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

Baehr, Carly; Kelcher, April M. Huseby; Khaimraj, Aaron; Reed, Dana E.; Pandit, Sujata G.; AuCoin, David P.; Averick, Saadyah; Pravetoni, Marco

doi:10.1124/jpet.120.000124

Cited by 38 publications

(49 citation statements)

References 45 publications

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“…Opioid-targeting murine mAbs have been previously reported and found efficacious in animal models. 32 , 33 , 39 In our work, the clones P1C3H9 and P1B6H7 were formed by the human constant domains and mouse variable domains. Mouse mAbs are not ideally suited for clinical use because they are typically immunogenic.…”

Section: Discussionmentioning

confidence: 82%

“…We measured the affinities of P1C3H9 and P1B6H7 using ED-LC-MS/MS and found that the fentanyl K d values (0.15 ± 0.03 and 1.28 ± 0.12 nM, respectively) are similar to the competitive IC 50 of the lead 6A4 mAb reported by Smith et al . 32 that had ~10 −11 M affinity and the mAb HY4-1F9 clone reported by Baehr et al ., 33 which had <2 nM. These affinity values, however, cannot be directly compared because different techniques were used to measure them.…”

Section: Discussionmentioning

confidence: 99%

“…For example, recent publications show that mAbs directed at fentanyl and related molecules can sequester large amounts of drug in the periphery and reduce biodistribution to the brain, suggesting these mAbs could be used as a treatment modality for OUD. 32 , 33 The preclinical studies strengthen the potential utility of mAbs as a viable treatment modality for OUD that would greatly benefit from proof-of-concept studies in humans.…”

Section: Introductionmentioning

confidence: 88%

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Novel chimeric monoclonal antibodies that block fentanyl effects and alter fentanyl biodistribution in mice

Ban

Barrientos

Oertel

et al. 2021

mAbs

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The prevalence and societal impact of opioid use disorder (OUD) is an acknowledged public health crisis that is further aggravated by the current pandemic. One of the devastating consequences of OUD is opioid overdose deaths. While multiple medications are now available to treat OUD, given the prevalence and societal burden, additional well-tolerated and effective therapies are still needed. To this point, we have developed chimeric monoclonal antibodies (mAb) that will specifically complex with fentanyl and its analogs in the periphery, thereby preventing them from reaching the central nervous system. Additionally, mAb-based passive immunotherapy offers a high degree of specificity to drugs of abuse and does not interfere with an individual’s ability to use any of the medications used to treat OUD. We hypothesized that sequestering fentanyl and its analogs in the periphery will mitigate their negative effects on the brain and peripheral organs. This study is the first report of chimeric mAb against fentanyl and its analogs. We have discovered, engineered the chimeric versions, and identified the selectivity of these antibodies, through in vitro characterization and in vivo animal challenge studies. Two mAb candidates with very high (0.1–1.3 nM) binding affinities to fentanyl and its analogs were found to be effective in engaging fentanyl in the periphery and blocking its effects in challenged animals. Results presented in this work constitute a major contribution in the field of novel therapeutics targeting OUD.

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Section: Discussionmentioning

confidence: 82%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 88%

See 1 more Smart Citation

Novel chimeric monoclonal antibodies that block fentanyl effects and alter fentanyl biodistribution in mice

Ban

Barrientos

Oertel

et al. 2021

mAbs

View full text Add to dashboard Cite

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“…Efforts in the laboratory of Dr. Pravetoni are currently underway to test whether B cell‐based biomarkers are likely to predict vaccine efficacy against opioids in humans. Promising preclinical data also support use of anti‐opioid mAbs to counteract acute respiratory depression and bradycardia in mice and rats challenged with heroin, oxycodone, or fentanyl 83 . Furthermore, it has been shown that anti‐opioid mAbs can increase survival from opioid overdose in mice and that anti‐opioid mAbs can be administered in postexposure scenarios to reduce opioid‐induced behavioral effects 84 .…”

