Distinct but overlapping epitopes are involved in alpha 4 beta 7-mediated adhesion to vascular cell adhesion molecule-1, mucosal addressin-1, fibronectin, and lymphocyte aggregation.

Abstract

The mouse CD8+ T cell lymphoma TK1 expresses high levels of alpha 4 beta 7 integrin, which it can use to interact with multiple ligands including mucosal addressin-1 (MAdCAM-1), VCAM-1, and fibronectin. In addition, alpha 4 beta 7 can support TK1 cell aggregation. Here we have produced and characterized a panel of mAbs against alpha 4 beta 7 to define antigenic and functional epitopes associated with its distinct functions. One mAb, DATK32, is unique in recognizing an epitope specific to the alpha 4 beta 7 heterodimer. Furthermore, DATK32 induces TK1 cell aggregation yet inhibits TK1 cell adhesion to MAdCAM-1, VCAM-1, and fibronectin. Considered as a whole, the panel of anti-alpha 4 beta 7 mAbs studied define unique patterns of inhibition for alpha 4 beta 7 binding to each of its defined molecular ligands. We conclude that alpha 4 beta 7 interactions with MAdCAM-1, VCAM-1, and fibronectin can be modulated by Ab binding to distinct epitopes and thus probably involve functionally separable, although physically overlapping binding sites on this multifunctional integrin. These findings are consistent with the general observation that integrins use distinct, potentially differentially regulated interaction sites for adhesion to multiple ligands. Extension of these concepts to alpha 4 beta 7 has important considerations for understanding the roles of this integrin in lymphocyte homing to mucosal sites and in cell-cell interactions during the immune response.

Exposure‐response relationships of etrolizumab in patients with moderately‐to‐severely active ulcerative colitis

“…Etrolizumab is a novel, humanized anti-β7 integrin antibody that selectively inhibits both the α4β7:MAdCAM-1mediated leukocyte trafficking to the gut mucosa as well as αEβ7:Ecadherin-mediated leukocyte retention in the intra-epithelial space, reducing the inflammatory effects on the gut lining. [7][8][9] Seven trials (1 phase I [ABS4246g], 1 phase II [EUCALYPTUS], and 5 phase III [HIBISCUS I, HIBISCUS II, HICKORY, LAUREL, and GARDENIA]) using etrolizumab have been completed in patients with UC. [10][11][12][13][14][15] The dosing regimen of 105 mg every 4 weeks (Q4W) subcutaneously (s.c.) investigated in phase III studies was selected based on the totality of safety and efficacy data from both phase I and phase II studies.…”

“…Etrolizumab is a novel, humanized anti‐β7 integrin antibody that selectively inhibits both the α4β7:MAdCAM‐1‐mediated leukocyte trafficking to the gut mucosa as well as αEβ7:E‐cadherin‐mediated leukocyte retention in the intra‐epithelial space, reducing the inflammatory effects on the gut lining 7–9 . Seven trials (1 phase I [ABS4246g], 1 phase II [EUCALYPTUS], and 5 phase III [HIBISCUS I, HIBISCUS II, HICKORY, LAUREL, and GARDENIA]) using etrolizumab have been completed in patients with UC 10–15 .…”

Possible Efficacy of Vedolizumab, an Anti-α4β7 Integrin Antibody, in Palmoplantar Pustulosis

“…In other inflammatory skin diseases such as psoriasis, the expressions of MAdCAM-1 and ITGB7 were not enhanced [4] . However, MAdCAM-1 is not the sole ligand of α4β7 integrin, but α4β7 integrin binds to vascular endothelial cell adhesion molecule-1 (VCAM-1) and fibronectin [5] . Since endothelial cells in PPP lesions express VCAM-1 while those in healthy skin do not [6] , vedolizumab might directly improve skin symptoms by acting on endothelial cells in PPP skin lesions to suppress lymphocyte infiltration.…”

A CD22‐Shp1 phosphatase axis controls integrin β 7 display and B cell function in mucosal immunity

“…Cell lysates were cleared from debris by centrifugation (16 000 × g, 10min, 4°C). After pre-clearing the lysates with unbound Dynabeads protein G beads (Invitrogen), β 7 integrin was pulled down by incubation of lysates with Dynabeads protein G bound to rat anti-mouse β 7 antibody FIB50451 for overnight with agitation. After several washes with IP buffer, the β 7 integrin was eluted with 100 mM glycine buffer at pH 2.5 for 15 min at 56°C with gentle agitation.…”