WO1989000051A1 - Fibrin-binding compound and method - Google Patents

Fibrin-binding compound and method Download PDF

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Publication number
WO1989000051A1
WO1989000051A1 PCT/US1988/002276 US8802276W WO8900051A1 WO 1989000051 A1 WO1989000051 A1 WO 1989000051A1 US 8802276 W US8802276 W US 8802276W WO 8900051 A1 WO8900051 A1 WO 8900051A1
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Prior art keywords
fibrin
gln
leu
synthetic peptide
substance
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PCT/US1988/002276
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French (fr)
Inventor
Mats Gustaf Ranby
Tor-Bjorn Wiman
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Cytrx Biopool Ltd.
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Publication of WO1989000051A1 publication Critical patent/WO1989000051A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
    • A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
    • A61K49/10—Organic compounds
    • A61K49/14—Peptides, e.g. proteins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
    • A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
    • A61K49/085—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier conjugated systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
    • A61K51/088—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins conjugates with carriers being peptides, polyamino acids or proteins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/86—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving blood coagulating time or factors, or their receptors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2123/00—Preparations for testing in vivo
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/745—Assays involving non-enzymic blood coagulation factors
    • G01N2333/75—Fibrin; Fibrinogen
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/90—Enzymes; Proenzymes
    • G01N2333/91—Transferases (2.)
    • G01N2333/91045—Acyltransferases (2.3)
    • G01N2333/91074—Aminoacyltransferases (general) (2.3.2)
    • G01N2333/9108—Aminoacyltransferases (general) (2.3.2) with definite EC number (2.3.2.-)
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/90—Enzymes; Proenzymes
    • G01N2333/91—Transferases (2.)
    • G01N2333/91045—Acyltransferases (2.3)
    • G01N2333/91074—Aminoacyltransferases (general) (2.3.2)
    • G01N2333/9108—Aminoacyltransferases (general) (2.3.2) with definite EC number (2.3.2.-)
    • G01N2333/91085—Transglutaminases; Factor XIIIq (2.3.2.13)

Abstract

The present invention relates to a method and compound that is useful for targeting deposits of fibrin. The present invention is a compound that can be acted upon by the enzyme Factor XIIIa so that the compound is covalently bound to fibrin deposits in the body. The compound can be used to prepare diagnostic or therapeutic reagents that will then be bound to fibrin deposits. This can facilitate detection or treatment of the fibrin deposit or disease process anatomically associated with fibrin. The compound can be attached to a fibrinolytic protein by either chemical or recombinant DNA methods thereby making the protein specific for fibrin.

Description

"FIBRIN-BINDING COMPOUND AND METHOD"
Technical Field The present invention relates to a method and compound that is useful for targeting deposits of fibrin. More particularly, the present invention relates to a compound that can be acted upon by the enzyme Factor Xllla so that the compound is specifically bound to fibrin deposits in the body. The compound can be attached to a fibrinolytic protein thereby making the protein specific for fibrin.
Background of the Invention
As used herein, "peptide" means a polymer made up of amino acids comprising at least two amino acids and not more than fifty amino acids. "Fibrinolytic protein" means any protein that can facilitate the dissolution of a thrombus including those proteins that cause the coversion of plasminogen to plasmin. "Thrombus" is a blood clot made up of cross-linked fibrin. Fibrin deposits result from a wide variety of pathological situations in the body. For example, clots can form in vessels in tissue resulting in deep vein coronary or cerebral artery thrombosis. Small accumulations of fibrin precede, and may provide, warning of impending catastrophic thrombosis. Examples include unstable angina pectoris, which is considered a warning of impending coronary thrombosis and transient ischemic attacks, which may precede strokes. Fibrin is frequently deposited in tissue in association with inflammation associated with many disease processes including, but not limited to, infection, autoimmune disease and cancer.
Another situation where fibrin is deposited is around abscesses caused by infection with microorganisms. If the fibrin that has been deposited around the abscess can be detected, much information can be collected concerning the size and location of the abscess. Fibrin deposits are frequently found around certain solid tumors. A method of detecting fibrin that has surrounded a tumor would be very useful in diagnosing and locating the tumor.
