title: Deciphering the In Vivo Performance of a Monoclonal Antibody to Neutralize Its Soluble Target at the Site of Action in a Mouse Collagen-Induced Arthritis Model.
abstract: OBJECTIVE
  Study the disposition and target-neutralization capability of an anti-interleukin-6 (IL-6) monoclonal antibody (mAb) at the joint in a mouse collagen-induced arthritis (CIA) model.
  
  
  METHODS
  A mechanistic pharmacokinetic/pharmacodynamic study was conducted in a mouse CIA model using CNTO 345, a rat anti-mouse IL-6 mAb, as model compound. The drug, total/free IL-6 concentrations in both serum and joint lavage fluid were quantitatively assessed and compared to those in the normal control mice.
  
  
  RESULTS
  CNTO 345 exhibited higher clearance and significantly higher joint lavage/serum ratio in the CIA mice than in the normal control mice. The mAb concentrations in the joint lavage are approximately proportional to the serum concentrations at all the time points being examined. Dosing of CNTO 345 led to sustained free IL-6 suppression in both serum and joint lavage in a dose-dependent manner. A dose-dependent increase in total IL-6 was observed in serum, but not in the joint lavage fluid. Though no change in disease activity was observed following a single dose of anti-IL-6 mAb at peak of the disease, a dose-dependent decrease in serum amyloid A, a downstream biomarker of IL-6, was observed.
  
  
  CONCLUSIONS
  This study provided quantitative assessments of the distribution and target-neutralization capability of an anti-IL-6 mAb at the site of action in an animal disease model.
authors.affiliation: Biologics Clinical Pharmacology, Janssen Research & Development, LLC, Spring House, Pennsylvania, USA.
authors.forename: Weirong
authors.initials: W
authors.lastname: Wang
authors.affiliation: Biologics Clinical Pharmacology, Janssen Research & Development, LLC, Spring House, Pennsylvania, USA.
authors.forename: Thomas S
authors.initials: TS
authors.lastname: McIntosh
authors.affiliation: Biologics Clinical Pharmacology, Janssen Research & Development, LLC, Spring House, Pennsylvania, USA.
authors.forename: Xiling
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Biologics Clinical Pharmacology, Janssen Research & Development, LLC, Spring House, Pennsylvania, USA.
authors.forename: Rajitha
authors.initials: R
authors.lastname: Doddareddy
authors.affiliation: Biologics Clinical Pharmacology, Janssen Research & Development, LLC, Spring House, Pennsylvania, USA.
authors.forename: Elayne C
authors.initials: EC
authors.lastname: Dell
authors.affiliation: Biologics Clinical Pharmacology, Janssen Research & Development, LLC, Spring House, Pennsylvania, USA. hzhou2@its.jnj.com.|Quantitative Sciences, Janssen Research & Development, LLC, Spring House, Pennsylvania, USA. hzhou2@its.jnj.com.
authors.forename: Honghui
authors.initials: H
authors.lastname: Zhou
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D001169:Arthritis, Experimental / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology; D003094:Collagen; D015850:Interleukin-6 / Q000032:analysis / Q000097:blood / Q000276:immunology*; D007596:Joints / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D051379:Mice; D008811:Mice, Inbred DBA; D051381:Rats
chemical_list: D000911:Antibodies, Monoclonal; D015850:Interleukin-6; C577686:interleukin-6, mouse; D003094:Collagen
keywords: CIA mouse model; mAb; pharmacokinetics; target engagement; tissue distribution