Advancing humanized monoclonal antibody for counteracting fentanyl toxicity towards clinical development

There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

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.

Related collections

Most cited references 78

Record: found
Abstract: found
Article: not found

Biophysical properties of the clinical-stage antibody landscape.

Tushar Jain, Tingwan Sun, Stéphanie Durand … (2017)

Antibodies are a highly successful class of biological drugs, with over 50 such molecules approved for therapeutic use and hundreds more currently in clinical development. Improvements in technology for the discovery and optimization of high-potency antibodies have greatly increased the chances for finding binding molecules with desired biological properties; however, achieving drug-like properties at the same time is an additional requirement that is receiving increased attention. In this work, we attempt to quantify the historical limits of acceptability for multiple biophysical metrics of "developability." Amino acid sequences from 137 antibodies in advanced clinical stages, including 48 approved for therapeutic use, were collected and used to construct isotype-matched IgG1 antibodies, which were then expressed in mammalian cells. The resulting material for each source antibody was evaluated in a dozen biophysical property assays. The distributions of the observed metrics are used to empirically define boundaries of drug-like behavior that can represent practical guidelines for future antibody drug candidates.

0 comments Cited 240 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Standard conformations for the canonical structures of immunoglobulins.

B Al-Lazikani, A Lesk, C Chothia (1997)

A comparative analysis of the main-chain conformation of the L1, L2, L3, H1 and H2 hypervariable regions in 17 immunoglobulin structures that have been accurately determined at high resolution is described. This involves 79 hypervariable regions in all. We also analysed a part of the H3 region in 12 of the 15 VH domains considered here. On the basis of the residues at key sites the 79 hypervariable regions can be assigned to one of 18 different canonical structures. We show that 71 of these hypervariable regions have a conformation that is very close to what can be defined as a "standard" conformation of each canonical structure. These standard conformations are described in detail. The other eight hypervariable regions have small deviations from the standard conformations that, in six cases, involve only the rotation of a single peptide group. Most H3 hypervariable regions have the same conformation in the part that is close to the framework and the details of this conformation are also described here. Copyright 1997 Academic Press Limited

0 comments Cited 182 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Fentanyl, fentanyl analogs and novel synthetic opioids: A comprehensive review.

Patil Armenian, Jill Barr-Walker, Kara L Lynch … (2018)

Deaths from opioid use are increasing in the US, with a growing proportion due to synthetic opioids. Until 2013, sporadic outbreaks of fentanyl and fentanyl analogs contaminating the heroin supply caused some deaths in heroin users. Since then, fentanyl has caused deaths in every state and fentanyl and its analogs have completely infiltrated the North American heroin supply. In 2014, the first illicit pills containing fentanyl, fentanyl analogs, and other novel synthetic opioids such as U-47700 were detected. These pills, which look like known opioids or benzodiazepines, have introduced synthetic opioids to more unsuspecting customers. As soon as these drugs are regulated by various countries, new compounds quickly appear on the market, making detection difficult and the number of cases likely underreported. Standard targeted analytical techniques such as GC-MS (gas chromatography mass spectrometry) and LC-MS/MS (liquid chromatography tandem mass spectrometry) can detect these drugs, but novel compound identification is aided by nontargeted testing with LC-HRMS (liquid chromatography high resolution mass spectrometry). Fentanyl, fentanyl analogs and other novel synthetic opioids are all full agonists of varying potencies at the μ-opioid receptor, leading to typical clinical effects of miosis and respiratory and central nervous system depression. Due to their high affinity for μ-opioid receptors, larger doses of naloxone are required to reverse the effects than are commonly used. Synthetic opioids are an increasingly major public health threat requiring vigilance from multiple fields including law enforcement, government agencies, clinical chemists, pharmacists, and physicians, to name a few, in order to stem its tide. This article is part of the Special Issue entitled 'Designer Drugs and Legal Highs.'

0 comments Cited 165 times – based on 0 reviews      Review now

Bookmark

All references

Author and article information

Journal

Journal ID (nlm-ta): Hum Vaccin Immunother

Journal ID (iso-abbrev): Hum Vaccin Immunother

Title: Human Vaccines & Immunotherapeutics

Publisher: Taylor & Francis

ISSN (Print): 2164-5515

ISSN (Electronic): 2164-554X

Publication date (Electronic, pub): 4 October 2022

Publication date (Electronic, collection): 2022

Publication date PMC-release: 4 October 2022

Volume: 18

Issue: 6

Electronic Location Identifier: 2122507

Affiliations

[a ]Department of Pharmacology, University of Minnesota; , Minneapolis, MN, USA

[b ]Center for Immunology, University of Minnesota; , Minneapolis, MN, USA

[c ]School of Medicine, Department of Psychiatry and Behavioral Sciences, University of Washington; , Seattle, WA, USA

Author notes

CONTACT Marco Pravetoni mprave@ 123456uw.edu Department of Psychiatry and Behavorial Sciences, University of Washington, Harborview Research & Training Building; , 300 9th Ave, Seattle, WA 98104, USA.

[*]

Co-first author.

Author information

Dustin Hicks https://orcid.org/0000-0002-6934-4050

Carly Baehr https://orcid.org/0000-0002-3395-6776

Pedro Silva-Ortiz https://orcid.org/0000-0001-6135-9111

Aaron Khaimraj https://orcid.org/0000-0002-2588-0900

Diego Luengas https://orcid.org/0000-0002-4550-841X

Fatima A. Hamid https://orcid.org/0000-0003-3496-2104

Marco Pravetoni https://orcid.org/0000-0003-1036-0184

Article

Publisher ID: 2122507

DOI: 10.1080/21645515.2022.2122507

PMC ID: 9746415

PubMed ID: 36194773

SO-VID: f618c507-7a38-4e5f-ab62-b1d311f29d1a

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License ( http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way.

Advancing humanized monoclonal antibody for counteracting fentanyl toxicity towards clinical development

Read this article at

ABSTRACT

Related collections

Bacterial extracellular vesicles

Most cited references 78

Biophysical properties of the clinical-stage antibody landscape.

Standard conformations for the canonical structures of immunoglobulins.

Fentanyl, fentanyl analogs and novel synthetic opioids: A comprehensive review.

Author and article information

Journal

Affiliations

Author notes

Author information

Article

History

Page count

Categories

Comments

Comment on this article

Similar content 357

Cited by 8