Thus, an improved method of targeting therapeutic agents, such as fibrinolytic enzymes, drugs or radioisotopes to fibrin deposits has long been sought as a means of treating a variety of diseases including thromboses and tumors.
The blood clotting system in a normal human is a delicately balanced system of many enzymes and other proteins. (See Mullertz, S, Fibrinolysis, 1, 3-12, 1987). However, if a blood clot or thrombus forms in a blood vessel and occludes the vessel thereby cutting off the supply of blood to tissue that is normally fed by the vessel, serious damage can result to that tissue.
Thrombin is an enzyme that plays a crucial role in blood clotting. It is formed only as a result of a complex series of reactions involving a number of plasma proteins and calcium ions.
As this sequence normally occurs only at the site of a wound, thrombin (clotting factor Ha) is not present as such, but is present in the form of its inactive precursor, prothrombin (factor II). For coagulation to occur, thromboplastin (Factor XIII) is activated to Factor Xllla and accelerates the conversion of prothrombin to thrombin, which then, in turn, catalyses the formation of fibrin (factor la) from fibrinogen (factor I). Thrombin is active enough to produce a quantity of fibrin a million times its own weight.
Formation of a clot (thrombus) of blood, within a blood vessel or inside a heart chamber can cause serious damage. The thrombus is usually attached to the inner lining (endothelial cells) of the vessel and obstructs the flow of blood through it. Among the various factors encouraging the process of thrombosis are: (1) damage to the endothelial cell lining of the affected vessel, (2) an increase in the clotting properties of the blood, and (3) stagnation of blood in the vessel affected. The thrombosis can start as a very small lump attached to the damaged part of the vessel lining. Its presence encourages further thrombosis to occur, and has the effect of causing a slow-down of blood flow by reducing the inner diameter of the vessel. Further slowing and extension of the thrombosis occur, encouraging growth of the initially small thrombus, and often leading to almost total blockage of the affected blood vessel.
If thrombosis takes place in one of the arteries, the tissues supplied by that artery may be deprived of oxygen and nutrition, causing damage or death of the tissue (gangrene). The severity of the damage depends upon the position and size of the thrombosis, the speed at which it grows and whether the affected area has only one artery or is supplied by an anastomosis of blood vessels. If the vessel to a vital organ is affected, e.g. the heart or the brain, the person may be severely crippled or killed. Sometimes a thrombus may contain infective organisms such as bacteria, and "septic thrombosis" may occur, with the formation of pus and infection of the surrounding tissues. Although the details are not fully understood, fibrin has multiple functions in addition to forming clots or thrombi which control bleeding or impair blood flow. Deposits of fibrin, which are not associated with blood clots, occur commonly in association with inflammation, infection, immunologic reactions and tumors. The fibrin around tumors may be deposited as a result of factors secreted by the tumor or as a result of the host immune response against the tumor.
Early attempts at detecting thrombi in the body include injecting radioactively-labeled fibrinogen into the patient and then detecting where the fibrinogen is deposited. The labeled fibrinogen that is injected into the body circulates in the blood stream until it is cleaved by circulating thrombin creating fibrin monomers. The labeled fibrin monomers are then polymerized forming fibrin. Because a thrombi in a blood vessel is constantly being degraded and then reformed by the fibrinolytic systems and the coagulation systems in the blood, the newly formed radioactively labeled fibrin monomers are incorporated into the thrombi as crosslinked fibrin. If the fibrinogen were labeled with 1311, for example, the body could be scanned with a gamma counter to locate the labeled clot.
There are several serious drawbacks to using radiolabeled fibrinogen to detect fibrin deposits. One of the major problems with using radiolabeled fibrinogen is the fact that the fibrinogen remains in the body for long periods of time. The fibrinogen will eventually be broken down into fibrin monomers and will be incorporated into clots long after the diagnostic procedure is completed. This presents a danger to the patient from long term radiation exposure. Another disadvantage associated with the use of radiolabeled fibrinogen as a diagnostic tool for localizing fibrin is the fact that the fibrinogen may be deposited at sites other than the problem thrombus thereby reducing the sensitivity of the method.
