may provide CB2-mediated protection against fentanyl-induced respiratory depression, a detrimental and unwanted side effect of opioid use and abuse.

Project description:Key pointsSleep apnoea increases susceptibility to opioid-induced respiratory depression (OIRD). Endogenous opioids are implicated as a contributing factor in sleep apnoea. Rats exposed to sleep-phase chronic intermittent hypercapnic hypoxia (CIHH) for 7 days exhibited exaggerated OIRD to systemic fentanyl both while anaesthetized and artificially ventilated and while conscious and breathing spontaneously, implicating heightened CNS inhibitory efficacy of fentanyl. CIHH also induced tonic endogenous opioid suppression of neural inspiration. Sleep-related episodes of hypercapnic hypoxia, as in sleep apnoea, promote hypersensitivity to OIRD, with tonic respiratory depression by endogenous opioids implicated as a potential underlying cause.AbstractSleep apnoea (SA) increases opioid-induced respiratory depression (OIRD) and lethality. To test the hypothesis that this results from chronic intermittent bouts of hypercapnic hypoxia (CIHH) accompanying SA, we compared OIRD across continuously normoxic control rats and rats exposed to sleep-phase (8 h/day) CIHH for 1 week. OIRD sensitivity was first assessed in anaesthetized (urethane/α-chloralose), vagotomized and artificially ventilated rats by recording phrenic nerve activity (PNA) to index neural inspiration and quantify PNA burst inhibition to graded doses (0, 2, 20, 50 μg kg-1 , i.v.) of the synthetic opioid fentanyl. Fentanyl dose-dependently reduced PNA burst frequency (P = 0.0098-0.0001), while increasing the duration of burst quiescence at 50 μg kg-1 (P < 0.0001, n = 5-6/group/dose). CIHH shifted the fentanyl dose-phrenic burst frequency response curve to the left (P = 0.0163) and increased the duration of burst quiescence (P < 0.0001). During fentanyl recovery, PNA burst width was increased relative to baseline in normoxic and CIHH rats. Systemic naloxone (1 mg kg-1 , i.v.) reversed fentanyl-induced PNA arrest in both groups (P = 0.0002), and increased phrenic burst amplitude above baseline (P = 0.0113) in CIHH rats only. Differential sensitivity to anaesthesia as a cause of CIHH-related OIRD hypersensitivity was excluded by observing in conscious spontaneously breathing rats that fentanyl at 20 μg kg-1 (i.v.), which silenced PNA in anaesthetized rats, differentially increased breathing variability in normoxic versus CIHH rats (P = 0.0427), while significantly reducing breathing frequency (P < 0.0001) and periodicity (P = 0.0003) in CIHH rats only. Findings indicate that CIHH increased OIRD sensitivity, with tonic inspiratory depression by endogenous opioids as a likely contributing cause.

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An Engineered Human-Antibody Fragment with Fentanyl Pan-Specificity that Reverses Carfentanil-Induced Respiratory Depression.

Publications

An Engineered Human-Antibody Fragment with Fentanyl Pan-Specificity that Reverses Carfentanil-Induced Respiratory Depression.

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