Section: Novel Treatments: Antibody‐based Strategiesmentioning

confidence: 97%

“…Promising preclinical data also support use of anti-opioid mAbs to counteract acute respiratory depression and bradycardia in mice and rats challenged with heroin, oxycodone, or fentanyl. 83 Furthermore, it has been shown that anti-opioid mAbs can increase survival from opioid overdose in mice and that anti-opioid mAbs can be administered in postexposure scenarios to reduce opioid-induced behavioral effects. 84 These data provide encouraging evidence to support translation of anti-opioid mAbs, but more advanced studies are needed to fully characterize their safety and efficacy.…”

Section: Novel Treatments: Antibody-based Strategiesmentioning

confidence: 99%

Countermeasures for Preventing and Treating Opioid Overdose

France

Ahern

Averick

et al. 2020

Clin Pharma and Therapeutics

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The only medication available currently to prevent and treat opioid overdose (naloxone) was approved by the US Food and Drug Administration (FDA) nearly 50 years ago. Because of its pharmacokinetic and pharmacodynamic properties, naloxone has limited utility under some conditions and would not be effective to counteract mass casualties involving large‐scale deployment of weaponized synthetic opioids. To address shortcomings of current medical countermeasures for opioid toxicity, a trans‐agency scientific meeting was convened by the US National Institute of Allergy and Infectious Diseases/National Institutes of Health (NIAID/NIH) on August 6 and 7, 2019, to explore emerging alternative approaches for treating opioid overdose in the event of weaponization of synthetic opioids. The meeting was initiated by the Chemical Countermeasures Research Program (CCRP), was organized by NIAID, and was a collaboration with the National Institute on Drug Abuse/NIH (NIDA/NIH), the FDA, the Defense Threat Reduction Agency (DTRA), and the Biomedical Advanced Research and Development Authority (BARDA). This paper provides an overview of several presentations at that meeting that discussed emerging new approaches for treating opioid overdose, including the following: (1) intranasal nalmefene, a competitive, reversible opioid receptor antagonist with a longer duration of action than naloxone; (2) methocinnamox, a novel opioid receptor antagonist; (3) covalent naloxone nanoparticles; (4) serotonin (5‐HT)1A receptor agonists; (5) fentanyl‐binding cyclodextrin scaffolds; (6) detoxifying biomimetic “nanosponge” decoy receptors; and (7) antibody‐based strategies. These approaches could also be applied to treat opioid use disorder.

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Clinical Trial Design Challenges and Opportunities for Emerging Treatments for Opioid Use Disorder

et al. 2023

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ImportanceNovel treatments for opioid use disorder (OUD) are needed to address both the ongoing opioid epidemic and long-standing barriers to existing OUD treatments that target the endogenous μ-opioid receptor (MOR) system. The goal of this review is to highlight unique clinical trial design considerations for the study of emerging treatments for OUD that address targets beyond the MOR system. In November 2019, the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) public-private partnership with the US Food and Drug Administration sponsored a meeting to discuss the current evidence regarding potential treatments for OUD, including cannabinoids, psychedelics, sedative-hypnotics, and immunotherapeutics, such as vaccines.ObservationsConsensus recommendations are presented regarding the most critical elements of trial design for the evaluation of novel OUD treatments, such as: (1) stage of treatment that will be targeted (eg, seeking treatment, early abstinence/detoxification, long-term recovery); (2) role of treatment (adjunctive with or independent of existing OUD treatments); (3) primary outcomes informed by patient preferences that assess opioid use (including changes in patterns of use), treatment retention, and/or global functioning and quality of life; and (4) adverse events, including the potential for opioid-related relapse or overdose, especially if the patient is not simultaneously taking maintenance MOR agonist or antagonist medications.Conclusions and RelevanceApplying the recommendations provided here as well as considering input from people with lived experience in the design phase will accelerate the development, translation, and uptake of effective and safe therapeutics for individuals struggling with OUD.

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

Cited by 38 publications

References 45 publications

Novel chimeric monoclonal antibodies that block fentanyl effects and alter fentanyl biodistribution in mice

Novel chimeric monoclonal antibodies that block fentanyl effects and alter fentanyl biodistribution in mice

Countermeasures for Preventing and Treating Opioid Overdose

Clinical Trial Design Challenges and Opportunities for Emerging Treatments for Opioid Use Disorder

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