The major problem which has impeded the use of labeled fibrinogen as a diagnostic reagent is the signal to noise ratio. The labeled fibrinogen mixes with the large pool of normal fibrinogen in the circulation. Only a small portion of the labeled fibrinogen becomes deposited in any particular site of disease. The diagnostic scanning typically must be delayed for up to a week for the unbound labeled protein in the circulation to be cleared sufficiently to reduce the background of scanning to acceptable levels. In the meantime, the normal fibrinolytic processes dissolve some of the fibrin and facilitate its removal from the disease site.
Finally, fibrinogen is purified from human blood plasma and thus a risk of hepatitis or HIV infection exits, which necessitates testing the purified fibrinogen preparations for virus contamination.
Another attempt at localizing fibrin deposits within the body is the use of antibodies that are specific for a protein associated with the fibrin deposit. The protein that is usually selected is fibrin itself. Typically, an antibody specific for the fibrin protein is produced by methods well known to those skilled in the art. The antibody is then labeled with a radioactive molecule such as 131I. The antibody is then injected into the patient. The labeled antibody circulates in the blood until it comes into contact with fibrin, presumably in a thrombus. The antibody binds to the fibrin protein making up the thrombus, and the localized radioactivity is detected by a gamma counter.
Some investigators proposed that the antibody might bind to fibrinogen in the circulation prior to being incorporated into the site of disease (See Day, et al, J. N.C.I. 22:413, 1959) In one study, 75% (129 out of 172 patients) human tumors of various types were located with 131ι labeled antibody to fibrin. The feasibility of labeled antibody against fibrin for cancer therapy was demonstrated by producing "substantial regression of clinical symptoms" in a few patients. (See Spar et al., Cancer 20:865, 1968)
Problems with the use of heterologous antibodies includes the possibility of anaphalactic shock by an acute immunological response against the injected proteins. Furthermore, injection of foreign antibodies commonly provokes a delayed immune response in the patient, which includes the formation of specific antibodies directed against the foreign antibodies. This can hamper future diagnosis using the same diagnostic antibodies. Another problem occurs because the radiolabeled antibodies remain in the body for a long period of time thereby exposing the body to radioactivity for a long period of time. The signal to noise ratio problems associated with labeled fibrinogen are also encountered with antibody to fibrin. Only a small portion of labeled antibody is taken up at a particular disease site and scanning must be delayed until the unbound label is cleared. In a therapeutic trial involving patients whose tumors localized fibrin antibodies avidly, up to 160 mC of --31 τ was administered to produced a dose to the tumor of only 2000 rads while the whole body dose was 150 rads.
Similar considerations pertain to the targeting of other therapeutic agents, including fibrinolytic enzymes, to fibrin deposits. Enzymes, such as streptokinase, produce beneficial effects of dissolving thrombi when localized on fibrin but produce toxic effects, such as hemorrhage, when present in excess concentration in the circulation.
What is needed is a method and compound which localizes on fibrin deposits in the body and is capable of targeting or delivering attached diagnostic or therapeutic agents to the fibrin while minimizing the concentration of the diagnostic or therapeutic agents in other regions of the body. The method and compound needs to have a short half-life in the blood and not cause an immunologic reaction when it is injected into the body. The method and compound need to be specific for fibrin and need to be firmly bound to the fibrin deposit. The compound should also bind to the fibrin deposit quickly because of its short half-life in circulation.
Summary of the Invention The present invention provides a method and compound for the in vivo targeting of diagnostic or therapeutic reagents to a fibrin deposit within the body. According to the present invention, a compound is provided that will specifically bind to a fibrin protein. The fibrin-binding compound of the present invention is any peptide that is a substrate for the blood enzyme commonly known as Factor Xllla. Factor XUla causes alpha-2 antiplasmin to be bound to fibrin by a transamination reaction.
