Monoclonal Nicotine-Specific Antibodies Reduce Nicotine Distribution to Brain in Rats: Dose- And Affinity-Response Relationships

Abstract

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 nicotinespecific monoclonal antibodies. The effects of antibodies on nicotine distribution to brain were studied using nicotine-specific monoclonal antibodies (NICmAbs) with K d values ranging from 60 to 250 nM and a high-affinity polyclonal rabbit antiserum (K d ‫؍‬ 1.6 nM). Pretreatment with NICmAbs substantially increased the binding of nicotine in serum after 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 nicotinespecific 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.

Other Pharmacological and Developing Treatments in Smoking Cessation/Nicotine Vaccines

“…Nikotin normalde serum proteinlerine %10 oranında bağlanır fakat deneysel çalışmalarda farelerde nikotinin antikorlara %80-99 oranında bağlandığı ve aşıların etkilerinin serumda oluştur-dukları yüksek antikor titreleri ile ortaya çıktığı gös-terilmiştir. Bu çalışmalarda nikotin antikorlarının nikotine bağlanması sonucunda kendiliğinden nikotin alımı gibi nikotin bağımlılığı ile ilişkili davranışlarda azalma olduğu gösterilmiştir (43,44) . Bağımlılık (kokain, eroin…) tedavisinde immunolojik yaklaşımlarla ilgili ilk çalışmalar 40 yıl önce başlamıştır.…”

Changes in maternal and fetal nicotine distribution after maternal administration of monoclonal nicotine-specific antibody to rats

“…Nic311 is a previously characterized murine monoclonal IgG 1 kappa with a high affinity (Kd = 60 nM) and specificity for nicotine; cross reactivity <1% for the nicotine metabolites cotinine, nicotine-N-oxide and nornicotine, and the endogenous nicotinic receptor ligands acetylcholine and choline) [20]. Nic311 was purified by protein G chromatography.…”

“…Nic311 was purified by protein G chromatography. Nic311 concentrations were measured by ELISA using nicotine hapten-polyglutamate as the coating antigen [20]. Nic311 was diluted in phosphate buffered saline for administration to a volume of 1 ml for the lower doses and 2 ml for the highest dose.…”

“…Nic311 was diluted in phosphate buffered saline for administration to a volume of 1 ml for the lower doses and 2 ml for the highest dose. Control antibody was human nonspecific IgG (Sandoglobulin, Sandoz, Vienna, Austria) which has no effect on nicotine distribution in rats and is comparable in this regard to nonspecific murine monoclonal antibody [20].…”

“…The Kd of Nic311 for nicotine (60 nM) is similar to that of serum from vaccinated rats (30-50 nM) so that comparisons of passive immunization with previous studies of vaccination are possible [20]. Nicotine was administered to the mother using a well characterized regimen which approximates the quantity and pattern of nicotine exposure from smoking [21].…”