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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1995;15:2195-2199.)
© 1995 American Heart Association, Inc.

Articles

A Monoclonal Antibody That Recognizes the GPIIb/IIIa Antagonist DMP 728

Reversal of the Effects of DMP 728 on Platelet Aggregation and Bleeding Time in the Dog

Thomas M. Reilly; Shaker A. Mousa; Adrienne L. Racanelli; Martin J. Thoolen; Sandra K. Flint; Jeffrey M. Bozarth; Dun X. Mu; Harry L. Walton

From the DuPont Merck Pharmaceutical Company, Wilmington, Del.

Correspondence to Thomas M. Reilly, PhD, the DuPont Merck Pharmaceutical Company, Cardiovascular Diseases Research, PO Box 80400, Wilmington, DE 19880-0400. E-mail reillytm@a1.lldmpc.umc.dupont.com.

Abstract Since hemorrhagic events represent a major safety concern associated with the use of new antithrombotic therapies such as glycoprotein (GP) IIb/IIIa receptor blockade, we evaluated the ability of a monoclonal antibody recognizing DMP 728 (cyclic [D-2-aminobutyryl-N2-methyl-L-argininyl-glycyl-L-aspartyl-3-aminomethyl-benzoic acid] methanesulfonic acid salt), a potent GPIIb/IIIa receptor antagonist, to reverse the pharmacological actions of DMP 728 in the dog. DC11 was chosen for in vivo evaluation based on its ability to inhibit the binding of [³H]DMP 728 to activated platelets and to attenuate the inhibition of ADP-induced aggregation on platelet-rich plasma ex vivo by DMP 728. After anesthesia mongrel dogs were given DMP 728 (20 µg/kg body wt IV) infused into the femoral vein, bleeding times were determined using a Simplate device from incisions on the backside of the tongue, and platelet aggregation was determined ex vivo. Nearly complete inhibition of platelet aggregation was observed for the dogs treated with DMP 728 (20 ug/kg IV) for up to 210 minutes, and bleeding times were prolonged >15 minutes for 2 hours and remained elevated for more than 4 hours. DC11 (0.2 or 1.0 mg/kg body wt IV) given to dogs 10 minutes after DMP 728 resulted in 50% attenuation of the effect of DMP 728 on aggregation at 3 hours. Approximately 34% inhibition of the DMP 728–mediated bleeding time was achieved at 1 hour with the 0.2 mg/kg dose, whereas approximately 50% inhibition of the bleeding time was observed for the 1 mg/kg dose at 1 hour. The bleeding time for the higher dose of DC11 returned to control levels at 2 hours, whereas the lower dose of DC11 returned to control levels at 3 hours. These results suggest that monoclonal antibody DC11 may have potential utility as an antidote to DMP 728 in neutralizing any unexpected bleeding complications associated with its use.

Key Words: glycoprotein IIb/IIIa • DMP 728 • platelet • antibody

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