One embodiment of the present invention contains a peptide that specifically binds to fibrin and is acted upon by Factor Xllla. Peptides that are contemplated by the present invention contain at least the following amino acids:
-Asn-Gln-Glu-Gln-
In one particular embodiment of the present invention, the peptide is labeled with 125I. The fibrin-binding compound of the present invention can safely be injected into a human or animal. The peptide will circulate in the blood until it encounters a fibrin deposit. The peptide will specifically bind to the fibrin protein in the fibrin deposit. After the peptide binds to the fibrin, it will be acted upon by another protein in the blood called Factor Xllla. Factor Xllla is a transaminase that reacts the glutamic acid in the number three position of the preferred peptide with a free amine group in the fibrin molecule forming an amide bond with the γ carboxyl group on the glutamic acid. Thus, the fibrin-binding compound of the present invention is covalently bound to the fibrin.
The present invention also includes a method for detecting fibrin deposits in vivo. The method for detecting fibrin deposits comprises the steps of injecting into the body a labeled fibrin-binding compound, allowing the fibrin-binding compound to bind to a fibrin deposit, and then detecting the fibrin deposit.
The present invention also includes a method of delivering therapeutic agents to fibrin deposits in vivo. Such agents include, but are not limited to, radioisotopes for treating tumors and enzymes for dissolving clots. Clot dissolving enzymes that can be used with the present invention include, but are not limited to, streptokinase and urokinase. The fibrin-binding compound of the present invention can be conjugated to a clot dissolving enzyme by chemical methods or it can be inserted into the enzyme by recombinant DNA methods.
Accordingly, it is an object of the present invention to provide a peptide that will covalently bind to fibrin after transamination through the action of Factor Xllla. It is another object of the present invention to provide a method for directing diagnostic or therapeutic agents to a fibrin deposit in an animal or human.
It is yet another object of the present invention to provide a compound that will not react immunologically with the immune system of the organism in which the compound is injected.
It is another object of the present invention to provide a fibrin-binding compound that can be chemically conjugated to a fibrinolytic enzyme, such as streptokinase and urokinase, so that the enzyme will be bound to a fibrin clot.
It is a further object of the present invention to provide a fibrin-binding compound that can be incorporated into a fibrinolytic enzyme, such as streptokinase and urokinase, by genetic engineering methods so that the enzyme will bind to a fibrin clot in the presence of Factor Xllla and will facilitate the dissolution of the clot.
It is yet another object of the present invention to provide a compound that will specifically bind to fibrin and can be labeled with a radioactive element. Yet another object of the present invention is to provide a compound and method for detecting fibrin around an abscess.
Another object of the present invention is to provide a compound and method for detecting a thrombus in its formative stages.
These and other objects, features and advantages of the present invention will become apparent after a review of the following detailed description of the disclosed embodiment and the appended claims.
Detailed Description of the Invention
The present invention provides a method and compound for the in vivo detection of a fibrin deposit within the body. According to the present invention, a peptide is provided that specifically binds to a fibrin protein. It is contemplated that the present invention is any peptide that is a substrate for the action of Factor Xllla. Peptides that are contemplated by the present invention contain at least the following amino acids:
-Asn-Gln-Glu-GIn-
One embodiment of the present invention is the native form of the NH2 terminal end of the alpha-2 antiplasmin enzyme. This native peptide has the following general formula:
1 2 3 4 5 6 7 8 9 10 11 12 Nf^ -Asn-Gln-Glu-Gln-Val-Ser-Pro-Leu-Thr-Leu-Lβu-Lys-OH
A more preferred peptide contemplated by the present invention contains the following amino acid sequence:
1 2 3 4 5 6 7 8 9 10 11 12 Nl^ -Asn-Gln-Glu-Gln-Val-Ser-Pro-Tyr-Thr-LθU-LθU-Lys-OH
This peptide is a modification of the NH2 terminal end of the alpha-2 antiplasmin enzyme in that a tyrosine at the number 8 position is substituted for the leucine in the native peptide.
In one particular embodiment of the present invention, the tyrosine in the number 8 position is labeled with 125I or !31τ or another suitable radioactive element or compound. It is to be understood that the tyrosine can be substituted elsewhere in the peptide. For example, the tyrosine could be substituted for the leucine at position 10 without appreciably diminishing the fibrin- binding activity of the present invention. Activity is reduced if the tyrosine is introduced in the first four positions.
It is to be understood that the fibrin binding compound of the present invention can be modified by inserting a group that can bind to radioactive atoms other than iodine. Radioactive elements that can be used according to the present invention include but are not limited to, iodine 125, iodine 131, and technetium 99.
