Structurally distinct nicotine immunogens elicit antibodies with non-overlapping specificities

M. Pravetoni, D. E. Keyler, R. R. Pidaparthi, F. I. Carroll, S. P. Runyon, M. P. Murtaugh, C. A. Earley, P. R. Pentel

Research output: Contribution to journalArticlepeer-review

49 Scopus citations

Abstract

Nicotine conjugate vaccine efficacy is limited by the concentration of nicotine-specific antibodies that can be reliably generated in serum. Previous studies suggest that the concurrent use of 2 structurally distinct nicotine immunogens in rats can generate additive antibody responses by stimulating distinct B cell populations. In the current study we investigated whether it is possible to identify a third immunologically distinct nicotine immunogen. The new 1′-SNic immunogen (2S)-N,N′-(disulfanediyldiethane-2,1-diyl) bis[4-(2-pyridin-3-ylpyrrolidin-1-yl)butanamide] conjugated to keyhole limpet hemocyanin (KLH) differed from the existing immunogens 3′-AmNic-rEPA and 6-CMUNic-BSA in linker position, linker composition, conjugation chemistry, and carrier protein. Vaccination of rats with 1′-SNic-KLH elicited high concentrations of high affinity nicotine-specific antibodies. The antibodies produced in response to 1′-SNic-KLH did not appreciably cross-react in ELISA with either 3′-AmNic-rEPA or 6-CMUNic-BSA or vice versa, showing that the B cell populations activated by each of these nicotine immunogens were non-overlapping and distinct. Nicotine retention in serum was increased and nicotine distribution to brain substantially reduced in rats vaccinated with 1′-SNic-KLH compared to controls. Effects of 1′-SNic-KLH on nicotine distribution were comparable to those of 3′-AmNic-rEPA which has progressed to late stage clinical trials as an adjunct to smoking cessation. These data show that it is possible to design multiple immunogens from a small molecule such as nicotine which elicit independent immune responses. This approach could be applicable to other addiction vaccines or small molecule targets as well.

Original languageEnglish (US)
Pages (from-to)543-550
Number of pages8
JournalBiochemical Pharmacology
Volume83
Issue number4
DOIs
StatePublished - Feb 15 2012

Bibliographical note

Funding Information:
The 3′-AmNic–rEPA immunogen and rEPA carrier protein were gifts of Nabi Biopharmaceuticals. Internal standard for the nicotine assay was a gift from P Jacob (University of California, San Francisco). Supported by NIH grants DA10714 , DA010714-13S1 , and a Career Development Award from the Minneapolis Medical Research Foundation (MP) .

Keywords

  • Addiction
  • Immunogenicity
  • Immunotherapy
  • Nicotine
  • Vaccine

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