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Comparative Study
.2013 May;169(1):51-68.
doi: 10.1111/bph.12134.

Pharmacology of AMG 181, a human anti-α4 β7 antibody that specifically alters trafficking of gut-homing T cells

Affiliations
Comparative Study

Pharmacology of AMG 181, a human anti-α4 β7 antibody that specifically alters trafficking of gut-homing T cells

W J Pan et al. Br J Pharmacol.2013 May.

Abstract

Background and purpose: AMG 181 is a human anti-α4 β7 antibody currently in phase 1 and 2 trials in subjects with inflammatory bowel diseases. AMG 181 specifically targets the α4 β7 integrin heterodimer, blocking its interaction with mucosal addressin cell adhesion molecule-1 (MAdCAM-1), the principal ligand that mediates α4 β7 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 β7 , but not α4 β1 or αE β7 , and potently inhibited α4 β7 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 β7 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.

© 2013 Amgen, Inc. British Journal of Pharmacology © 2013 The British Pharmacological Society.

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Figures

Figure 1
Figure 1
AMG 181 binds to α4β7 receptors on human CD4+CD45RA-memory T cells as well as on cynomolgus monkey CD4+CD28+CD95+ central memory T cells (A), thus blocks binding of MAdCAM-1 to α4β7 receptors (B). Symbols represent observations (mean ± SEM), while lines represent the four-parameter Hill equation fitted curves. For the binding study on monkey T cells (n = 2), range is plotted instead of SEM (A). For the blocking of binding study on monkey T cells (2 sets of experiments at different titrated AMG 181 concentrations), individual observations are plotted (B).
Figure 2
Figure 2
AMG 181 binds to both low- and high-affinity conformations of α4β7: human PBMCs were stained with 1 μg·mL−1 of biotinylated MAdCAM-Fc (A, B) or biotinylated AMG 181 (C, D) in the absence (A, C) or presence (B, D) of 1 mM Mn2+ as indicated. MAdCAM-Fc or AMG 181 binding to the human CD4+CD45RA-memory T cells was measured by FACS analysis.X-axis represents fluorescence intensity of staining with biotinylated MAdCAM-Fc (upper panels) or biotinylated AMG 181 (lower panel) plus streptavidin-PE.Y-axis is the cell count.
Figure 3
Figure 3
The CD4+CD45RA-memory T cell population was gated to assess MAdCAM-Fc binding in the absence (A) or presence (B) of retinoic acid.X-axis represents fluorescence intensity and theY-axis is the cell count. AMG 181 blocks MAdCAM-Fc binding to retinoic acid-induced α4β7 on human CD4+CD45RA-memory T cells (C). Symbol represents observations, while line represents the four-parameter Hill equation fitted curve.
Figure 4
Figure 4
AMG 181 inhibits α4β7 : MAdCAM-1-mediated HuT78 cell, and primary human and cynomolgus monkey T cell adhesion. Symbols represent observations (mean ± SEM), while lines represent the four-parameter Hill equation fitted curves.
Figure 5
Figure 5
AMG 181 does not block VCAM-1 binding to T cells (A) or VCAM-1-mediated T cell adhesion (B).
Figure 6
Figure 6
Mean (±SD) serum AMG 181 concentration–time profiles after single (A) or multiple (B) s.c. or i.v. administrations in cynomolgus monkeys.
Figure 7
Figure 7
Percent change from pre-dose baseline of CD4+ central memory cell count and α4β7 receptor occupancy after single i.v. or s.c. dose of AMG 181 in cynomolgus monkeys (symbol: individual observation; line: mean): α4β7 receptor occupancy (A); cell count (B and C); α4β7high cell count (D).
Figure 8
Figure 8
Percent change from pre-dose baseline after two weekly s.c. doses of AMG 181 in cynomolgus monkeys (symbol: individual observation; line: mean): total lymphocytes (A); total CD4+ cells (B); total CD4+ central memory cells (C); α4β7low CD4+ central memory cells (D); α4β7high CD4+ central memory cells (E).
Figure 9
Figure 9
Percent change from pre-dose baseline after 13 weekly s.c. or i.v. doses of AMG 181 in cynomolgus monkeys (symbol: individual observation; line: mean): rate of free α4β7 receptor (100% minus receptor occupancy) on CD4+ central memory cell (A); CD4+ central memory cell count (B).
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