Other compounds that can be conjugated to the fibrin- binding compound of the present invention are compounds that can be detected by methods such as nuclear magnetic resonance. Nuclear magnetic resonance detectable substances include, but are not limited to carbon 13, oxygen 17, and fluorine 19.
Large or small chemical groups can be chemically conjugated to the fibrin binding compound of the present invention.
The large groups could be proteins or enzymes, such as streptokinase or urokinase. These groups can be conjugated by techniques well-known to those of ordinary skill in the art utilizing gluteraldehyde, carbodiimmide or other conjugating compounds. The present invention also includes a method of detecting a fibrin deposit in an animal or human comprising the steps of injecting into the blood a labeled peptide that specifically binds to a fibrin deposit, allowing the labeled peptide to bind to the fibrin deposit and then detecting the fibrin deposit by measuring the label on the peptide. If the label is a radioactive element, instrumentation suitable for measuring that element can be used. If the label is a nuclear magnetic resonance detectable label, instrumentation that can measure nuclear magnetic resonance is used. The fibrin binding peptide of the present invention can be attached to, or incorporated into, the peptide sequence of a protein by means of genetic engineering technology. The genetic sequence coding for the peptide could be combined with that of the diagnostic or therapeutic group by recombinant DNA techniques well-known to those of ordinary skill in the art. The combined preparation can then be synthesized as a single unit by using an appropriate expression vector. The present invention includes a method of attaching the fibrin binding compound by ligation of a synthetic oligonucleotide encoding the fibrin-binding compound to the cDNA sequence of the thromboiytic protein. Thrombolytic proteins that can be used in accordance with the present invention include, but are not limited to, streptokinase, tissue plasminogen activator, urokinase, and protein S
Although not wanting to be bound by the following mechanism, it is believed that the present invention works by the following mechanism: The fibrin binding compound of the present invention circulates in the blood until it encounters a fibrin deposit. The compound specifically binds to the fibrin protein in the fibrin deposit. After the compound binds to the fibrin, it can be acted upon by another protein in the blood called Factor Xllla. Factor
Xllla is a transaminase that catalyzes the reaction of the glutamic acid in the number three position of the preferred peptide with a free amine group in the fibrin molecule forming an amide bond with the γ carboxyl group on the glutamic acid. Thus, the fibrin- binding compound of the present invention is covalently bound to the fibrin. It is to be understood that the fibrin binding compound of the present invention is any compound that is acted upon by Factor Xllla thereby binding the compound to fibrin.
The fibrin-binding compound of the present invention binds rapidly with the fibrin protein. This is an important attribute of the present invention because the fibrin-binding compound of the present invention is rapidly eliminated from the blood circulation. This is a distinct advantage over prior art methods of detecting fibrin deposits, such as monoclonal antibodies and radiolabeled fibrinogen, because these methods employ large proteins as carriers of the label. These large proteins are eliminated from the circulation slowly thereby exposing the body to radiation and adversely affecting the signal to noise ratio of diagnostic procedures and the risk to benefit ratio of therapeutic procedures.
The present invention also includes a method for detecting fibrin deposits in vivo. The method for detecting fibrin deposits comprises the steps of injecting into the body a labeled fibrin-binding compound, allowing the fibrin-binding compound to bind to a fibrin deposit, and then detecting the fibrin deposit.
Detection of the fibrin deposit can be performed in a number of ways including, but not limited to, gamma detectors and nuclear magnetic resonance. The fibrin-binding compound can be detected by a variety of methods that are well known to one of ordinary skill in the art. For example, if a gamma emitter, such as 125I or 131I is used to label the fibrin-binding compound, a gamma counter can be scanned over the body to determine where the fibrin deposit is located.
The invention will now be described with specific examples which are only given for illustrative and not limiting purposes.
Example I
The following peptide is labeled with l25Iodine.
