Chemistry: natural resins or derivatives; peptides or proteins; – Proteins – i.e. – more than 100 amino acid residues – Blood proteins or globulins – e.g. – proteoglycans – platelet...
Reexamination Certificate
1997-12-09
2001-09-04
Low, Christopher S. F. (Department: 1653)
Chemistry: natural resins or derivatives; peptides or proteins;
Proteins, i.e., more than 100 amino acid residues
Blood proteins or globulins, e.g., proteoglycans, platelet...
C530S324000, C530S328000, C530S384000, C530S829000, C530S830000, C514S002600, C514S012200, C514S016700, C514S802000, C514S834000, C424S529000, C424S532000
Reexamination Certificate
active
06284871
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to methods for the preparation of highly specific anticoagulants which can be used in therapeutic compositions for the treatment of thrombosis. The biologically active ingredient of said preparations comprises one or more peptides that selectively inhibit the Factor IX-dependent coagulation pathway. This invention provides methods for obtaining such peptides, and for their formulation into pharmaceutical compositions with antithrombotic activity.
BACKGROUND OF THE INVENTION
The arrest of bleeding involves the concerted action of various haemostatic pathways, which eventually lead to thrombus formation. Thrombi are depositions of blood constituents on the surface of the vessel wall, and are mainly composed of aggregated blood platelets and insoluble, cross-linked fibrin. Fibrin formation occurs by limited proteolysis of fibrinogen by thrombin. This enzyme is the final product of the coagulation cascade, a sequence of zymogen activations which occur at the surface of activated platelets and leukocytes, and of a variety of vascular cells (for review see K. G. Mann et al.,
Blood
vol 76, 1990, pp 1-16).
Normally thrombus formation remains localized at sites of vascular injury, since platelet aggregation and adhesion is mediated by agonists associated with the growing thrombus, such as locally formed thrombin. Under certain pathological conditions however, the formation of these depositions does not remain limited to the site of injury. Thrombi then may occur in arteries and veins anywhere in the circulation, which may ultimately result in vessel obstruction and blood flow arrest. This provides the mechanism underlying a variety of thrombotic disorders, including deep vein thrombosis, pulmonary embolism, disseminated intravascular coagulation, peripheral arterial disease, myocardial infarction and stroke (J. F. Mustard et al., in: A. L. Bloom and D. P. Thomas (Eds.),
Haemostasis and Thrombosis
, 2nd edition, Churchill-Livingstone, Edinburgh, 1987, pp 503-526).
Numerous strategies have been developed for the treatment of thrombotic disorders. These antithrombotic therapies have in common that they are based on interference in the haemostatic system. This approach carries the inherent risk of bleeding, since the haemostatic system is no longer fully responsive to potential injury. Therefore, antithrombotic benefits are inevitably associated with antihaemostatic risks. In attempts to improve the benefit-to-risk ratio, novel antithrombotic agents are continuously being developed. The various antithrombotic strategies have been extensively reviewed elsewhere, and some are briefly summarized below to illustrate the various developments in this field. These include:
(a) General inhibitors of thrombin formation. One well established strategy consists of oral anticoagulant therapy employing vitamin K antagonists. This interferes in the biosynthesis of the so-called vitamin K-dependent coagulation factors, which include Factors VII, IX, X and prothrombin. This therapy thus is aspecific, as it affects both the extrinsic and the intrinsic coagulation pathway (see FIG.
1
). Although widely used, oral anticoagulation requires intensive monitoring in order to reduce the bleeding risk associated with this therapy (see J. Hirsh et al., in: R. W. Colman et al. (Eds.),
Hemostasis and Thrombosis, Basic Principles and Clinical Practice
, 3rd edition, Lippincott, Philadelphia, 1994, pp 1567-1583). A similarly aspecific therapy consists of the administration of heparin. This compound accelerates the inactivation of a number of components, including thrombin and the activated forms of Factors IX and X (Factors IXa and Xa), by their natural inhibitor Antithrombin III. Over the past two decades, low molecular weight derivatives of heparin, which display an increased specificity for Factor Xa over thrombin inhibition, have been developed in an attempt to reduce the bleeding risk associated this therapy (see T. W. Barrowcliffe and D. P. Thomas, in: A. L. Bloom et al. (Eds.),
Haemostasis and Thrombosis
, 3rd edition, Churchill-Livingstone, Edinburgh, 1994, pp 1417-1438).
