Selection of a novel anti-nicotine vaccine: influence of antigen design on antibody function in mice
Anti-nicotine vaccines may aid smoking cessation via the induction of anti-nicotine antibodies (Ab) which reduce nicotine entering the brain, and hence the associated reward. Ab function depends on both the quantity (titer) and the quality (affinity) of the Ab. Anti-nicotine vaccines tested previous...
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Published in | PloS one Vol. 8; no. 10; p. e76557 |
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Main Authors | , , , , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
Public Library of Science
01.10.2013
Public Library of Science (PLoS) |
Subjects | |
Online Access | Get full text |
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Summary: | Anti-nicotine vaccines may aid smoking cessation via the induction of anti-nicotine antibodies (Ab) which reduce nicotine entering the brain, and hence the associated reward. Ab function depends on both the quantity (titer) and the quality (affinity) of the Ab. Anti-nicotine vaccines tested previously in clinical studies had poor efficacy despite high Ab titer, and this may be due to inadequate function if Ab of low affinity were induced. In this study, we designed and synthesized a series of novel nicotine-like haptens which were all linked to diphtheria toxoid (DT) as carrier, but which differed in the site of attachment of linker to nicotine, the nature of linker used, and the handle used to attach the hapten to DT. The resulting hapten conjugates were evaluated in a mouse model, using CpG (a TLR9 agonist) and aluminum hydroxide (Al(OH)3) as adjuvants, whereby Ab titers, affinity and function were evaluated using a radiolabeled nicotine challenge model. A series of additional linkers varying in length, rigidity and polarity were used with a single hapten to generate additional DT-conjugates, which were also tested in mice. Conjugates made with different haptens resulted in various titers of anti-nicotine Ab. Several haptens gave similarly high Ab titers, but among these, Ab affinity and hence function varied considerably. Linker also influenced Ab titer, affinity and function. These results demonstrate that immune responses induced in mice by nicotine-conjugate antigens are greatly influenced by hapten design including site of attachment of linker to nicotine, the nature of linker used, and the handle used to attach the hapten to DT. While both Ab titer and affinity contributed to function, affinity was more sensitive to antigen differences. |
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Bibliography: | Current address: Health Protection Agency, Process and Analytical Development Group, Porton Down, Salisbury, United Kingdom Current address: UCB Celltech, Slough, Berkshire, United Kingdom Conceived and designed the experiments: DP LJ DG DS D. Blakemore MS AB JC M. Badland D. Beal RG YW GM PW NZ M. Benoit KR JM HD MM. Performed the experiments: DP LJ DG DS D. Blakemore MS M. Badland D. Beal RG YW GM NZ M. Benoit KR. Analyzed the data: DP LJ DG DS D. Blakemore MS M. Badland D. Beal PW NZ M. Benoit KR JM HD MM. Contributed reagents/materials/analysis tools: DP LJ DG DS D. Blakemore MS M. Badland D. Beal RG YW GM NZ M. Benoit KR. Wrote the manuscript: DP LJ DG DS D. Blakemore MS AB JC M. Badland D. Beal RG YW GM PW NZ M. Benoit KR JM HD MM. Current address: C-Tech Innovation Ltd, Chester, United Kingdom Current address: School of Biosciences, University of Kent, Canterbury, Kent, United Kingdom Current address: School of Chemistry, the University of Manchester, Manchester, United Kingdom Competing Interests: All authors were either under paid employment or consultancy agreement with Pfizer at the time of these studies. Co-authors YW, GM, and RG were employed by Peakdale Molecular Ltd at the time of these studies. Pfizer is pursuing patents and product development on compounds that are mentioned in this paper. There are no marketed products to declare. DP, LJ, DG, DS, D. Blakemore, MS, AB, JC, M. Badland, D. Beal, PW, NZ, M. Benoit, KR, JM, HD and MM all hold shares or share options of Pfizer. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials. |
ISSN: | 1932-6203 1932-6203 |
DOI: | 10.1371/journal.pone.0076557 |