1 2 3 4 5 6 7 8 9 10 11 12 Nf- -Asn-Gln-Glu-Gln-Val-Ser-Pro-Tyr-Thr-Leu-Lβu-Lys-OH
Presumably, the iodine labels the tyrosine at the number 8 position. The 125I labeled peptide is added to normal plasma and the plasma is clotted by the addition of thrombin and Ca2+. Approximately 20% of the labeled peptide is covalently bound to the fibrin clot within 5 minutes. As a control, virtually no radioactivity is associated with the fibrin clot if the plasma is clotted with bathroxobin, which is known not to activate Factor XH
It should be understood that the foregoing relates only to a preferred embodiment of the present invention and that numerous modifications or alterations may be made without departing from the spirit and scope of the invention as set forth in the appended claims.

Claims

Claims
1. A compound for detecting fibrin deposits in a human or animal body comprising a substance that is covalently bound to fibrin by activated Factor Xllla.
2. The compound of Claim 1 wherein said substance is labeled with a radioactive element.
3. The compound of Claim 2, wherein said radioactive element is selected from the group consisting of iodine 125, iodine 131, and technetium 99.
4. The compound of Claim 1 , wherein said substance can be labeled with a nuclear magnetic resonance detectable substance.
5. The compound of Claim 4, wherein the nuclear magnetic resonance detectable substance is selected from the group consisting of carbon 13, oxygen 17, and fluorine 19.
6. The compound of Claim 1 , wherein said substance is a synthetic peptide.
7. The compound of Claim 6, wherein the synthetic peptide comprises at least the following amino acids:
-Asn-Gln-Glu-Gln-
8. The compound of Claim 6, wherein the synthetic peptide comprises the following formula:
NH2-Asn-Gln-Glu-Gln-Val-Ser-Pro-Leu-Thr-Leu-Leu-Lys-OH
9. The compound of Claim 6, wherein the synthetic peptide comprises the following formula:
NH2-Asn-Gln-Glu-Gln-VaI-Ser-Pro-Tyr-Thr-Leu-Leu-Lys-OH
10. A method of detecting a fibrin deposit in an animal or human comprising the steps of: a. injecting into the blood a labeled fibrin- binding substance that can be covalently bound to fibrin by Factor Xllla; b. allowing the labeled substance to bind to the fibrin deposit; and c. detecting the fibrin deposit.
5 11. The method of Claim 10, wherein the fibrin- binding substance is a synthetic peptide.
12. The method of Claim 11, wherein the synthetic peptide comprises at least the following amino acids: Q -Asn-Gln-Glu-Gln-
13. The method of Claim 11 wherein the synthetic peptide comprises the following formula:
5 NH2-Asn-Gln-Glu-Gln-Val-Ser-Pro-Leu-Thr-Leu-Leu-Lys-OH
14. The method of Claim 11 wherein the synthetic peptide comprises the following formula:
0 NH2-Asn-Gln-Glu-Gln-Val-Ser-Pro-Tyr-Thr-Leu-Leu-Lys-OH
15. The method of Claim 10 wherein said substance is labeled with a radioactive element.
16. The method of Claim 15, wherein said radioactive element is selected from the group consisting of iodine 125, iodine 131, and technetium 99.
5 17. The method of Claim 10, wherein said substance can be labeled with a nuclear magnetic resonance detectable substance.
18. The method of Claim 17, wherein the nuclear 10 magnetic resonance detectable substance is selected from the group consisting of carbon 13, oxygen 17, and fluorine 19.
19. A fibrin-binding thrombolytic enzyme comprising a thrombolytic enzyme attached to a fibrin binding
15 substance having the ability to covalently bind to fibrin through the action of Factor Xllla.
20. The fibrin-binding thrombolytic enzyme of Claim 19, wherein the thrombolytic enzyme is selected from the
20 group consisting of streptokinase, tissue plasminogen activator, urokinase, and protein S.
21. The fibrin-binding thrombolytic enzyme of Claim 19, wherein the fibrin-binding substance is a synthetic
25 peptide.
