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

Autor: 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
Jazyk: angličtina
Rok vydání: 2021
Předmět:
Zdroj: PLoS ONE, Vol 16, Iss 7, p e0254247 (2021)
Druh dokumentu: article
ISSN: 1932-6203
DOI: 10.1371/journal.pone.0254247
Popis: 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.
Databáze: Directory of Open Access Journals
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