Attenuating nicotine's effects with high affinity human anti-nicotine monoclonal antibodies

Michael D. Raleigh, Nicola Beltraminelli, Stephanie Fallot, Mark G LeSage, Amy Saykao, Paul R Pentel, Steve Fuller, Thomas Thisted, Zuzanna Biesova, Stephen Horrigan, Darryl Sampey, Bin Zhou, Matthew W. Kalnik

Research output: Contribution to journalArticlepeer-review

Abstract

Use of nicotine-specific monoclonal antibodies (mAbs) to sequester and reduce nicotine distribution to brain has been proposed as a therapeutic approach to treat nicotine addiction (the basis of tobacco use disorder). A series of monoclonal antibodies with high affinity for nicotine (nic•mAbs) was isolated from B-cells of vaccinated smokers. Genes encoding 32 unique nicotine binding antibodies were cloned, and the mAbs expressed and tested by surface plasmon resonance to determine their affinity for S-(-)-nicotine. The highest affinity nic•mAbs had binding affinity constants (KD) between 5 and 67 nM. The 4 highest affinity nic•mAbs were selected to undergo additional secondary screening for antigen-specificity, protein properties (including aggregation and stability), and functional in vivo studies to evaluate their capacity for reducing nicotine distribution to brain in rats. The 2 most potent nic•mAbs in single-dose nicotine pharmacokinetic experiments were further tested in a dose-response in vivo study. The most potent lead, ATI-1013, was selected as the lead candidate based on the results of these studies. Pretreatment with 40 and 80 mg/kg ATI-1013 reduced brain nicotine levels by 56 and 95%, respectively, in a repeated nicotine dosing experiment simulating very heavy smoking. Nicotine self-administration was also significantly reduced in rats treated with ATI-1013. A pilot rat 30-day repeat-dose toxicology study (4x200mg/kg ATI-1013) in the presence of nicotine indicated no drug-related safety concerns. These data provide evidence that ATI-1013 could be a potential therapy for the treatment of nicotine addiction.

Original languageEnglish (US)
Article numbere0254247
JournalPloS one
Volume16
Issue number7 July
DOIs
StatePublished - Jul 2021

Bibliographical note

Publisher Copyright:
Copyright: © 2021 Raleigh et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

PubMed: MeSH publication types

  • Journal Article

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