US6156321A
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Tissue factor methods and compositions for coagulation and tumor treatment
Assignee: The University of Texas System
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Filing: 1998-01-20
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Granted: 2000-12-05
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Expires: 2018-01-20
Abstract
Abstract The invention embodies the surprising discovery that Tissue Factor (TF) compositions and variants thereof specifically localize to the blood vessels within a vascularized tumor following systemic administration. The invention therefore provides methods and compositions comprising coagulant-deficient Tissue Factor for use in effecting specific coagulation and for use in tumor treatment. The TF compositions and methods of present invention may be used alone, as TF conjugates with improved half-life, or in combination with other agents, such as conventional chemotherapeutic drugs, targeted immunotoxins, targeted coaguligands, and/or in combination with Factor VIIa (FVIIa) or FVIIa activators.
Inventors
- 👤 Philip E. Thorpe
- 👤 Steven W. King
- 👤 Boning Gao
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-11-07 17:53
CPC Classifications
A; A61; A61K; A61K39/00; A61K39/395; A61K47/00; A61K47/50; A61K47/51; A61K47/68; A61K47/6801; A61K47/6803; A61K47/6811; A61K47/6813; A61K47/62; A61K47/64; A61K47/6435; A61P; A61P35/00; A61P7/00; A61P7/02; A61P7/04; Y; Y10; Y10S; Y10S530/00; Y10S530/827; Y10S530/829
Claims Analysis
Total Claims: 55
Claim 1
Independent Claim
44 words
A method for treating an animal having a vascularized tumor, comprising administering to said animal a biologically effective amount of a composition that comprises an amount of a first coagulation-deficient Tissue Factor compound sufficient to specifically promote coagulation in the vasculature of said tumor.
Claim 2
Independent Claim
44 words
A method for treating an animal having a vascularized tumor, comprising administering to said animal a biologically effective amount of a composition that comprises an amount of a first coagulation-deficient Tissue Factor compound sufficient to specifically promote coagulation in the vasculature of said tumor.
Claim 3
Dependent Claim
16 words
The method of claim 1, wherein said composition is administered to said animal via intravenous injection.
Claim 4
Independent Claim
49 words
A method for treating an animal having a vascularized tumor, comprising systemically administering to said animal a biologically effective amount of a composition comprising at least a first coagulation-deficient Tissue Factor compound in an amount effective to promote coagulation specifically in the tumor vasculature and to cause tumor necrosis.
Claim 5
Independent Claim
49 words
A method for treating an animal having a vascularized tumor, comprising systemically administering to said animal a biologically effective amount of a composition comprising at least a first coagulation-deficient Tissue Factor compound in an amount effective to promote coagulation specifically in the tumor vasculature and to cause tumor necrosis.
Claim 6
Dependent Claim
28 words
The method of claim 3, wherein said coagulation-deficient Tissue Factor compound is between about 100-fold and about 1,000,000-fold less active in coagulation than full length, native Tissue Factor.
Claim 7
Dependent Claim
26 words
The method of claim 4, wherein said coagulation-deficient Tissue Factor compound is at least about 1,000-fold less active in coagulation than full length, native Tissue Factor.
Claim 8
Dependent Claim
26 words
The method of claim 5, wherein said coagulation-deficient Tissue Factor compound is at least about 10,000-fold less active in coagulation than full length, native Tissue Factor.
Claim 9
Dependent Claim
26 words
The method of claim 6, wherein said coagulation-deficient Tissue Factor compound is at least about 100,000-fold less active in coagulation than full length, native Tissue Factor.
Claim 10
Dependent Claim
17 words
The method of claim 3, wherein said coagulation-deficient Tissue Factor compound is a human Tissue Factor compound.
Claim 11
Dependent Claim
16 words
The method of claim 3, wherein said coagulation-deficient Tissue Factor compound is prepared by recombinant expression.
Claim 12
Dependent Claim
19 words
The method of claim 3, wherein said coagulation-deficient Tissue Factor compound is deficient in binding to a phospholipid surface.
Claim 13
Dependent Claim
16 words
The method of claim 3, wherein said coagulation-deficient Tissue Factor compound is a truncated Tissue Factor.
Claim 14
Dependent Claim
18 words
The method of claim 11, wherein said coagulation-deficient Tissue Factor compound is about 219 amino acids in length.
Claim 15
Dependent Claim
22 words
The method of claim 11, wherein said coagulation-deficient Tissue Factor compound consists essentially of the amino acid sequence of SEQ ID NO:1.
Claim 16
Dependent Claim
16 words
The method of claim 3, wherein said coagulation-deficient Tissue Factor compound is a dimeric Tissue Factor.
Claim 17
Dependent Claim
16 words
The method of claim 3, wherein said coagulation-deficient Tissue Factor compound is a polymeric Tissue Factor.
Claim 18
Dependent Claim
24 words
The method of claim 3, wherein said coagulation-deficient Tissue Factor compound is a mutant Tissue Factor deficient in the ability to activate Factor VII.
