Arteriosclerosis, Thrombosis, and Vascular Biology. 1997;17:528-535
© 1997 American Heart Association, Inc.
Articles |
7E3 Monoclonal Antibody Directed Against the Platelet Glycoprotein IIb/IIIa Cross-reacts With the Leukocyte Integrin Mac-1 and Blocks Adhesion to Fibrinogen and ICAM-1
From the Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass (D.I.S., H.X., C.R., N.K.R.); Celltech Therapeutics Ltd, Slough, UK (S.O.); and Harvard-MIT Division of Health Sciences and Technology, Cambridge, Mass (C.R.).
Correspondence to Daniel I. Simon, MD, Cardiovascular Division PBB-A3, Brigham and Women's Hospital, 75 Francis St, Boston, MA 02115. E-mail disimon{at}bics.bwh.harvard.edu.
Abstract Recent clinical trials suggest that blockade of
integrins is a promising strategy for the treatment of acute coronary
syndromes. Administration of 7E3 monoclonal antibody (mAb) Fab fragment
(c7E3 Fab) directed against platelet integrin IIb/IIIa (
IIbß3,
CD41/CD61) reduces acute ischemic complications of coronary
angioplasty and clinical restenosis at 6 months. However, 7E3 mAb is
not selective for platelet IIb/IIIa but also cross-reacts with the
leukocyte integrin Mac-1 (Mß2, CD11b/CD18) and the vitronectin
receptor (vß3, CD51/CD61). Information regarding how this mAb may
affect other cells important in vascular repair is scant. Potential
interactions of c7E3 Fab with inflammatory (ie, monocytes and
neutrophils), vascular smooth muscle, and endothelial cells may
contribute to the in vivo actions of c7E3 Fab. In this study we
explored the binding of 7E3 to monocytic cells and the functional
effect of 7E3 and c7E3 Fab on Mac-1–mediated adhesion to fibrinogen
(FGN) and intercellular adhesion molecule-1 (ICAM-1), ligands abundant
in the injured vessel wall. Flow cytometry demonstrated that 7E3 bound
to THP-1 monocytic cells and identified a subpopulation (
10%) of
Mac-1 that was qualitatively similar to that recognized by CBRM1/5, a
mAb directed to an activation-specific neoepitope present on a subset
of Mac-1 molecules. mAb 7E3 bound to K562 cells transfected with just
the subunit (CD11b) of Mac-1 but not to nontransfected cells,
confirming a direct interaction between 7E3 and Mac-1. mAb 7E3 and c7E3
Fab blocked the adhesion of Mac-1–bearing cells to FGN (80±11% and
78±9% inhibition, respectively) and ICAM-1 (62±14% and 62±17%).
Both 7E3 and c7E3 Fab significantly inhibited (70±6% and 62±26%)
soluble FGN binding to human peripheral blood monocytes. Thus, c7E3 Fab
cross-reacts with the CD11b subunit of Mac-1 and interrupts
cell-extracellular matrix and cell-cell adhesive interactions and may
thereby influence the recruitment of circulating monocytes to sites of
vessel injury. Given the recent evidence that adherent and infiltrating
monocyte number directly correlates with the extent of neointimal
hyperplasia, inhibition of Mac-1–dependent adhesion and
IIb/IIIa-dependent function by c7E3 Fab may jointly contribute to the
regulation of vascular repair and to the sustained clinical benefits
observed with c7E3 Fab after angioplasty.
Key Words: integrins • monocytes • cellular adhesion • restenosis • monoclonal antibody
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