22. The fibrin-binding thrombolytic enzyme of Claim 21, wherein the synthetic peptide comprises at least the following amino acids:
•3Q -Asn-Gln-Glu-GIn-
23. The fibrin-binding thrombolytic enzyme of Claim 21, wherein the synthetic peptide comprises the following formula:
NH2-Asn-Gln-Glu-Gln-Val-Ser-Pro-Leu-Thr-Leu-Leu-Lys-OH
24. The fibrin-binding thrombolytic enzyme of Claim 21, wherein the synthetic peptide comprises the following formula:
NH2-Asn-Gln-Glu-Gln-Val-Ser-Pro-Tyr-Thr-Leu-Leu-Lys-OH
25. The fibrin-binding thrombolytic enzyme of Claim 21, wherein the synthetic peptide is incorporated into the peptide structure of the thrombolytic enzyme by ligation of a synthetic oligonucleotide encoding the synthetic peptide to the cDNA sequence of the thrombolytic protein.
26. The fibrin-binding thrombolytic enzyme of
Claim 19, wherein the fibrin-binding substance is attached to the peptide structure of the thrombolytic enzyme by chemical means.
27. A method for creating a fibrin-binding thrombolytic enzyme comprising the step of attaching a thrombolytic enzyme to a substance having the ability to covalently bind to fibrin through the action of factor Xllla.
28. The method of Claim 27, wherein the thrombolytic enzyme is selected from the group consisting of streptokinase, tissue plasminogen activator, urokinase, and protein S.
29. The method of Claim 27, wherein the fibrin- binding substance is a synthetic peptide.
30. The method of Claim 29, wherein the synthetic peptide comprises at least the following amino acids:
-Asn-Gln-Glu-Gln-
31. The method of Claim 29, wherein the synthetic peptide comprises the following formula:
NH2-Asn-Gln-Glu-Gln-Val-Ser-Pro-Leu-Thr-Leu-Leu-Lys-OH
32. The method of Claim 29, wherein the synthetic peptide comprises the following formula:
NH2-Asn-Gln-Glu-Gln-Val-Ser-Pro-Tyr-Thr-Leu-Leu-Lys-OH
33. The method of Claim 29, wherein the synthetic peptide is incorporated into the peptide structure of the thrombolytic enzyme by ligation of a synthetic oligonucleotide encoding the synthetic peptide to the cDNA sequence of the thrombolytic protein.
34. The method of Claim 27, wherein the synthetic peptide is chemically attached to the thrombolytic enzyme.
PCT/US1988/002276 1987-07-07 1988-07-01 Fibrin-binding compound and method WO1989000051A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US7071087A 1987-07-07 1987-07-07
US070,710 1987-07-07

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EP0397366A1 (en) * 1989-05-09 1990-11-14 The Board Of Regents Of The University Of Oklahoma Hybrid streptokinases with fibrin binding domains and methods for the synthesis of same
WO1990015867A1 (en) * 1989-06-13 1990-12-27 Nippon Soda Co., Ltd. Human prourokinase-like polypeptides and their preparation methods
EP0411895A1 (en) * 1989-07-31 1991-02-06 Merck & Co. Inc. Imidazole compounds and their use as transglutaminase inhibitors
WO1991016931A1 (en) * 1990-05-10 1991-11-14 Zymogenetics, Inc. Clot imaging agents and use thereof
EP0651799A4 (en) * 1990-05-21 1993-10-05 Bio Technology General Corp Fibrin binding domain polypeptides and uses and methods of producing same.
