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

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.