Pharmacology of AMG 181, a human anti-α4 ß7 antibody that specifically alters trafficking of gut-homing T cells.

BACKGROUND AND PURPOSE: AMG 181 is a human anti-α4 ß7 antibody currently in phase 1 and 2 trials in subjects with inflammatory bowel diseases. AMG 181 specifically targets the α4 ß7 integrin heterodimer, blocking its interaction with mucosal addressin cell adhesion molecule-1 (MAdCAM-1), the principal ligand that mediates α4 ß7 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 α4 ß7 , but not α4 ß1 or αE ß7 , and potently inhibited α4 ß7 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 80 mg·kg(-1) , while AUC increased more than dose proportionally. Following s.c. 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 two- to threefold after 13 weekly 80 mg·kg(-1) 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, α4 ß7 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.

Transport of cyanide into guinea pig cardiac mitochondria.

The transport of cyanide (CN) into cells has been presumed to be by passive diffusion. Recently, there have been reports that CN, in the form of an anion, may enter the cell by active or facilitated transport. To characterize the mechanism(s) and kinetics of CN movement across the cell membrane, we measured the rate of 14CN (Na salt) uptake into guinea-pig mitochondria. Initial velocities of CN movement into mitochondria were determined at time points ranging from 10-100 msec and at CN concentrations ranging from 1 microM-10 mM using a rapid filtration device. A Hofstee plot of the data suggests that an active or facilitated transport predominates at lower CN concentrations (less than 10 microM), whereas passive diffusion of CN predominates at higher CN concentrations. The kinetic constants for the active phase transport were Jmax = 0.9 pmol/ms and Kt = 14 microM. These results suggest that a large portion of CN movement across the cell membrane is due to an active or facilitated transport phenomenon.