US5443816A (en) * 1990-08-08 1995-08-22 Rhomed Incorporated Peptide-metal ion pharmaceutical preparation and method
US5643549A (en) * 1992-02-20 1997-07-01 Rhomed Incorporated Leukostimulatory agent for in vivo leukocyte tagging
US5736122A (en) * 1991-02-08 1998-04-07 Diatide, Inc. Technetium-99m labeled peptides for thrombus imaging
US5776428A (en) * 1992-04-30 1998-07-07 Diatide, Inc. Technetium-99m labeled peptides for imaging
US5783170A (en) * 1991-11-27 1998-07-21 Diatide, Inc. Peptide-metal chelate conjugates
WO1998043686A1 (en) * 1997-04-03 1998-10-08 California Institute Of Technology Enzyme-mediated modification of fibrin for tissue engineering
US5849260A (en) * 1991-02-08 1998-12-15 Diatide, Inc. Technetium-99M labeled peptides for thrombus imaging
US5849261A (en) * 1991-02-08 1998-12-15 Diatide, Inc. Radiolabeled vasoactive intestinal peptides for diagnosis and therapy
US5866097A (en) * 1991-11-27 1999-02-02 Diatide, Inc. Technetium-99m labeled peptides for imaging
US5869616A (en) * 1988-12-29 1999-02-09 Bio-Technology General Corp. Fibrin binding domain polypeptides and uses and methods of producing same
US5876973A (en) * 1992-08-10 1999-03-02 Cambridge Neuroscience, Inc. Method for making antibodies which specifically bind to glial growth factors
US5879657A (en) * 1993-03-30 1999-03-09 The Dupont Merck Pharmaceutical Company Radiolabeled platelet GPIIb/IIIa receptor antagonists as imaging agents for the diagnosis of thromboembolic disorders
US5925331A (en) * 1992-05-21 1999-07-20 Diatide, Inc. Technetium-99m labeled peptides for thrombus imaging
US5951981A (en) * 1996-12-02 1999-09-14 Diatide, Inc. Thrombolytic agents with antithrombotic activity
US5968476A (en) * 1992-05-21 1999-10-19 Diatide, Inc. Technetium-99m labeled peptides for thrombus imaging
US5976494A (en) * 1992-06-05 1999-11-02 Diatide, Inc. Technetium-99m labeled peptides for imaging
WO1999060018A1 (en) * 1998-05-15 1999-11-25 Nycomed Amersham Plc Labelled glutamine and lysine analogues
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US5997844A (en) * 1991-02-08 1999-12-07 Diatide, Inc. Technetium-99m labeled peptides for imaging
US6248304B1 (en) 1991-02-08 2001-06-19 Berlex Laboratories, Inc. Scintigraphic imaging agents
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US7087722B1 (en) 1988-12-29 2006-08-08 Savient Pharmaceuticals, Inc. Fibrin binding domain polypeptides and uses and methods of producing same
US7241730B2 (en) 1998-08-27 2007-07-10 Universitat Zurich Enzyme-mediated modification of fibrin for tissue engineering: fibrin formulations with peptides
US7247609B2 (en) 2001-12-18 2007-07-24 Universitat Zurich Growth factor modified protein matrices for tissue engineering
US20090175783A1 (en) * 2005-08-03 2009-07-09 Zubeldia Jose M Compounds and imaging methods
US7601685B2 (en) 1998-08-27 2009-10-13 Eidgenossische Technische Hochschule Zurich Growth factor modified protein matrices for tissue engineering
US8226942B2 (en) 2007-12-28 2012-07-24 Kuros Biosurgery Ag PDGF fusion proteins incorporated into fibrin foams
US8318674B2 (en) 2005-01-06 2012-11-27 Kuros Biosurgery Ag Local treatment of bone defects
US8575101B2 (en) 2005-01-06 2013-11-05 Kuros Biosurgery Ag Supplemented matrices for the repair of bone fractures
US8961947B2 (en) 2007-04-13 2015-02-24 Kuros Biosurgery Ag Polymeric tissue sealant
US10589001B2 (en) 2011-03-16 2020-03-17 Kuros Biosurgery Ag Pharmaceutical formulation for use in spinal fusion

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US5965383A (en) * 1988-12-29 1999-10-12 Bio-Technology General Corp. Fibrin binding domain polypeptides and uses and methods of producing same
US5270030A (en) * 1988-12-29 1993-12-14 Bio-Technology General Corp. Fibrin binding domain polypeptide and method of producing
US7087722B1 (en) 1988-12-29 2006-08-08 Savient Pharmaceuticals, Inc. Fibrin binding domain polypeptides and uses and methods of producing same
US6121426A (en) * 1988-12-29 2000-09-19 Bio-Technology General Corp. Fibrin binding domain polypeptides and uses and methods of producing same
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US5316934A (en) * 1989-06-13 1994-05-31 Nippon Soda Co., Ltd. Effective thrombosis mediated by human prourokinase-like polypeptides with increased binding affinity for thrombosis
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US6248304B1 (en) 1991-02-08 2001-06-19 Berlex Laboratories, Inc. Scintigraphic imaging agents
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