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J Leukoc Biol ; 80(4): 905-14, 2006 Oct.
Article in English | MEDLINE | ID: mdl-16888085

ABSTRACT

LFA-1 (alpha(L)beta(2)) mediates cell-cell and cell-extracellular matrix adhesions essential for immune and inflammatory responses. One critical mechanism regulating LFA-1 activity is the conformational change of the ligand-binding alpha(L) I domain from low-affinity (LA), closed form, to the high-affinity (HA), open form. Most known integrin antagonists bind both forms. Antagonists specific for the HA alpha(L) I domain have not been described. Here, we report the identification and characterization of a human antibody AL-57, which binds to the alpha(L) I domain in a HA but not LA conformation. AL-57 was discovered by selection from a human Fab-displaying library using a locked-open HA I domain as target. AL-57 Fab-phage bound HA I domain-expressing K562 cells (HA cells) in a Mg(2+)-dependent manner. AL-57 IgG also bound HA cells and PBMCs, activated by Mg(2+)/EGTA, PMA, or DTT. The binding profile of AL-57 IgG on PBMCs was the same as that of ICAM-1, the main ligand of LFA-1. In contrast, an anti-alpha(L) murine mAb MHM24 did not distinguish between the HA and LA forms. Moreover, AL-57 IgG blocked ICAM-1 binding to HA cells with a potency greater than MHM24. It also inhibited ICAM-1 binding to PBMCs, blocked adhesion of HA cells to keratinocytes, and inhibited PHA-induced lymphocyte proliferation with potencies comparable with MHM24. These results indicate that specifically targeting the HA I domain is sufficient to inhibit LFA-1-mediated, adhesive functions. AL-57 represents a therapeutic candidate for treatment of inflammatory and autoimmune diseases.


Subject(s)
Antibodies, Monoclonal/pharmacology , Leukocytes, Mononuclear/drug effects , Lymphocyte Function-Associated Antigen-1/drug effects , Antibodies, Monoclonal/chemistry , Antigen-Antibody Reactions , Binding Sites , Cell Adhesion/drug effects , Cell Line , Cell Proliferation/drug effects , Humans , Immunoglobulin G/pharmacology , Intercellular Adhesion Molecule-1/drug effects , Keratinocytes/drug effects , Lymphocyte Function-Associated Antigen-1/immunology , Molecular Sequence Data , Phytohemagglutinins/antagonists & inhibitors , Phytohemagglutinins/pharmacology , Structure-Activity Relationship
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