on February 22, 2007
Published online before print February 22, 2007, doi: 10.1161/ATVBAHA.106.138875
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Submitted on March 4, 2006
Accepted on January 19, 2007
Targeting Ligand-Induced Binding Sites on GPIIb/IIIa via Single-Chain Antibody Allows Effective Anticoagulation Without Bleeding Time Prolongation
Patrick Stoll ;
From the Centre for Thrombosis & Myocardial Infarction (P.S., N.B., C.E.H., S.U.E., C.Y.C., K.P.), Baker Heart Research Institute, Melbourne, Australia; the Departments of Cardiology (P.S., M.S., I.A., C.B.) and Anaesthesiology (R.S.), University of Freiburg, Germany; the National Institutes of Health (Y.K.), Bethesda, Md; and the Department of Anaesthesia (B.P.), University Hospital Duesseldorf, Germany.
* To whom correspondence should be addressed. E-mail: christoph.hagemeyer{at}baker.edu.au.
Objective--Therapeutic anticoagulation is widely used, but limitations in efficacy and bleeding complications cause an ongoing search for new agents. However, with new agents developed it seems to be an inherent problem that increased efficiency is accompanied by an increase in bleeding complications. We investigate whether targeting of anticoagulants to activated platelets provides a means to overcome this association of potency and bleeding.
Methods and Results--Ligand-induced binding sites (LIBS) on fibrinogen/fibrin-binding GPIIb/IIIa represent an abundant clot-specific target. We cloned an anti-LIBS single-chain antibody (scFvanti-LIBS) and genetically fused it with a potent, direct factor Xa (fXa) inhibitor, tick anticoagulant peptide (TAP). Specific antibody binding of fusion molecule scFvanti-LIBS-TAP was proven in flow cytometry; anti-fXa activity was demonstrated in chromogenic assays. In vivo anticoagulative efficiency was determined by Doppler-flow in a ferric chloride-induced carotid artery thrombosis model in mice. ScFvanti-LIBS-TAP prolonged occlusion time comparable to enoxaparine, recombinant TAP, and nontargeted mutant-scFv-TAP. ScFvanti-LIBS-TAP revealed antithrombotic effects at low doses at which the nontargeted mutant-scFv-TAP failed. In contrast to the other anticoagulants tested, bleeding times were not prolonged by scFvanti-LIBS-TAP.
Conclusions--The novel clot-targeting approach of anticoagulants via single-chain antibody directed against a LIBS-epitope on GPIIb/IIIa promises effective anticoagulation with reduced bleeding risk.
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