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

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 i...

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Autores principales:	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
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/20970bf6715646829279dd4d4d1ec7c3
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spelling	oai:doaj.org-article:20970bf6715646829279dd4d4d1ec7c32021-12-02T20:08:50ZAttenuating nicotine's effects with high affinity human anti-nicotine monoclonal antibodies.1932-620310.1371/journal.pone.0254247https://doaj.org/article/20970bf6715646829279dd4d4d1ec7c32021-01-01T00:00:00Zhttps://doi.org/10.1371/journal.pone.0254247https://doaj.org/toc/1932-6203Use 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.Michael D RaleighNicola BeltraminelliStephanie FallotMark G LeSageAmy SaykaoPaul R PentelSteve FullerThomas ThistedZuzanna BiesovaStephen HorriganDarryl SampeyBin ZhouMatthew W KalnikPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 16, Iss 7, p e0254247 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q 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 Attenuating nicotine's effects with high affinity human anti-nicotine monoclonal antibodies.
description	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.
format	article
author	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
author_facet	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
author_sort	Michael D Raleigh
title	Attenuating nicotine's effects with high affinity human anti-nicotine monoclonal antibodies.
title_short	Attenuating nicotine's effects with high affinity human anti-nicotine monoclonal antibodies.
title_full	Attenuating nicotine's effects with high affinity human anti-nicotine monoclonal antibodies.
title_fullStr	Attenuating nicotine's effects with high affinity human anti-nicotine monoclonal antibodies.
title_full_unstemmed	Attenuating nicotine's effects with high affinity human anti-nicotine monoclonal antibodies.
title_sort	attenuating nicotine's effects with high affinity human anti-nicotine monoclonal antibodies.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/20970bf6715646829279dd4d4d1ec7c3
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Attenuating nicotine's effects with high affinity human anti-nicotine monoclonal antibodies.

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