title: Combined active and passive immunization against nicotine: minimizing monoclonal antibody requirements using a target antibody concentration strategy.
abstract: Nicotine vaccines have shown preliminary evidence of efficacy for enhancing smoking cessation rates, but the serum nicotine-specific antibody (NicAb) concentrations produced are highly variable and many subjects do not develop effective levels. As an alternative to vaccination, passive immunization with nicotine-specific monoclonal antibodies could produce more uniform serum NicAb concentrations, but its use is limited by their high cost and shorter elimination half-life. This study investigated supplementing vaccination with monoclonal antibodies in a targeted fashion to increase vaccine efficacy while minimizing the required monoclonal antibody dose. Rats were vaccinated and then given individualized supplemental doses of the nicotine-specific monoclonal antibody Nic311 to achieve a target total serum NicAb concentration known to be effective for blocking locomotor sensitization (LMS) to nicotine. Rats received vaccine, Nic311, both, or neither, followed by 0.3 mg/kg nicotine s.c. for 10 days to produce LMS. Combination immunotherapy completely blocked the development of LMS, while monotherapy with vaccine or Nic311 alone was only minimally effective. Lower brain nicotine levels were associated with reduced locomotor activity averaged over days 7-10. Despite its greater efficacy, combination immunotherapy did not reduce the variability in the resulting total serum NicAb concentrations. Variability in total serum NicAb concentrations was contributed to by both vaccine-generated antibody and by Nic311. These data show that combination immunotherapy, using a Nic311 dose that is by itself only minimally effective, can substantially enhance nicotine vaccine efficacy. However, variability in serum NicAb levels with combination immunotherapy may make translation of this approach challenging.
authors.affiliation: Department of Pharmacology, University of Minnesota, Minneapolis, MN 55455, USA. corni026@umn.edu
authors.forename: Katherine E
authors.initials: KE
authors.lastname: Cornish
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Harris
authors.forename: Mark G
authors.initials: MG
authors.lastname: LeSage
authors.forename: Dan E
authors.initials: DE
authors.lastname: Keyler
authors.forename: Danielle
authors.initials: D
authors.lastname: Burroughs
authors.forename: Cathy
authors.initials: C
authors.lastname: Earley
authors.forename: Paul R
authors.initials: PR
authors.lastname: Pentel
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000915:Antibody Affinity / Q000276:immunology; D000917:Antibody Formation / Q000276:immunology; D001921:Brain / Q000378:metabolism; D005240:Feasibility Studies; D007116:Immunization, Passive / Q000379:methods; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009538:Nicotine / Q000097:blood / Q000276:immunology* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012907:Smoking / Q000276:immunology; D016540:Smoking Cessation / Q000379:methods*; D000074606:Smoking Prevention; D014018:Tissue Distribution; D014611:Vaccination / Q000379:methods; D014612:Vaccines / Q000008:administration & dosage / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; C557119:NicVAX; D014612:Vaccines; D009538:Nicotine