Antithrombotic Potency of Hirudin Is Increased in Nonhuman Primates by Fibrin Targeting

Abstract

These data indicate that targeting a thrombin inhibitors such as hirudin to an epitope present in thrombi results in increased antithrombotic potency.

Comparative immunohistochemical staining of atherosclerotic plaques using F16, F8 and L19: Three clinical-grade fully human antibodies

“…However, the antibody-based delivery of IL2 has recently been reported to reduce the number of atherosclerotic plaques in the ApoE -/-mouse model [27]. Interestingly, the use of anti-fibrin antibodies for the delivery of hirudin has been reported to potently inhibit fibrin deposition on experimental clot surfaces in baboon plasma [40], while an enhanced thrombolytic and anti-thrombotic potency has been reported for the targeted delivery of recombinant uPA to thrombi. Thus, antibody-based pharmacodelivery strategies may be more suitable for the prevention of thrombotic complication after plaque rupture, rather than for the promotion of plaque dissolution: a very ambitious goal in cardiovascular research.…”

Construction and Functional Evaluation of a Single-Chain Antibody Fusion Protein With Fibrin Targeting and Thrombin Inhibition After Activation by Factor Xa

“…10,11 Furthermore, a chemical conjugate of the fibrinspecific mAb 59D8 and the direct thrombin inhibitor hirudin inhibited fibrin deposition on experimental clots 12 and demonstrated an increase in antithrombotic potency in baboons. 13 To increase the yield and activity of antibody-targeted hirudin and to further improve the risk/benefit ratio of anticoagulation, we have developed a recombinant fusion molecule consisting of an antifibrin single-chain antibody and hirudin. In addition to fibrin targeting, the generation of a free N-terminus, which is essential for the antithrombin activity of hirudin, forms the basis of a unique pharmacological approach.…”

“…Sufficient amounts of fibrin are present even in platelet-rich thrombi. 13 In addition to mAb 59D8, the mAb MA-15C5, directed against the fragment D-dimer of cross-linked human fibrin, has been used successfully to target plasminogen activators to clots. 19 Several reports imply that direct thrombin inhibitors may be superior to heparin.…”

“…10,11 A chemical conjugate between hirudin and 59D8 effectively inhibited fibrin deposition on experimental clots 12 and demonstrated potent antithrombotic activity in nonhuman primates. 13 Nevertheless, chemical coupling of hirudin to mAbs has several limitations, the major ones being low yield and loss of hirudin activity. 12 We tried to bypass these limitations by the use of recombinant technology.…”

Targeted Treatments for Restenosis and Vein Graft Disease

“…There are many ways in which antirestenotic agents can be locally or site-delivered, including directly via luminal delivery catheters, in gels or microspheres placed around the adventitia, or on coated stents, but some of these techniques may result in greater trauma to the vessel than the potential benefit of therapy [101]. Agents that interact only with certain types of cells (such as rapidly proliferating cells or cells with a particular membrane receptor) or antibodies linked to agents may also be used [102][103][104][105][106][107]. The locally delivered substances result in increased concentrations of the drug in the place where it is required, leaving the remainder of the body with much lower levels of the drug.…”