title: Preclinical development of AMG 139, a human antibody specifically targeting IL-23.
abstract: OBJECTIVE
  AMG 139 is a human anti-IL-23 antibody currently in a phase II trial for treating Crohn's disease. To support its clinical development in humans, in vitro assays and in vivo studies were conducted in cynomolgus monkeys to determine the pharmacology, preclinical characteristics and safety of this monoclonal antibody.
  
  
  METHODS
  The in vitro pharmacology, pharmacokinetics (PK), pharmacodynamics and toxicology of AMG 139, after single or weekly i.v. or s.c. administration for up to 26 weeks, were evaluated in cynomolgus monkeys.
  
  
  RESULTS
  AMG 139 bound with high affinity to both human and cynomolgus monkey IL-23 and specifically neutralized the biological activity of IL-23 without binding or blocking IL-12. After a single dose, linear PK with s.c. bioavailability of 81% and mean half-life of 8.4-13 days were observed. After weekly s.c. dosing for 3 or 6 months, AMG 139 exposure increased approximately dose-proportionally from 30 to 300 mg·kg(-1) and mean accumulation between the first and last dose ranged from 2- to 3.5-fold. Peripheral blood immunophenotyping, T-cell-dependent antigen responses and bone formation markers were not different between AMG 139 and vehicle treatment. No adverse clinical signs, effects on body weight, vital signs, ophthalmic parameters, clinical pathology, ECG, organ weights or histopathology were observed in the monkeys with the highest dose of AMG 139 tested (300 mg·kg(-1) s.c. or i.v.).
  
  
  CONCLUSIONS
  The in vitro pharmacology, PK, immunogenicity and safety characteristics of AMG 139 in cynomolgus monkeys support its continued clinical development for the treatment of various inflammatory diseases.
authors.affiliation: Pharmacokinetics and Drug Metabolism, Amgen Inc., Seattle, WA, USA.
authors.forename: K
authors.initials: K
authors.lastname: Köck
authors.forename: W J
authors.initials: WJ
authors.lastname: Pan
authors.forename: J M
authors.initials: JM
authors.lastname: Gow
authors.forename: M J
authors.initials: MJ
authors.lastname: Horner
authors.forename: J P
authors.initials: JP
authors.lastname: Gibbs
authors.forename: A
authors.initials: A
authors.lastname: Colbert
authors.forename: T J
authors.initials: TJ
authors.lastname: Goletz
authors.forename: K J
authors.initials: KJ
authors.lastname: Newhall
authors.forename: W A
authors.initials: WA
authors.lastname: Rees
authors.forename: Y
authors.initials: Y
authors.lastname: Sun
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.forename: J C
authors.initials: JC
authors.lastname: O'Neill
authors.forename: A N
authors.initials: AN
authors.lastname: Umble-Romero
authors.forename: S P
authors.initials: SP
authors.lastname: Prokop
authors.forename: C D
authors.initials: CD
authors.lastname: Krill
authors.forename: L
authors.initials: L
authors.lastname: Som
authors.forename: S A
authors.initials: SA
authors.lastname: Buntich
authors.forename: M W
authors.initials: MW
authors.lastname: Trimble
authors.forename: W H
authors.initials: WH
authors.lastname: Tsuji
authors.forename: J E
authors.initials: JE
authors.lastname: Towne
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity; D061067:Antibodies, Monoclonal, Humanized; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D053759:Interleukin-23 / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D007694:Killer Cells, Natural / Q000187:drug effects / Q000378:metabolism; D008252:Macaca fascicularis; D008297:Male; D018675:Toxicity Tests
chemical_list: C000600954:AMG 139; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D053759:Interleukin-23; D007371:Interferon-gamma