Abstract
Innovative therapies to complement current treatments are needed to curb the growing incidence of fatal overdoses related to synthetic opioids. Murine and chimeric monoclonal antibodies (mAb) specific for fentanyl and its analogs have demonstrated pre-clinical efficacy in preventing and reversing drug-induced toxicity in rodent models. However, mAb-based therapeutics require extensive engineering as well as in vitro and in vivo characterization to advance to first-in-human clinical trials. Here, novel murine anti-fentanyl mAbs were selected for development based on affinity for fentanyl, and efficacy in counteracting the pharmacological effects of fentanyl in mice. Humanization and evaluation of mutations designed to eliminate predicted post-translational modifications resulted in two humanized mAbs that were effective at preventing fentanyl-induced pharmacological effects in rats. These humanized mAbs showed favorable biophysical properties with respect to aggregation and hydrophobicity by chromatography-based assays, and thermostability by dynamic scanning fluorimetry. These results collectively support that the humanized anti-fentanyl mAbs developed herein warrant further clinical development for treatment of fentanyl toxicity.
| Original language | English (US) |
|---|---|
| Article number | 2122507 |
| Journal | Human Vaccines and Immunotherapeutics |
| Volume | 18 |
| Issue number | 6 |
| DOIs | |
| State | Published - 2022 |
Bibliographical note
Funding Information:Research reported in this publication was supported by the National Institute On Drug Abuse of the National Institutes of Health under Award Number U01DA051658 (MP). The U01DA051658 was awarded under the auspices of the trans-NIH CounterACT program, and the Office Of The Director, National Institutes Of Health (OD). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors thank Jennifer Vigliaturo from the Pravetoni Lab for LCMS technical support. The authors thank Dr. Terry L. Kirley from the University of Cincinnati College of Medicine for providing expert support in establishing the DSF method for determining Fab Tm.
Publisher Copyright:
© 2022 The Author(s). Published with license by Taylor & Francis Group, LLC.
Keywords
- PTM mitigation
- antibody characterization
- antibody engineering
- clinical development
- fentanyl
- humanized antibody
- mAb
- manufacturability
- opioid use disorder
- synthetic opioids
