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Pharmacology of AMG 181, a human anti-?4 ?7 antibody that specifically alters trafficking of gut-homing T cells.

ABSTRACT: AMG 181 is a human anti-?4 ?7 antibody currently in phase 1 and 2 trials in subjects with inflammatory bowel diseases. AMG 181 specifically targets the ?4 ?7 integrin heterodimer, blocking its interaction with mucosal addressin cell adhesion molecule-1 (MAdCAM-1), the principal ligand that mediates ?4 ?7 T cell gut-homing.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.AMG 181 bound to ?4 ?7 , but not ?4 ?1 or ?E ?7 , and potently inhibited ?4 ?7 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, ?4 ?7 receptor occupancy and elevation in gut-homing CD4+ central memory T cell count displayed apparent correlations.AMG 181 has in vitro pharmacology, and pharmacokinetic/pharmacodynamic and safety characteristics in cynomolgus monkeys that are suitable for further investigation in humans.

SUBMITTER: Pan WJ

PROVIDER: S-EPMC3632238 | biostudies-other | 2013 May

REPOSITORIES: biostudies-other

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

Pan W J WJ Hsu H H Rees W A WA Lear S P SP Lee F F Foltz I N IN Rathanaswami P P Manchulenko K K Chan B M BM Zhang M M Xia X Z XZ Patel S K SK Prince P J PJ Doherty D R DR Sheckler C M CM Reynhardt K O KO Krill C D CD Harder B J BJ Wisler J A JA Brandvig J L JL Lynch J L JL Anderson A A AA Wienkers L C LC Borie D C DC

British journal of pharmacology 20130501 1

<h4>Background and purpose</h4>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.<h4>Experimental approach</h4>We studied the in vitro pharmacology of AMG 181, and the pharmacokinetics and pharmacodynamics of AMG 181 after sin ...[more]

PMID: 23425116

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Project description:The mammalian intestinal tract is heavily colonized with a dense, complex, and diversified microbial populations. In healthy individuals, an array of epithelial antimicrobial agents is secreted in the gut to aid intestinal homeostasis. Enterochromaffin cells (EC) in the intestinal epithelium are a major source of chromogranin A (CgA), which is a pro-hormone and can be cleaved into many bioactive peptides that include catestatin (CST). This study was carried out to evaluate the possible impact of CST on gut microbiota in vivo using a mouse model. The CST (Human CgA352-372) or normal saline was intrarectally administered in C57BL/6 male mice for 6 days and then sacrificed. Feces and colonic mucosa tissue samples were collected, DNA was extracted, the V4 region of bacterial 16S rRNA gene was amplified and subjected to MiSeq Illumina sequencing. The ?-diversity was calculated using Chao 1 and ?-diversity was determined using QIIME. Differences at the genus level were determined using partial least square discriminant analysis (PLS-DA). Phylogenetic investigation of communities by reconstruction of unobserved states (PICRUSt) was used to predict functional capacity of bacterial community. CST treatment did not modify bacterial richness in fecal and colonic mucosa-associated microbiota; however, treatment significantly modified bacterial community composition between the groups. Also, CST-treated mice had a significantly lower relative abundance of Firmicutes and higher abundance of Bacteroidetes, observed only in fecal samples. However, at lower phylogenetic levels, PLS-DA analysis revealed that some bacterial taxa were significantly associated with the CST-treated mice in both fecal and colonic mucosa samples. In addition, differences in predicted microbial functional pathways in both fecal and colonic mucosa samples were detected. The results support the hypothesis that CST treatment modulates gut microbiota composition under non-pathophysiological conditions, however, the result of this study needs to be further validated in a larger experiment. The data may open new avenues for the development of a potential new line of antimicrobial peptides and their use as therapeutic agents to treat several inflammatory conditions of the gastrointestinal tract, such as inflammatory bowel disease (IBD), inflammatory bowel syndrome (IBS), or other health conditions.

Dataset Information

Pharmacology of AMG 181, a human anti-?4 ?7 antibody that specifically alters trafficking of gut-homing T cells.

Publications

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

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