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

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 (alpha IIb beta 3, 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 (alpha M beta 2, CD11b/CD18) and the vitronectin receptor (alpha v beta 3, CD51/CD61). Information regarding how this mAb may affect other cells important in vascular repair is scant. Potential interactions of c7E3 Fab with inflammatory (i.e., 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 (approximately 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 alpha 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.

Effects of the P‐Selectin Antagonist Inclacumab on Myocardial Damage After Percutaneous Coronary Intervention According to Timing of Infusion: Insights From the SELECT‐ACS Trial

“…Given the long half‐life of inclacumab comparable to that of other human IgG antibodies and the persistent inhibition of platelet–leukocyte aggregates demonstrated after inclacumab administration,24, 25 alternative signaling cascades involving rapidly activated pathways and short‐term effects at maximum drug concentrations achieved at the end of the infusion may have accounted for these findings. Furthermore, cross‐reactivity of inclacumab with other receptors, similar to the observations reported for different drugs including glycoprotein IIb/IIIa antagonists,26, 27 may come into play. This raises the question of whether shorter (<1 hour) time intervals between study drug infusion and PCI or continuous infusions administered throughout the procedure, along with intracoronary infusion methods, would have caused an even larger effect.…”

Activated Monocytes Induce Smooth Muscle Cell Death

“…This effect could be mediated by Mac-1 binding of abciximab on the surface of monocytes, thereby preventing the adhesion of monocytes to ligands such as ICAM-1 displayed by VSMCs. 26 The effect of an anti-CD-18 -blocking antibody effect that was similar to that of abciximab on VSMC killing by M-CSF-activated macrophages supports the participation of the Mac-1 receptor in the process.…”

Effects of Abciximab, Ticlopidine, and Combined Abciximab/Ticlopidine Therapy on Platelet and Leukocyte Function in Patients Undergoing Coronary Angioplasty

“…14,15 Abciximab also binds to the integrin ␣ V ␤ 3 16,17 and Mac-1 (␣M␤ 2 ) receptors. 18 The phase III Evaluation of IIb-IIIa platelet receptor antagonist 7E3 in Preventing Ischemic Complications (EPIC) study demonstrated that abciximab decreased acute ischemic events after PTCA by 35% and that it decreased restenosis 6 months after PTCA by 23%. 19 Ticlopidine has also been successful in reducing adverse cardiac events after PTCA with stent implantation.…”