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

Abstract

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.

An Ultrasensitive Norfentanyl Sensor Based on a Carbon Nanotube-Based Field-Effect Transistor for the Detection of Fentanyl Exposure

“…31 Similarly, the binding between norfentanyl and norfentanyl antibody likely relies on the nonpolar hydrogen−π interaction and cationic-π interaction between norfentanyl and amino acid residues inside the binding sites of the antibody such as aspartate (Asp) and tyrosine (Try). 42 Therefore, we attributed the sensor response to the redistribution of charges on the antibody upon norfentanyl binding, making the antibody less positively charged and consequently p-doping the sc-SWCNTs.…”

Advancing humanized monoclonal antibody for counteracting fentanyl toxicity towards clinical development

“…Anti-fentanyl murine mAb and chAb isolated by other groups have been shown to prevent fentanyl-induced antinociception and brain distribution at similar mAb and fentanyl doses to those used here. 20 , 21 Meanwhile, HY6-F9_Mu has been shown to prevent fentanyl effects in both mice and rats, 19 and to reverse respiratory depression in rats, 40 a more clinically relevant measure for fentanyl overdose than antinociception. However, as murine and chimeric mAbs are unsuitable for human use due to ADA responses, 26–28 humanization is essential for clinical advancement.…”

An Epitope-Focused Trypanosome-Derived Vaccine Platform Elicits High-Affinity Antibodies and Immunity Against Fentanyl Effects

“…Although anti-fentanyl mAb have been described to effectively protect from fentanyl challenge before (Smith et al ., 2019; Baehr et al ., 2020; Ban et al ., 2021), the modality of fentanyl binding of these antibodies has yet to be elucidated. Interestingly, all of our crystallized antibodies bind fentanyl in a strikingly deep and narrow pocket.…”

“…These strategies have also been used to generate mAbs against a variety of target drugs of abuse including fentanyl. Notably, fentanyl-specific mAbs are effective in both preventing and reversing fentanyl's pharmacological effects in rodent models, further highlighting the promise of immunotherapeutics in the opioid space (Smith et al, 2019;Baehr et al, 2020Baehr et al, , 2022Ban et al, 2021). While promising indeed, there remains a lack of clinical output in this space and a desperate need for additional intervention options.…”