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

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

doi:10.1371/journal.pone.0254247

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.

Highlights

Tobacco use is the leading preventable cause of illness and death in the world today [1]
enzyme-linked immunosorbant assay (ELISA) screening of 54 million single monoclonal antibodies (mAbs) expressing B-cells for the small subset that bound S(–)-nicotine and did not bind S-(–)-cotinine produced a set of 32 novel and unique, fully human anti-nicotine mAbs
The key findings of this study were that the fully human anti-nicotine mAb, Antidote Therapeutics (ATI)-1013: 1) had a very high affinity and selectivity towards nicotine; 2) had a very long half-life in rodent models; 3) dose-dependently reduced nicotine distribution to brain following multiple doses of nicotine simulating very heavy smoking; 4) significantly reduced the reinforcing effects of nicotine in a self-administration model; and 5) was demonstrated to be safe in a non-GLP toxicology study. These data suggest that ATI-1013 is safe, long-lasting, and at a sufficient dose could be an effective treatment for tobacco use disorders

Summary

Introduction

Tobacco use is the leading preventable cause of illness and death in the world today [1]. Over 36 million Americans smoke tobacco [2]. Sixteen million live with a smoking-attributable disease and yet 30–40% of these individuals continue to smoke [3]. Efficacy of high affinity human anti-nicotine monoclonal antibodies collection and analysis, decision to publish, or preparation of the manuscript. As the prime awardee of the NicmAb Strategic Alliance, Antidote Therapeutics (ATI) had a significant role in study design, data collection and analysis, decision to publish, or preparation of the manuscript as this program was run as a consortium with regular steering committee meetings with all subawardees and subcontractors, led by ATI

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