Oral treatment with a novel small molecule alpha 4 integrin antagonist, AJM300, prevents the development of experimental colitis in mice.

Abstract

BACKGROUND AND AIMS:

Inhibition of lymphocyte trafficking by treatment with an anti-α4 integrin antibody has been clinically validated as a therapeutic approach for inflammatory bowel disease (IBD), and the orally effective 'anti-α4 integrin therapy' may be more convenient in clinical practice. The aim of this study was to investigate the pharmacological profile and anti-inflammatory effect of a novel, orally active small molecule α4 integrin antagonist, AJM300.

METHODS:

The binding specificity/potency of HCA2969 (the active metabolite of AJM300) were investigated in vitro. The pharmacodynamics for α4 integrin antagonism of AJM300 was investigated in mice. The anti-inflammatory effect of AJM300 fed in a diet and the anti-α4 integrin monoclonal antibody was evaluated in a mouse colitis model induced by transfer of IL-10 deficient T cells.

RESULTS:

HCA2969 selectively inhibited the in vitro binding of α4 integrin (α4β7/α4β1) to the cell adhesion molecules. Oral treatment with AJM300 dose-dependently inhibited lymphocyte homing to Peyer's patches and increased the peripheral lymphocyte count in the same dose range. AJM300 dose-dependently prevented the development of experimental colitis in mice. A significant inhibition of colon weight increase was accompanied by inhibition of T-cell infiltration into the lamina propria of colon. The maximum efficacy of AJM300 (1% diet) was comparable to that achieved by the saturated α4 integrin blockade with antibody.

CONCLUSIONS:

Oral treatment with the selective small molecule α4 integrin antagonist (AJM300) prevented the development of colitis and its efficacy was comparable to that of the anti-α4 integrin antibody.

• Authors: Toshihiko Sugiura, Shunsuke Kageyama, Ayatoshi Andou, Tomoko Miyazawa, Chieko Ejima, Akira Nakayama, Taeko Dohi, Hiroyuki Eda
• Journal: Journal of Crohn's & colitis (J Crohns Colitis) Vol. 7 Issue 11 Pg. e533-42 (Dec 2013) ISSN: 1876-4479 [Electronic] England
• PMID: 23623333 (Publication Type: Journal Article)
• Copyright: Copyright © 2013 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.

Chemical References

• AJM300
• Antibodies, Monoclonal
• Cell Adhesion Molecules
• Quinazolinones
• Integrin alpha4
• Phenylalanine

Topics

• Administration, Oral
• Animals
• Antibodies, Monoclonal (pharmacology)
• Biopsy, Needle
• Cell Adhesion Molecules (drug effects)
• Colitis, Ulcerative (drug therapy, pathology, prevention & control)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Drug Administration Schedule
• Drug Delivery Systems (methods)
• Female
• Immunohistochemistry
• Integrin alpha4 (drug effects)
• Male
• Mice
• Mice, Inbred BALB C
• Phenylalanine (administration & dosage, analogs & derivatives)
• Quinazolinones (administration & dosage)
• Random Allocation
• Reference Values