Claim 19
Dependent Claim
25 words
The method of claim 16, further comprising administering to said animal an amount of Factor VIIa sufficient to increase tumor vasculature coagulation and tumor necrosis.
Claim 20
Dependent Claim
20 words
The method of claim 3, wherein said coagulation-deficient Tissue Factor compound has been modified to increase its biological half life.
Claim 21
Dependent Claim
30 words
The method of claim 18, wherein said coagulation-deficient Tissue Factor compound is operatively linked to a carrier molecule that increases the biological half life of said coagulation-deficient Tissue Factor compound.
Claim 22
Dependent Claim
14 words
The method of claim 19, wherein said carrier molecule is a protein carrier molecule.
Claim 23
Dependent Claim
15 words
The method of claim 20, wherein said carrier molecule is an albumin or a globulin.
Claim 24
Dependent Claim
36 words
The method of claim 20, wherein said carrier molecule is an antibody or portion thereof, wherein the antibody does not exhibit significant specific binding to a component of a tumor cell, tumor vasculature or tumor stroma.
Claim 25
Dependent Claim
32 words
The method of claim 22, wherein said carrier molecule is an IgG molecule that does not exhibit significant specific binding to a component of a tumor cell, tumor vasculature or tumor stroma.
Claim 26
Dependent Claim
16 words
The method of claim 22, wherein said carrier molecule is an Fc portion of an antibody.
Claim 27
Dependent Claim
38 words
The method of claim 22, wherein said coagulation-deficient Tissue Factor compound has been introduced into an IgG molecule in place of the CH 3 domain to create an IgG carrier molecule that comprises said coagulation-deficient Tissue Factor compound.
Claim 28
Dependent Claim
14 words
The method of claim 19, wherein said carrier molecule is a non-protein carrier molecule.
Claim 29
Dependent Claim
14 words
The method of claim 26, wherein said carrier molecule is a polysaccharide carrier molecule.
Claim 30
Dependent Claim
15 words
The method of claim 26, wherein said carrier molecule is a synthetic polymer carrier molecule.
Claim 31
Dependent Claim
18 words
The method of claim 19, wherein said coagulation-deficient Tissue Factor compound is covalently linked to said carrier molecule.
Claim 32
Dependent Claim
22 words
The method of claim 29, wherein said coagulation-deficient Tissue Factor compound is covalently linked to said carrier molecule by a biochemical cross-linker.
Claim 33
Dependent Claim
56 words
The method of claim 29, wherein said coagulation-deficient Tissue Factor compound is covalently linked to said carrier molecule by preparing a fusion protein by expressing a recombinant vector in a host cell, wherein said vector comprises a DNA sequence encoding said coagulation-deficient Tissue Factor operatively linked, in frame, to a DNA sequence encoding said carrier molecule.
Claim 34
Dependent Claim
39 words
The method of claim 7, further comprising administering to said animal a biologically effective amount of at least a second therapeutic compound selected from the group consisting of Factor VIIa, an activator of Factor VII and an anti-cancer agent.
Claim 35
Dependent Claim
22 words
The method of claim 32, further comprising administering to said animal a biologically effective amount of at least a first anti-cancer agent.
Claim 36
Dependent Claim
17 words
The method of claim 33, wherein said at least a first anti-cancer agent is a chemotherapeutic agent.
Claim 37
Dependent Claim
52 words
The method of claim 33, wherein said at least a first anti-cancer agent is an antibody construct comprising an antibody or antigen binding region that specifically binds to a component of a tumor cell, tumor vasculature or tumor stroma, the antibody operatively linked to a cytotoxic agent or to a coagulation factor.
Claim 38
Dependent Claim
28 words
The method of claim 29, further comprising administering to said animal a biologically effective amount of at least one of Factor VIIa or an activator of Factor VII.
Claim 39
Dependent Claim
16 words
The method of claim 3, wherein said composition is administered to said animal via intravenous injection.
Claim 40
Dependent Claim
21 words
The method of claim 3, wherein said composition further comprises at least a second, distinct type of coagulation-deficient Tissue Factor compound.
Claim 41
Dependent Claim
18 words
The method of claim 3, wherein said animal has a vascularized tumor of at least about medium size.
Claim 42
Dependent Claim
13 words
The method of claim 39, wherein said animal has a large vascularized tumor.
Claim 43
Dependent Claim
12 words
The method of claim 3, wherein said animal is a human subject.
Claim 44
Independent Claim
41 words
A method for treating an animal having a vascularized tumor, comprising administering to said animal a composition that comprises an amount of at least a first coagulation-impaired Tissue Factor compound effective to specifically promote coagulation in the vasculature of said tumor.
Claim 45
Independent Claim
41 words
A method for treating an animal having a vascularized tumor, comprising administering to said animal a composition that comprises an amount of at least a first coagulation-impaired Tissue Factor compound effective to specifically promote coagulation in the vasculature of said tumor.
