7E3 F(ab')2, an effective antagonist of rat alphaIIbbeta3 and alphavbeta3, blocks in vivo thrombus formation and in vitro angiogenesis.
Abciximab (c7E3 Fab, ReoPro) blocks GPIIb/IIIa and alphavbeta3 and inhibits thrombotic and proliferative events only in humans and non-human primates. The bivalent F(ab')2 fragment is an effective anti-thrombotic agent in canine models. In the present study, 7E3 F(ab')2 was also found to bind to rat GPIIb/IIIa (KD = 27 +/- 4 microg/mL) and alphavbeta3 (KD = 9 +/- 8 microg/mL), to block in vitro rat platelet aggregation (IC50 = 16 +/- 6 microg/mL), and to inhibit alphavbeta3-mediated microvessel sprout formation in a rat aortic ring assay. Following administration of 7E3 F(ab')2 (4 mg/kg) to rats, platelet aggregation was completely blocked for up to 6 h and thrombus formation in response to a rat abdominal aorta double crush injury was prevented. Effective chronic dosing was achieved with 6 mg/kg daily I.P. injections. In vitro mixing experiments indicated that 7E3 F(ab')2 redistributed to unlabeled platelets in 2 h. Ex vivo, 7E3 F(ab')2 was detected on platelets for up to 4 days after a single 4-mg/kg injection. These data suggest that 7E3 F(ab')2 may be a useful agent to study the effects of GPIIb/IIIa and alphavbeta3 blockade in rat models of thrombosis and vascular disease.
Sassoli
P M
PM
Biology Research Centocor, Malvern, PA 19355, USA.
Emmell
E L
EL
Tam
S H
SH
Trikha
M
M
Zhou
Z
Z
Jordan
R E
RE
Nakada
M T
MT
D000077284:Abciximab; D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000494:pharmacology*; D001011:Aorta / Q000293:injuries / Q000473:pathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D007140:Immunoglobulin Fab Fragments / Q000737:chemistry / Q000494:pharmacology*; D007700:Kinetics; D008297:Male; D051379:Mice; D008833:Microcirculation; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D010974:Platelet Aggregation / Q000187:drug effects; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D019030:Receptors, Vitronectin / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D013927:Thrombosis / Q000188:drug therapy* / Q000517:prevention & control
D000911:Antibodies, Monoclonal; D007140:Immunoglobulin Fab Fragments; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D019030:Receptors, Vitronectin; D000077284:Abciximab