Pharmacology of AMG 181, a human anti-α4β7 antibody that specifically alters trafficking of gut-homing T cells

Background and Purpose AMG 181 is a human anti-47 antibody currently in phase 1 and 2 trials in subjects with inflammatory bowel diseases. AMG 181 specifically targets the 47 integrin heterodimer, blocking its interaction with mucosal addressin cell adhesion molecule-1 (MAdCAM-1), the principal ligand that mediates 47 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 i.v. or s.c. administration in cynomolgus monkeys for up to 13 weeks. Key Results AMG 181 bound to 47, but not 41 or E7, and potently inhibited 47 binding to MAdCAM-1 (but not vascular cell adhesion molecule-1) and thus inhibited T cell adhesion. Following single i.v. administration, AMG 181 Cmax was dose proportional from 0.01 to 80mg center dot kg1, while AUC increased more than dose proportionally. Following s.c. administration, dose-proportional exposure was observed with single dose ranging from 5 to 80mg center dot kg1 and after 13 weekly doses at levels between 20 and 80mg center dot kg1. AMG 181 accumulated two- to threefold after 13 weekly 80mg center dot kg1 i.v. or s.c. doses. AMG 181 had an s.c. 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, 47 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.