Agents which bind to epitopes of glycoprotein VI

Abstract

The present invention provides anti-thrombotic agents, methods for screening for said anti-thrombotics agents and methods of treating thrombotic and other cardiovascular disorders.

Description

PRIORITY CLAIM [0001] This application is a continuation-in-part of U.S. application Ser. No. 11 / 009,106, filed Dec. 10, 2004, which is a continuation-in-part of U.S. application Ser. No. 10 / 489,053, filed Sep. 24, 2004, which is the national stage under 35 U.S.C. § 371 of International Application No. PCT / EP2003 / 05929, filed Jun. 5, 2003, which was published in English under PCT Article 2(2), and which claims the benefit of European Patent Application No. EP 02 012 742.9, filed Jun. 7, 2002. This application is also a continuation-in-part of International Application No. PCT / EP2004 / 013779, which was published in English under PCT Article 2(2), and which claims the benefit of European Patent Application No. 03 027 772.7, filed Dec. 3, 2003. This application also claims the benefit under 35 U.S.C. § 119 of Great Britain Application No. 0511590.2, filed Jun. 7, 2005. All of the prior applications are incorporated herein by reference in their entirety.FIELD OF THE INVENTION [0002] This...

AI Technical Summary

Benefits of technology

[0024] The present disclosure provides the first direct in vivo evidence indicating that GPVI is in fact strictly required in the process of platelet recruitment under physiological shear stress following vascular injury. In different mouse models of endothelial denudation both inhibition or absence of GPVI virtually abolished platelet-vessel wall interactions and platelet aggregation, identifying GPVI as the major determinant of arterial thrombus formation. This indicates that inhibition of GPVI-ligand interactions prevents arterial thrombosis in the setting of atherosclerosis. The present invention uses the antithrombotic potential of a specific soluble form of GPVI. Specifically, a fusion protein is provided, which contains the extracellular domain of GPVI and a human N-terminal Fc tag. The soluble form of human GPVI specifically binds to collagen with high affinity and attenuated platelet adhesion to immobilized collagen in vitro and to sites of vascular injury in vivo. Accordingly, the present invention is based on the recognition that the precondition for intraarterial thrombosis as an acute clinical complication is the initial adhesion of platelets to active lesions in the vessel walls. The present inventors have recognised that platelet adhesion to subendothelial matrix collagen at a lesion of the vessel wall by the glycoprotein VI (GPVI) receptor represents the key event for the formation of thrombosis. The inhibition of the adhesion of platelets to subendothelial matrix collagen of the fusion protein of the invention is therefore capable of not only preventing adhesion of platelets to an active lesion, but also to prevent aggregation of platelets at the active lesion. Thereby, the formation of intravascular thrombosis can be efficiently avoided without impairing the general ability of the platelets for aggregation.

Problems solved by technology

Even in case of an initial survival of such a cardiovascular event, many patients suffer from life-threatening complications such as intravascular thrombosis leading to further myocardial infarction or stroke.

However, a recent meta-analysis of clinical trials revealed a significant remaining risk for death or myocardial infarction despite optimal antithrombotic intervention (Boersma E, Harrington R A, Moliterno D J, White H, Theroux P, Van de Werf F, de Torbal A, Armstrong P W, Wallentin L C, Wilcox R G, Simes J, Califf R M, Topol E J, Simoons M L. Platelet glycoprotein IIb / IIIa inhibitors in acute coronary syndromes: a meta-analysis of all major randomised clinical trials.

Specific severe side effects of this therapeutic regimen are bleeding complications.

The inhibition of platelet aggregation leads to a general impairment of the platelets with regard to their ability to aggregate.

Therefore, the administration of inhibitors of platelet aggregation inherently leads to severe side effects such as bleedings which may cause further life-threatening complications.

These side effects are of course still more problematic in patients suffering from diabetes.

Additionally diabetes constitutes an increased risk of life threatening complications and excess morbidity in patients presenting with acute vascular and especially coronary syndromes.

The link between increased atheroprogression, and increased platelet responsiveness and diabetes is so far an unresolved problem.

This mechanism has only been observed in mice and cannot be used in a patient.

EP 1224942 does not disclose the humanized form of JAQ1 and does not provide data in man or human platelets.

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