Claim 46
Independent Claim
54 words
A method for treating an animal having a vascularized tumor, comprising administering to said animal a composition that comprises an amount of at least a first coagulation-impaired Tissue Factor compound effective to achieve coagulation and tissue necrosis that are substantially confined to the vascularized tumor and do not substantially extend to normal, healthy tissues.
Claim 47
Independent Claim
54 words
A method for treating an animal having a vascularized tumor, comprising administering to said animal a composition that comprises an amount of at least a first coagulation-impaired Tissue Factor compound effective to achieve coagulation and tissue necrosis that are substantially confined to the vascularized tumor and do not substantially extend to normal, healthy tissues.
Claim 48
Independent Claim
74 words
A method for treating an animal having a vascularized tumor, comprising administering to said animal a composition that comprises an amount of at least a first Tissue Factor compound effective to promote coagulation in the tumor vasculature and to induce tumor necrosis; wherein said at least a first Tissue Factor compound is rendered coagulation-deficient by being deficient in binding to a phospholipid surface or deficient in inserting into a phospholipid membrane or lipid bilayer.
Claim 49
Independent Claim
74 words
A method for treating an animal having a vascularized tumor, comprising administering to said animal a composition that comprises an amount of at least a first Tissue Factor compound effective to promote coagulation in the tumor vasculature and to induce tumor necrosis; wherein said at least a first Tissue Factor compound is rendered coagulation-deficient by being deficient in binding to a phospholipid surface or deficient in inserting into a phospholipid membrane or lipid bilayer.
Claim 50
Independent Claim
69 words
A method for treating an animal having a vascularized tumor, comprising administering to said animal a composition that comprises an amount of at least a first Tissue Factor compound effective to promote coagulation in the tumor vasculature and to induce tumor necrosis; wherein said at least a first Tissue Factor compound is rendered coagulation-deficient by including a mutation that confers a deficiency in the ability to activate Factor VII.
Claim 51
Independent Claim
69 words
A method for treating an animal having a vascularized tumor, comprising administering to said animal a composition that comprises an amount of at least a first Tissue Factor compound effective to promote coagulation in the tumor vasculature and to induce tumor necrosis; wherein said at least a first Tissue Factor compound is rendered coagulation-deficient by including a mutation that confers a deficiency in the ability to activate Factor VII.
Claim 52
Independent Claim
87 words
A method for treating an animal having a vascularized tumor, comprising administering to said animal a composition that comprises an amount of at least a first coagulation-deficient Tissue Factor compound effective to promote coagulation in the tumor vasculature and to induce tumor necrosis; wherein said coagulation-deficient Tissue Factor compound substantially retains its ability to bind to Factor VII or Factor VIIa and is rendered coagulation-deficient by being deficient in binding to a phospholipid surface, deficient in inserting into a phospholipid membrane or deficient in activating Factor VII.
Claim 53
Independent Claim
87 words
A method for treating an animal having a vascularized tumor, comprising administering to said animal a composition that comprises an amount of at least a first coagulation-deficient Tissue Factor compound effective to promote coagulation in the tumor vasculature and to induce tumor necrosis; wherein said coagulation-deficient Tissue Factor compound substantially retains its ability to bind to Factor VII or Factor VIIa and is rendered coagulation-deficient by being deficient in binding to a phospholipid surface, deficient in inserting into a phospholipid membrane or deficient in activating Factor VII.
Claim 54
Independent Claim
90 words
A method for treating an animal having a vascularized tumor, comprising administering to said animal a composition that comprises an amount of at least a first coagulation-deficient Tissue Factor compound effective to promote coagulation in the tumor vasculature and to induce tumor necrosis; wherein said coagulation-deficient Tissue Factor compound is rendered coagulation-deficient by being deficient in binding to a phospholipid surface, deficient in inserting into a phospholipid membrane or deficient in activating Factor VII and yet retains the catalytic activity of activating Factor X in the presence of Factor VIIa.
Claim 55
Independent Claim
90 words
A method for treating an animal having a vascularized tumor, comprising administering to said animal a composition that comprises an amount of at least a first coagulation-deficient Tissue Factor compound effective to promote coagulation in the tumor vasculature and to induce tumor necrosis; wherein said coagulation-deficient Tissue Factor compound is rendered coagulation-deficient by being deficient in binding to a phospholipid surface, deficient in inserting into a phospholipid membrane or deficient in activating Factor VII and yet retains the catalytic activity of activating Factor X in the presence of Factor VIIa.
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USPTO Annuity & Maintenance Windows
| Annuity Stage | Window Opens | Payment Deadline | Surcharge Period Until | Estimated Fee | Status |
|---|---|---|---|---|---|
| 3.5 Years (Year 4) | 2003-12-05 | 2004-06-05 | 2004-12-05 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 2007-12-05 | 2008-06-05 | 2008-12-05 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 2011-12-05 | 2012-06-05 | 2012-12-05 | $7700.00 | Window Closed / Lapsed |