Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1997-12-05
2001-02-20
Jones, Dwayne C. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S012200, C514S013800, C514S014800, C514S015800, C514S016700, C514S822000
Reexamination Certificate
active
06191103
ABSTRACT:
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH
Not applicable.
FIELD OF THE INVENTION
The present invention relates to compositions and methods for use in enhancing thrombolysis in mammals.
BACKGROUND OF THE INVENTION
Formation of a blood clot (thrombus) in a blood vessel entails two principal events: platelet aggregation and deposition of fibrin. Within seconds of vessel injury, resting platelets become activated and are bound to the exposed surface of the injured area by a phenomenon called platelet adhesion. Activation of platelets also leads to enhanced binding of the surface adhesion molecule gpIIbIIIa (CD41), causing platelets to bind to each other in a process called platelet aggregation to form a platelet plug. Inhibitors of platelet activation, or of gpIIbIIIa activity, have been shown to prevent platelet aggregation and, hence, to reduce thrombus formation. The platelet plug can stop bleeding quickly, but it must be reinforced by fibrin for long-term effectiveness, until the vessel injury can be permanently repaired.
The coagulation system, involved in thrombus formation, has a natural counterpart in the fibrinolytic system. In the process of blood coagulation, a cascade of enzyme activities are involved in generating a fibrin network which forms the framework of a clot. Degradation of the fibrin network (fibrinolysis) is accomplished by the action of the enzyme plasmin. Plasminogen is the inactive precursor of plasmin and conversion of plasminogen to plasmin is accomplished by cleavage of the peptide bond between arginine 561 and valine 562 of plasminogen. Under physiological conditions this cleavage is catalysed by tissue-type plasminogen activator (tPA) or by urokinase-type plasminogen activator (uPA).
If the balance between the clotting and fibrinolytic systems becomes locally disturbed, intravascular clots may form at inappropriate locations leading to conditions such as coronary thrombosis and myocardial infarction, deep vein thrombosis, stroke, peripheral arterial occlusion and embolism. In such cases, the administration of fibrinolytic agents has been shown to be a beneficial therapy for the promotion of clot dissolution.
Fibrinolytic therapy has become relatively widespread with the availability of a number of plasminogen activators such as tPA, uPA, streptokinase and the anisoylated plasminogen streptokinase activator complex, APSAC. Each of these agents has been shown to promote clot lysis, but all have deficiencies in their activity profile which makes them less than ideal as therapeutic agents for the treatment of thrombosis (reviewed by Marder and Sherry, New England Journal of Medicine 1989, 318: 1513-1520). One of the major problems with tPA for the treatment of acute myocardial infarction or other thrombotic disorders is that it is rapidly cleared from the circulation with a plasma half-life in man of around 5 minutes (Bounameaux et al. in: “Contemporary Issues in Haemostasis and Thrombosis” vol 1 pp. 5-91, 1985. Collen et al. eds, Churchill Livingstone). This results in the need to administer tPA by infusion in large doses. The treatment is therefore expensive and is usually delayed since the patient has to be hospitalized before treatment can commence. Urokinase, in either the single chain form or the two chain form, has a similar rapid plasma clearance and also requires administration by continuous infusion.
A major problem shared by all of these agents is that at clinically useful doses, they are not thrombus specific as they activate plasminogen in the general circulation. The principal consequence of this is that proteins such as fibrinogen involved in blood clotting are destroyed and dangerous bleeding can occur. This also occurs with tPA despite the fact that, at physiological concentrations, it binds to fibrin and shows fibrin selective plasminogen activation. Significant efforts have been expended to find mutant or other forms of tPA and other fibrinolytic or thrombolytic agents with desirable activity, specificity, and duration.
Accordingly, a need exists in the art for additional agents which can enhance fibrinolysis. The subject invention fills this and other needs.
SUMMARY OF THE INVENTION
The subject invention discloses that agents which inhibit the interaction between the band 3 protein and its ligand (hereafter sometimes referred to as “interaction inhibitors” or “inhibitors”), CD36/thrombospondin, can also be used to enhance thrombolysis. The inhibitors can be peptides which contain sequences present in exofacial loops of the band 3 protein, or can be non-natural, D-isomer forms of the same sequences, or can be peptides, peptidomimetics, or non-peptidic molecules which interfere with band 3 protein—ligand interactions. One preferred group of such inhibitors comprises peptides characterized by the sequence motif
Z
2
Z
3
Z
2
UX
−
UUU
U
X
−
(SEQ ID NO:44),
wherein Z
2
represents a hydrophobic residue, U represents unobstructive residues, Z
3
is either Z
2
or an unobstructive residue and X
−
represents negatively charged residues. Another preferred group of such inhibitors comprises peptides characterized by the sequence motif
Z
1
UKUUUX
+
(SEQ ID NO:45),
wherein Z
1
is selected from the group consisting of tyrosine, phenylalanine and alanine; K is a lysine residue; U represents unobstructive residues; and X
+
is a positively charged residue. The reverse sequences of these peptides are also active. The inhibitors of the subject method can be administered alone or in combination with one or more additional therapeutic agents. Administration can be oral, intravenous or by other means, in amounts between about 0.1 mg/kg to about 20 mg/kg.
REFERENCES:
patent: 9629086 (1996-09-01), None
Crandall, Ian et al.,Proc. Natl. Acad. Sci. USA, 90:4703-4707 (1993).
Ito, S. et al.,The International Journal of Artificial Organs, 15 (12) :737-745 (1992).
Land, K.M. et al.,Parasitology Today, 11 (1) :19-23 (1995).
Thevenin, B.J.-M. et al., SS Boston National Sickle Cell Program, Abstract, “A Peptide Comprising Residues 546-553 of Human Erythrocyte Band 3 Inhibits Sickle Cell Adherence to the Endothelium, ” Mar. 18-21, (1995).
Thevenin, B.J.-M. et al., Assn. American Physicians San Diego Clinical Res. Mtg., Abstract, “Inhibition of Sickle Cell Cytoadherence by Peptides from Exofacially Exposed Sites of Band 3, ” May 5-8, (1995).
“Taking the bite out of killer malaria, ”The Press-Enterprise, May 15, 1993.
“UC Scientists Block Attachment of Malaria-Infected Cells to Endothelium, ”Genetic Engineering News, Jun. 1, 1993.
Sherman Irwin
Shohet Stephen B.
von Andrian Ulrich
Delacroix-Muirheid C.
Jones Dwayne C.
The Regents of the University of California
Townsend and Townsend / and Crew LLP
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