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Drug Metabolism and Disposition Fast Forward
First published on April 20, 2005; DOI: 10.1124/dmd.105.004234

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Received for publication February 23, 2005.
Revised April 14, 2005.
Accepted for publication April 15, 2005.

Monoclonal nicotine-specific antibodies reduce nicotine distribution to brain in rats: Dose- and affinity-response relationships

Dan E. Keyler 1, Sam A. Roiko 2, Elhabib Benlhabib 3, Mark G. LeSage 4, John V. St. Peter 5, Solomon Stewart 6, Steve Fuller 6, Chap T. Le 7, Paul R. Pentel 8*

1 Minneapolis Medical Research Foundation, University of Minnesota College of Pharmacy 2 Minneapolis Medical Reserach Foundation, University of Minnesota Medical School 3 University of MInnesota Medical School 4 Minneapolis Medical Research Foundation 5 University of MInnesota College of Pharmacy 6 Nabi Biopharmaceuticals 7 University of Minnesota, School of Public Health, Department of Biostatistics 8 U. Minnesota and Minneapolis Medical Research Foundation

* Address correspondence to: E-mail: pentel{at}umn.edu

Abstract

Vaccination against nicotine is being studied as a potential treatment for nicotine dependence. Some of the limitations of vaccination, such as variability in antibody titer and affinity, might be overcome by instead using passive immunization with nicotine-specific monoclonal antibodies. The effects of antibodies on nicotine distribution to brain were studied using nicotine-specific monoclonal antibodies (NICmAbs) with Kds ranging from 60 to 250 nM and a high affinity polyclonal rabbit antiserum (Kd 1.6 nM). Pretreatment with NICmAb substantially increased the binding of nicotine in serum following a single nicotine dose, reduced the unbound nicotine concentration in serum, and reduced the distribution of nicotine to brain. Efficacy was directly related to antibody affinity for nicotine. Efficacy of the highest affinity NICmAb (NICmAb311) was dose-related, with the highest dose reducing nicotine distribution to brain by 78%. NICmAb311 decreased nicotine clearance by 90% and prolonged the terminal half-life of nicotine by 120%. At equivalent doses, NICmAb311 was less effective than the higher affinity rabbit antiserum, but comparable efficacy could be achieved by increasing the NICmAb311 dose. These data suggest that passive immunization with nicotine-specific monoclonal antibodies substantially alters nicotine pharmacokinetics in a manner similar to that previously reported for vaccination against nicotine. Antibody efficacy is a function of both dose and affinity for nicotine.


Key words: antibodies, drug distribution, immunotherapy


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