(b) Specific thrombin inhibitors. As thrombin is the key enzyme in platelet activation, fibrin formation, and activation of the cofactors Factors V and VIII (see FIG.
1
), it may seem an attractive target for antithrombotic therapy. Numerous studies have been devoted to the small leech protein called hirudin, and to peptides derived thereof (J. M. Maraganore,
Thromb. Haemostasis
vol 70, 1993, pp 208-211). Although these components are more effective than for instance heparin in animal models of experimental thrombosis, clinical trials initially revealed an unexpectedly high frequency of bleeding, demonstrating that the thrombin-directed approach may produce a significant antihaemostatic effect, with a relatively unfavorable benefit-to-risk ratio (L. A. Harker,
Biomedical Progress
vol 8, 1995, 17-26).
(c) Specific Factor Xa inhibitors. Suppression of thrombin formation can effectively be achieved by inhibiting Factor Xa, which is the prothrombin activating enzyme in the coagulation cascade (see FIG.
1
). Theoretically, this has the advantage of inhibiting vascular thrombus formation while still permitting a small, but haemostatically important amount of thrombin to be produced. Two naturally occurring peptide inhibitors of Factor Xa have recently been developed, the tick anticoagulant peptide (G. P. Vlasuk,
Thromb. Haemostasis
vol 70, 1993, pp 212-216) and antistasin, a leech anticoagulant (G. P. Tuszynsky et al.,
J. Biol. Chem
. vol 262, 1987, pp 9718-9723). These polypeptides, and various oligopeptide derivatives thereof (N. Ohta et al.,
Thromb, Haemostasis
vol 72, 1994, pp 825-830) may provide a more favorable benefit-to-risk ratio than agents with a broader specificity.
(d) Inhibitors of platelet activation and adhesion. Numerous studies have addressed this strategy, which has the theoretical advantage of specifically interrupting thrombin-dependent platelet recruitment at sites of vascular injury, while sparing the production of fibrin (see L. A. Harker et al., in: R. W. Colman et al. (Eds.),
Hemostasis and Thrombosis, Basic Principles and Clinical Practice
, 3rd edition, Lippincott, Philadelphia, 1994, pp 1638-1660). This strategy can be accomplished by various agents, including synthetic thrombin receptor antagonists, or monoclonal antibodies or peptides that interfere in the adhesion process. Although this approach seems particularly useful in arterial thrombosis, bleeding episodes still have been reported, suggesting that the specificity of this strategy may not have satisfactorily eliminated the antihaemostatic risk.
In summary, evaluation of current antithrombotic strategies in terms of antithrombotic benefits versus antihaemostatic risks reveals that the benefit-to risk ratio tends to be more favorable for strategies that interfere in one specific step rather than in a more general phase of the haemostatic system (L. A. Harker,
Biomedical Progress
vol 8, 1995, 17-26). Although the development of inhibitors specific for Factor Xa seems to be a promising improvement, this approach still blocks the common (intrinsic and extrinsic) pathway of thrombin generation (see FIG.
1
), and thereby thrombin-dependent platelet activation as well. An urgent need therefore exists for more specific anti-thrombotic agents that inhibit one single haemostatic pathway, while leaving other pathways unaffected.
More selective inhibition of the haemostatic system should be achievable if agents would exist that exclusively interfere in the intrinsic pathway of Factor X activation. This would leave the extrinsic pathway intact, allowing the formation of small, but haemostatically important amounts of Factor Xa and thrombin. While the formation of the platelet plug associated with the initial phase of bleeding arrest thus would remain unaffected, the formation of larger amounts of thrombin and fibrin would be suppressed (see FIG.
1
). A potentially successful strategy for achieving sele
Lenting Petrus Johannes
Mertens Koenraad
Hoffman & Baron LLP
Low Christopher S. F.
Mohamed Abdel A.
Stiching Centraal Laboratorium van de Bloedtransfusiedienst van
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