IBT 9302 (Heparinase III): a novel enzyme for the management of reperfusion injury-related vascular damage, restenosis and wound healing

Abstract

IBT 9302 (heparinase III, EC 4.2.2.8), purified from Flavobacterium heparinum, selectively cleaves heparan sulfate proteoglycans (HSPGs) from cellular surfaces and extracellular matrices. HSPGs serve as binding sites for P- and L-selectins, as well as for pro-inflammatory chemokines, such as interleukin (IL)-8. IBT 9302 reversibly removes these binding sites and inflammatory mediators, thereby limiting tissue damage following reperfusion of ischaemic areas by reducing leukocyte rolling, adhesion and extravasation. In models of myocardial ischaemia/reperfusion injury, infusion of IBT 9302 the time of transport and reperfusions, reduces the area of necrosis/area at risk ratios relative to vehicle-treated animals. Cardioprotection is accompanied by a reduction in serum creatine kinase levels and neutrophil adherence to coronary vessels, and the preservation of endothelial relaxation responsiveness to acetylcholine. HSPGs also serve as accumulation sites for most growth factors and IBT 9302 limits both proliferation and migration of vascular smooth muscle cells to platelet-derived growth factor (PDGF), basic fibroblast growth factor (bFGF) and endothelial growth factor (EGF). In vivo, the application of IBT 9302 at the time of vascular injury significantly reduces arterial medial proliferation. External application of IBT 9302 to wounds in a steroid-impaired wound healing model increases tensile strength by releasing mitogenic growth factors and HSPGs from the surrounding extracellular matrix. Pharmacokinetic studies show a simple monoexponential decay following iv. bolus dosing of IBT 9302, with a half-life of 5 - 6 min. The majority of [¹²⁵I]-IBT 9302 goes to the liver (60%) and kidneys (25%), following iv. dosing. Preliminary toxicology studies in rats following single iv. bolus (10 mg/kg) or infusion (10 μg/kg/min) dosing show no untoward effects. These results suggest that IBT 9302 may have therapeutic utility in treating myocardial ischaemia/reperfusion injury, ischaemic stroke, restenosis or in healing diabetic ulcer wounds, by virtue of its ability to selectively cleave HSPGs.

• growth factors
• heparinase
• myocardial ischaemia
• restenosis
• selectins
• wound healing