Chimeric 7E3 prevents carotid artery thrombosis in cynomolgus monkeys.
OBJECTIVE
We compared the current antithrombotic strategy of antiplatelet therapy with aspirin, and anticoagulant therapy with heparin, with a specific genetically engineered chimeric antibody (c7E3 Fab) directed against the human glycoprotein IIb/IIIa receptor in an animal model of arterial thrombosis.


METHODS
Anesthetized cynomolgus monkeys (Macaca fascicularis) were instrumented for monitoring of arterial blood pressure, heart rate, and carotid artery flow velocity. Animals were treated with saline (n = 6), aspirin (25 mg PO daily for 3 days; n = 6), heparin (100 U/kg i.v. plus infusion adjusted to maintain activated partial thromboplastin time at 2 to 3 times baseline; n = 6), aspirin plus heparin (as administered separately, n = 6), or c7E3 Fab (0.10 mg/kg i.v., n = 7; 0.15 mg/kg i.v., n = 6; 0.20 mg/kg i.v., n = 6; 0.25 mg/kg i.v., n = 6). Thrombus formation via anodal electrolytic stimulation (100 microA) to the intimal surface of the right carotid artery was initiated 15 minutes after drug administration and continued for 180 minutes. Electrolytic injury to the left carotid artery began 210 minutes after drug administration and continued for 180 minutes. Whole blood cell counts, glycoprotein IIb/IIIa receptor blockade, ex vivo platelet aggregation, template bleeding time, and activated partial thromboplastin time were assessed at various time points throughout the experimental protocol.


RESULTS
Hemodynamic and hematologic parameters were comparable among groups at baseline. Treatment with c7E3 Fab inhibited ex vivo platelet aggregation, increased bleeding time, decreased thrombus weight, and increased time to occlusion in a dose-dependent manner in both vessels. Treatment with aspirin, heparin, or the combination of aspirin plus heparin was ineffective for the prevention of carotid artery thrombosis in this model.


CONCLUSIONS
Inhibition of the platelet glycoprotein IIb/IIIa receptor with c7E3 Fab was found to be safe and effective for the prevention of primary thrombus formation, whereas treatment with either aspirin or heparin or the combination of the two agents failed to protect against occlusive thrombus formation in cynomolgus monkeys.
Rote
W E
WE
Dept of Pharmacology, University of Michigan Medical School, Ann Arbor 48108-0626.
Nedelman
M A
MA
Mu
D X
DX
Manley
P J
PJ
Weisman
H
H
Cunningham
M R
MR
Lucchesi
B R
BR
D000077284:Abciximab; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000097:blood / Q000627:therapeutic use*; D001241:Aspirin / Q000008:administration & dosage / Q000627:therapeutic use; D001777:Blood Coagulation / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D002341:Carotid Artery Thrombosis / Q000097:blood / Q000503:physiopathology / Q000517:prevention & control*; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004906:Erythrocyte Count; D006339:Heart Rate / Q000187:drug effects; D006400:Hematocrit; D006454:Hemoglobins / Q000032:analysis; D006493:Heparin / Q000008:administration & dosage / Q000627:therapeutic use; D007140:Immunoglobulin Fab Fragments / Q000008:administration & dosage / Q000097:blood / Q000627:therapeutic use*; D039421:Integrin alpha2; D008252:Macaca fascicularis; D008297:Male; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000627:therapeutic use*; D019038:Platelet Glycoprotein GPIb-IX Complex; D010980:Platelet Membrane Glycoproteins; D011947:Receptors, Antigen, B-Cell / Q000032:analysis / Q000037:antagonists & inhibitors; D011956:Receptors, Cell Surface / Q000032:analysis / Q000037:antagonists & inhibitors; D012039:Regional Blood Flow / Q000187:drug effects; D013997:Time Factors
D000911:Antibodies, Monoclonal; D004338:Drug Combinations; D006454:Hemoglobins; C056564:ITGA2B protein, human; D007140:Immunoglobulin Fab Fragments; D039421:Integrin alpha2; D008562:Membrane Glycoproteins; D010975:Platelet Aggregation Inhibitors; D019038:Platelet Glycoprotein GPIb-IX Complex; D010980:Platelet Membrane Glycoproteins; D011947:Receptors, Antigen, B-Cell; D011956:Receptors, Cell Surface; C040580:glycoprotein GP III; C032193:glycoprotein receptor GPIb-IX; D006493:Heparin; D001241:Aspirin; D000077284:Abciximab