The GP IIb/IIIa inhibitor abciximab (c7E3) inhibits the binding of various ligands to the leukocyte integrin Mac-1 (CD11b/CD18, alphaMbeta2).
Cross-reactivity with integrins other than glycoprotein IIb/IIIa (GP IIb/IIIa) is discussed as a potential reason for the overall clinical benefits of the GP IIb/IIIa-blocking antibody-fragment abciximab. We evaluated whether abciximab binds to the leukocyte integrin Mac-1, whether it inhibits binding of the distinct ligands and thereby may modulate inflammation, cell proliferation and coagulation. Binding of fluorescence-labelled abciximab to phorbolmyristate acetate-stimulated monocytes and to a monocytic cell line (THP-1) could be detected in flow cytometry. The binding of fibrinogen, the inactivated complement factor 3b (iC3b), and the coagulation factor X to Mac-1 could be inhibited by abciximab (10 microg/ml) in vitro. As a functional consequence, the conversion of factor X to factor Xa mediated by Mac-1, as detected by the chromogenic substrate SZ-2222, was impaired by abciximab. Adhesion of THP-1 cells to immobilized intercellular adhesion molecule 1 (ICAM-1) and to fibrinogen was reduced significantly by abciximab. Fibrinogen-mediated cell aggregation was also impaired. In conclusion, we describe binding of abciximab to Mac-1 on stimulated monocytes. Thereby, abciximab inhibits binding of the ligands fibrinogen, ICAM-1, iC3b and factor X. Furthermore, we demonstrated that Mac-1-dependent conversion from factor X to factor Xa is impaired by abciximab, arguing for the direct modulation of the coagulation cascade by abciximab. Overall, the inhibition of Mac-1 could provide additional clinical benefits of abciximab beyond the well-described blockade of GP IIb/IIIa.
Schwarz
Meike
M
Department of Internal Medicine III, University of Freiburg, Freiburg, Germany. schwarz@med1.uk1.uni-freiburg.de
Nordt
Thomas
T
Bode
Christoph
C
Peter
Karlheinz
K
D000077284:Abciximab; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects; D003179:Complement C3b / Q000187:drug effects / Q000378:metabolism; D005170:Factor X / Q000037:antagonists & inhibitors / Q000378:metabolism; D005340:Fibrinogen / Q000378:metabolism; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000494:pharmacology*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008024:Ligands; D016177:Macrophage-1 Antigen / Q000187:drug effects / Q000378:metabolism*; D009000:Monocytes / Q000737:chemistry / Q000166:cytology / Q000187:drug effects; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors; D011485:Protein Binding / Q000187:drug effects; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D007140:Immunoglobulin Fab Fragments; D008024:Ligands; D016177:Macrophage-1 Antigen; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D018799:Intercellular Adhesion Molecule-1; D003179:Complement C3b; D005170:Factor X; D005340:Fibrinogen; D000077284:Abciximab