Abstract
BACKGROUND AND PURPOSE: AMG 181 is a human anti-α(4) β(7) antibody currently in phases 1 and 2 trials in subjects with inflammatory bowel diseases. AMG 181 specifically targets the α(4) β(7) integrin heterodimer, blocking its interaction with MAdCAM-1, the principal ligand that mediates α(4) β(7) T cell gut-homing.
EXPERIMENTAL APPROACH: We studied the in vitro pharmacology of AMG 181, and the pharmacokinetics and pharmacodynamics of AMG 181 after single or weekly intravenous or subcutaneous administration in cynomolgus monkeys for up to 13 weeks.
KEY RESULTS: AMG 181 bound to α(4) β(7) , but not α(4) β(1) or α(E) β(7) , and potently inhibited α(4) β(7) binding to MAdCAM-1 (not VCAM-1) and thus inhibited T cell adhesion. Following single intravenous administration, AMG 181 C(max) was dose-proportional from 0.01 to 80 mg kg(-1) , while AUC increased more than dose proportionally. Following subcutaneous administration, dose-proportional exposure was observed with single dose ranging from 5 to 80 mg kg(-1) and after 13 weekly doses at levels between 20 and 80 mg kg(-1) . AMG 181 accumulated 2- to 3-fold after 13 weekly 80 mg kg(-1) intravenous or subcutaneous doses. AMG 181 had a subcutaneous bioavailability of 80%. The linear elimination half-life was 12 days, with a volume of distribution close to the intravascular plasma space. The mean trend for the magnitude and duration of AMG 181 exposure, immunogenicity, α(4) β(7) receptor occupancy, and elevation in gut-homing CD4+ central memory T cell count displayed apparent correlations.
CONCLUSIONS AND IMPLICATIONS: AMG 181 has in vitro pharmacology, and pharmacokinetic/pharmacodynamic and safety characteristics in cynomolgus monkeys that are suitable for further investigation in humans.