Pharmacology of AMG 181, a human anti‐α4β7 antibody that specifically alters trafficking of gut‐homing T cells. (12th April 2013)

• Record Type: Journal Article
• Authors: Pan, WJ; Hsu, H; Rees, WA; Lear, SP; Lee, F; Foltz, IN; Rathanaswami, P; Manchulenko, K; Chan, BM; Zhang, M; Xia, XZ; Patel, SK; Prince, PJ; Doherty, DR; Sheckler, CM; Reynhardt, KO; Krill, CD; Harder, BJ; Wisler, JA; Brandvig, JL; Lynch, JL; Anderson, AA; Wienkers, LC; Borie, DC
• Is Part Of: British journal of pharmacology. Volume 169:Number 1(2013:May)
• Page Start: 51
• Page End: 68
• Publication Date: 2013-04-12
• Subjects: Pharmacology -- Periodicals; Chemotherapy -- Periodicals; Drug Therapy -- Periodicals; Pharmacology -- Periodicals; 615.1
• DOI: 10.1111/bph.12134
• Languages: English
• ISSNs: 0007-1188

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="bph12134-sec-0001" sec-type="section"> <title>Background and Purpose</title> <p>AMG 181 is a human anti‐α<sub>4</sub>β<sub>7</sub> antibody currently in phase 1 and 2 trials in subjects with inflammatory bowel diseases. AMG 181 specifically targets the α<sub>4</sub>β<sub>7</sub> integrin heterodimer, blocking its interaction with mucosal addressin cell adhesion molecule‐1 (MAdCAM‐1), the principal ligand that mediates α<sub>4</sub>β<sub>7</sub> T cell gut‐homing.</p> </sec> <sec id="bph12134-sec-0002" sec-type="section"> <title>Experimental Approach</title> <p>We studied the <italic>in vitro</italic> 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.</p> </sec> <sec id="bph12134-sec-0003" sec-type="section"> <title>Key Results</title> <p>AMG 181 bound to α<sub>4</sub>β<sub>7</sub>, but not α<sub>4</sub>β<sub>1</sub> or α<sub>E</sub>β<sub>7</sub>, and potently inhibited α<sub>4</sub>β<sub>7</sub> binding to MAdCAM‐1 (but not vascular cell adhesion molecule‐1) and thus inhibited T cell adhesion. Following single i.v. administration, AMG 181 <italic>C</italic><sub>max</sub> was dose proportional from 0.01 to 80 mg·kg<sup>−1</sup>, 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<sup>−1</sup> and after 13 weekly doses at levels between 20 and 80 mg·kg<sup>−1</sup>. AMG 181 accumulated two‐ to threefold after 13 weekly 80 mg·kg<sup>−1</sup> 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, α<sub>4</sub>β<sub>7</sub> receptor occupancy and elevation in gut‐homing CD4+ central memory T cell count displayed apparent correlations.</p> </sec> <sec id="bph12134-sec-0004" sec-type="section"> <title>Conclusions and Implications</title> <p>AMG 181 has <italic>in vitro</italic> pharmacology, and pharmacokinetic/pharmacodynamic and safety characteristics in cynomolgus monkeys that are suitable for further investigation in humans.</p> </sec> </abstract>