Use of non-catalytic form of heparanase and peptides thereof for reversing the anti-coagulant effects of heparinoids

A technology of heparanase and anticoagulant activity, applied in medical preparations containing active ingredients, blood diseases, peptide/protein components, etc., can solve the problem of not being able to obtain a unified

Inactive Publication Date: 2009-07-22
HADASIT MEDICAL RES SERVICES & DEVMENT +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Various attempts to clarify the substrate specificity of heparanase have pointed to the importance of sulfation, but these attempts have not been able to reach a unified conclusion [Pikas (1998), supra; Okada Y. et al. J. Biol. Chem. 277: 42488-42495 (2002)]

Method used

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  • Use of non-catalytic form of heparanase and peptides thereof for reversing the anti-coagulant effects of heparinoids
  • Use of non-catalytic form of heparanase and peptides thereof for reversing the anti-coagulant effects of heparinoids
  • Use of non-catalytic form of heparanase and peptides thereof for reversing the anti-coagulant effects of heparinoids

Examples

Experimental program
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Effect test

Embodiment 1

[0181] Heparanase zymogen has no direct effect on coagulation

[0182] To examine the possible role of heparanase in the coagulation process, the inventors performed various coagulation tests, including activated partial thromboplastin time (aPTT, which tests the intrinsic coagulation pathway), prothrombin time ( PT, which tests the extrinsic coagulation pathway), thrombin time (TT, which measures thrombin-mediated fibrinogenesis), and protein C and protein S (both are inhibitors of coagulation).

[0183] The effect of heparanase on platelet aggregation stimulated by various mediators (eg ADP, collagen, thrombin) was next tested. As shown in Table 1, all of these coagulation functions were unaffected by the presence of the proheparanase zymogen and they were all within the normal range.

[0184] Table 1. Heparanase zymogens that do not directly affect coagulation

[0185]

[0186] * Shown is a single representative experiment out of 2-4 experiments performed.

Embodiment 2

[0188] Proheparanase zymogen reverses heparin-induced shortening of aPTT and TT responses

[0189] The extent of the blood coagulation response requires a balance of anticoagulant components and associated coagulation inhibitors in the microenvironment of the endothelium represented by cell surface HSPGs. Heparanase released by platelets upon activation acts as a physiological coagulant. Therefore, the inventors tested the heparanase-mediated down-regulation of heparanase on coagulation activity under conditions that do not support its enzymatic activity (e.g. using inactive heparanase zymogen at neutral pH). effect. Two coagulation assays were affected by heparinoids: the activated partial thromboplastin time (aPTT), which measures the intrinsic coagulation pathway, and the thrombin time, which measures the thrombin-mediated conversion of fibrinogen to fibrin ( TT). Such as figure 1 As shown, in both cases, heparin forms a ternary complex with the natural thrombin inhibit...

Embodiment 3

[0191] Heparanase zymogen reverses the anticoagulant effect of heparin by restoring factor Xa activity in vitro and in the plasma of human patients treated with LMWH

[0192] Such as figure 1 Another mode of ATIII activity was shown to be the formation of inhibitory complexes with activated coagulation factor X (Xa). This factor will associate Factor Va with prothrombin, thereby forming a prothrombinase complex on the endothelium, leading to thrombin generation and subsequent clot formation. Unfractionated heparin or low molecular weight heparan (LMWH) binds to AT and induces a conformational change leading to the binding of factor Xa and inhibition of factor Xa activity.

[0193] In recent years, LMWH has been widely used as an anticoagulant due to its outstanding anticoagulant activity and improved pharmacokinetics compared with unfractionated heparin. However, antidotes that can inhibit these clinically highly abundant anticoagulants are not yet available in terms of urge...

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Abstract

The present invention relates to inhibition of heparinoids anti-coagulation activity by a non-active form of a eukaryotic endoglycosidase or any fragment or peptide thereof comprising at least one heparin-binding domain. More particularly, the invention provides compositions and methods for the inhibition of heparinoids anti-coagulation activity and for the treatment of coagulation related pathologic clinical conditions, using a non-active form of mammalian heparanase or peptides thereof comprising at least one heparin-binding domain.

Description

technical field [0001] The present invention relates to methods and compositions for the treatment of pathological clinical conditions associated with coagulation. More specifically, the present invention provides the use of an inactive form of mammalian heparanase or a peptide thereof in the treatment of pathological clinical symptoms associated with coagulation by inhibiting heparan-like anticoagulant activity. Background technique [0002] All publications mentioned throughout this application, including all references cited therein, are hereby incorporated by reference in their entirety. [0003] A major physiological role of the endothelium is to maintain the integrity of the vasculature and provide a non-thrombotic surface through its permeability barrier properties. Thus, the endothelial cell surface functions as a major regulatory site for the coagulation response. Under normal conditions, injury to the vascular endothelial cells lining blood vessels triggers a hem...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K38/47A61P7/00
CPCA61K38/47A61P37/02A61P41/00A61P7/00A61P7/02A61P7/04
Inventor 伊斯拉埃尔·弗洛达夫斯基内塔·伊兰弗隆尼亚·利维-亚当本-齐翁·卡茨
Owner HADASIT MEDICAL RES SERVICES & DEVMENT
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