Blood coagulation protein antagonists and uses therefor

Details Blood coagulation protein antagonists and uses therefor Blood coagulation protein antagonists and uses therefor

1998-01-16

2001-04-24

Housel, James C. (Department: 1641)

Chemistry: molecular biology and microbiology

Animal cell, per se ; composition thereof; process of...

Animal cell, per se, expressing immunoglobulin, antibody, or...

C530S389300, C530S387100, C530S388100, C530S388250

Reexamination Certificate

active

06221659

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to antibodies and functional fragments thereof and, more particularly, to the treatment of patients for thrombotic disease or the prevention of thrombotic disease using anti-thrombotic agents including immunoglobulin protein and protein fragments or derivatives directed to certain blood coagulation-related proteinaceous antigens and epitopic regions thereof.
BACKGROUND OF THE INVENTION
Hemostasis is a naturally occurring process which results in the spontaneous arrest of bleeding from damaged blood vessels. For example, precapillary vessels will contract immediately when an individual is cut. Within seconds after such a cut, the process of hemostasis begins. At a site of injury with disruption of a blood vessel or exposure of subendothelial vascular tissue, two events rapidly occur. The two limbs of the hemostatic system, each comprised of many molecules, are activated. The coagulation (clotting) system is immediately initiated producing thrombin; and blood platelets adhere to matrix proteins. The platelets are activated, in part by thrombin, and release adenosine diphosphate (“ADP”) leading to aggregation of additional platelets into a growing platelet plug in concert with the conversion of fibrinogen in the blood to the insoluble fibrin gel. This hemostatic plug is strengthened by additional enzymatic cross-linking. Over time it is dissolved during tissue repair to result in normal tissue and blood vessel, with or without residual pathology of the local vessel wall or tissue.
Thrombogenesis is an altered, pathogenic state of one or both limbs of the hemostatic system. In such states, an intravascular (arterial or venous) thrombus results from a pathological disturbance of hemostasis. A platelet-rich thrombus, for example, is thought to be initiated by the adhesion of circulating platelets to the wall of an arterial vessel. This initial adhesion, activation by thrombin or other agonists, and the concomitant release of ADP from platelets, is followed by platelet-platelet interaction or aggregation. Fibrin formation is associated with the platelet thrombus but is a minor component. The arterial thrombus can grow to occlusive proportions in areas of slower blood flow.
In contrast, fibrin-predominant thrombi develop initially in areas of stasis or slow blood flow in blood vessels and may resemble a blood clot formed in vitro. The bulk of venous thrombi comprise a fibrin network enmeshed with red blood cells and platelets. A venous thrombus can establish a “tail” that can detach and result in embolization of the pulmonary arteries. Thus, it will be understood that arterial thrombi cause serious disease by local ischemia, whereas venous thrombi do so primarily by distant embolization.
A platelet plug formed solely by ADP-stimulating platelet interaction is unstable. Immediately after the initial aggregation and viscous metamorphosis of platelets, as noted above, fibrin becomes a constituent of a platelet-rich thrombus. Production of thrombin occurs by activation of the reactions of blood coagulation at the site of the platelet mass. This thrombin may activate the initial adherent platelets and stimulates further platelet aggregations. Platelet aggregation is stimulated not only by inducing the release of ADP from the platelets, but also by stimulating the synthesis of prostaglandins, which as aggregating agents-are more powerful than ADP, and by the assembly of the prothrombinase complex on the activated platelets to accelerate the formation of more thrombin, the very powerful activator of platelets.
The coagulation of blood results in the formation of fibrin. It involves the interaction of more than a dozen proteins in a cascading series of proteolytic reactions. At each step a clotting factor zymogen undergoes limited proteolysis and itself becomes an active protease. This clotting-factor enzyme activates the next clotting factor zymogen until thrombin is formed which connects fibrinogen to the insoluble fibrin clot. The blood clotting factors include factor I (fibrinogen), factor II (prothrombin), tissue factor (formerly known as factor III), factor IV (Ca
2+
), factor V (labile factors), factor VII (proconvertin), factor VIII (antihemophilic globulin, or “AHG”), factor IX (Christmas factor), factor X (Stuart factor), factor XI (plasma thromboplastin antecedent, or “PTA”), factor XII (Hageman factor), factor XIII (fibrin-stabilizing factor), and factors HMW-K (high-molecular-weight kininogen, or Fitzgerald factor), PRE-K (prekallikrein, or Fletcher factor), Ka (kallikrein), and PL (phospholipid).
Fibrinogen is a substrate for the enzyme thrombin (factor IIa), a protease that is formed during the coagulation process by the activation of a circulating zymogen, prothrombin (factor II). Prothrombin is converted to the active enzyme thrombin by activated factor X in the presence of activated factor V, Ca
2+
, and phospholipid.
Two separate pathways, called the “intrinsic” and “extrinsic” systems, lead to the formation of activated factor X. In the intrinsic system, all the protein factors necessary for coagulation are present in the circulating blood. In the extrinsic system, tissue factor, which is not present in the circulating blood, is expressed on damaged endothelium, on activated monocytes by cells in the arteriosclerotic plaque or by cells outside the vessel wall. Tissue factor then acts as the receptor and essential cofactor for the binding of factor VII resulting in a bimolecular enzyme [tissue factor:VIIa] to initiate the extrinsic pathway of coagulation. This mechanism also activates the intrinsic pathway of coagulation. The tissue factor pathway can very rapidly clot blood.
Blood can also be clotted by the contact system via the intrinsic pathway of coagulation. The mechanism is somewhat slower than the tissue factor pathways, presumably because of the larger number of reactions that are required. Both the intrinsic system and extrinsic system pathways must be intact for adequate hemostasis. See Zwaal, R. F. A., and Hemker, H. C. “Blood cell membranes and hemostasis.” Haemostasis, 11:12-39 (1982).
Thrombosis and a variety of related forms of diseases are associated with, and result from, activation of one or more of the coagulation protease cascades pathways, and disorders of regulation of the combined coagulation/anticoagulation/fibrinolytic pathways. These diseases affect approximately 2.5 million individuals annually in the United States. Some three percent of the U.S. population over the age of 45 develop some form of thrombotic disease or disseminated coagulation each year. Other thrombotic diseases are hereditary and may affect 100,000 people annually. Seventy percent of such diseases are fatal by 45 years of age.
Of acquired thrombotic diseases, coronary thrombosis at about 1.5 million cases per year, pulmonary thromboembolism at about 400,000 cases per year and severe septic shock at more than 300,000 cases per year, disseminated intravascular coagulation (DIC) at about 350,000 cases per year, and deep vein thrombosis at about 175,000 cases per year, predominate. However, diseases such as menigococemia, hemorrhagic fever virus infections, and a variety of other diseases produce significant morbidity and mortality as well. See, e.g., Kaplan, K. “Coagulation Proteins in Thrombosis.” In
Hemostasis and Thrombosis,
Colman, R. W., et al. eds., pages 1098 et seq. (2d Ed. J. B. Lippincott Co. 1987). Some of the most acutely severe forms of disseminated intravascular coagulation affect children secondary to a variety of infectious diseases. Current treatment for thromboembolic disease is by no means satisfactory, and includes the use of anticoagulants, antithrombotic drugs and thrombolytic agents.
One of the most well-known anticoagulants is heparin. Discovered in 1922, heparin is a heterogenous group of straight-chain anionic mucopolysaccharides, called glycosaminoglycans, of molecular weights that average 15,000 daltons. Commercial heparin typically consists of polymers of two repeating disacchar

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