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α 4 β 7 /α 4 β 1 Dual Integrin Antagonists Block α 4 β 7 -Dependent Adhesion under Shear Flow

The Journal of Pharmacology and Experimental Therapeutics, ISSN: 0022-3565, Vol: 302, Issue: 1, Page: 153-162
2002
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Article Description

The α 4 integrin, α 4 β 7, plays an important role in recruiting circulating lymphocytes to the gastrointestinal tract, where its ligand mucosal addressin cell adhesion molecule-1 (MAdCAM-1) is preferentially expressed on high endothelial venules (HEVs). Dual antagonists of α 4 β 1 and α 4 β 7, N -(2,6-dichlorobenzoyl)-( l )-4-(2′,6′-bis-methoxyphenyl)phenylalanine (TR14035) and N -{ N -[(3,5-dichlorobenzene)sulfonyl]-2-( R )-methylpropyl}-( d )-phenylalanine (compound 1), were tested for their ability to block the binding of α 4 β 7 -expressing cells to soluble ligand in suspension and under in vitro and in vivo shear flow. Compound 1 and TR14035 blocked the binding of human α 4 β 7 to an 125 I-MAdCAM-Ig fusion protein with IC 50 values of 2.93 and 0.75 nM, respectively. Both compounds inhibited binding of soluble ligands to α 4 β 1 or α 4 β 7 on cells of human or rodent origin with similar potency. Under shear flow in vitro, TR14035 and compound 1 blocked binding of human α 4 β 7 -expressing RPMI-8866 cells or murine mesenteric lymph node lymphocytes to MAdCAM-Ig with IC 50 values of 0.1 and 1 μM, respectively. Intravital microscopy was used to quantitate α 4 -dependent adhesion of fluorescent murine lymphocytes in Peyer’s patch HEVs. When cells were prestimulated with 2 mM Mn 2+ to activate α 4 β 7 binding to ligand, anti-α 4 monoclonal antibody (mAb) [10 mg/kg (mpk) i.v.] blocked adhesion by 95%, and anti-β 1 mAb did not block adhesion, demonstrating that this interaction was dependent on α 4 β 7. TR14035 blocked adhesion to HEVs [ED 50 of 0.01–0.1 mpk i.v.], and compound 1 blocked adhesion by 47% at 10 mpk i.v. Thus, α 4 β 7 /α 4 β 1 antagonists blocked α 4 β 7 -dependent adhesion of lymphocytes to HEVs under both in vitro and in vivo shear flow.

Bibliographic Details

Egger, Linda A; Kidambi, Usha; Cao, Jin; Van Riper, Gail; McCauley, Ermengilda; Mumford, Richard A; Amo, Suzanne; Lingham, Russell; Lanza, Thomas; Lin, Linus S; De Laszlo, Stephen E; Young, David N; Kopka, Ihor E; Tong, Sharon; Pikounis, Bill; Benson, Evelyn; Warwood, Sarah; Bargatze, Robert F; Hagmann, William K; Schmidt, John A; Detmers, Patricia A

Elsevier BV

Biochemistry, Genetics and Molecular Biology; Pharmacology, Toxicology and Pharmaceutics

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