CA2235393A1 - Therapeutic antiangiogenic endostatin compositions and methods of use - Google Patents
Therapeutic antiangiogenic endostatin compositions and methods of useInfo
- Publication number
- CA2235393A1 CA2235393A1 CA 2235393 CA2235393A CA2235393A1 CA 2235393 A1 CA2235393 A1 CA 2235393A1 CA 2235393 CA2235393 CA 2235393 CA 2235393 A CA2235393 A CA 2235393A CA 2235393 A1 CA2235393 A1 CA 2235393A1
- Authority
- CA
- Canada
- Prior art keywords
- protein
- endostatin
- angiogenesis
- recombinantly produced
- kda
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 238000000034 method Methods 0.000 title claims abstract 19
- 108010079505 Endostatins Proteins 0.000 title claims 29
- 239000000203 mixture Substances 0.000 title claims 5
- 102100031162 Collagen alpha-1(XVIII) chain Human genes 0.000 title 1
- 230000001772 anti-angiogenic effect Effects 0.000 title 1
- 230000001225 therapeutic effect Effects 0.000 title 1
- 230000033115 angiogenesis Effects 0.000 claims abstract 18
- 206010028980 Neoplasm Diseases 0.000 claims abstract 14
- 210000002889 endothelial cell Anatomy 0.000 claims abstract 6
- 201000010099 disease Diseases 0.000 claims abstract 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract 5
- 108010001463 Collagen Type XVIII Proteins 0.000 claims abstract 4
- 102000047200 Collagen Type XVIII Human genes 0.000 claims abstract 4
- 230000002401 inhibitory effect Effects 0.000 claims abstract 3
- 230000004663 cell proliferation Effects 0.000 claims abstract 2
- 102000004169 proteins and genes Human genes 0.000 claims 32
- 108090000623 proteins and genes Proteins 0.000 claims 32
- 102400001047 Endostatin Human genes 0.000 claims 20
- 150000001875 compounds Chemical class 0.000 claims 9
- 230000001419 dependent effect Effects 0.000 claims 9
- 238000001502 gel electrophoresis Methods 0.000 claims 9
- 102400000068 Angiostatin Human genes 0.000 claims 5
- 108010079709 Angiostatins Proteins 0.000 claims 5
- FZCSTZYAHCUGEM-UHFFFAOYSA-N aspergillomarasmine B Natural products OC(=O)CNC(C(O)=O)CNC(C(O)=O)CC(O)=O FZCSTZYAHCUGEM-UHFFFAOYSA-N 0.000 claims 5
- 208000002125 Hemangioendothelioma Diseases 0.000 claims 4
- 241001529936 Murinae Species 0.000 claims 4
- 201000011510 cancer Diseases 0.000 claims 4
- 230000002062 proliferating effect Effects 0.000 claims 4
- 238000013268 sustained release Methods 0.000 claims 4
- 239000012730 sustained-release form Substances 0.000 claims 4
- 101800001415 Bri23 peptide Proteins 0.000 claims 3
- 102400000107 C-terminal peptide Human genes 0.000 claims 3
- 101800000655 C-terminal peptide Proteins 0.000 claims 3
- 125000001429 N-terminal alpha-amino-acid group Chemical group 0.000 claims 3
- 239000012634 fragment Substances 0.000 claims 3
- 210000004027 cell Anatomy 0.000 claims 2
- 238000003259 recombinant expression Methods 0.000 claims 2
- 206010000050 Abdominal adhesions Diseases 0.000 claims 1
- 208000003120 Angiofibroma Diseases 0.000 claims 1
- 201000001320 Atherosclerosis Diseases 0.000 claims 1
- 208000003732 Cat-scratch disease Diseases 0.000 claims 1
- 208000032544 Cicatrix Diseases 0.000 claims 1
- 241000588724 Escherichia coli Species 0.000 claims 1
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 claims 1
- 241000238631 Hexapoda Species 0.000 claims 1
- 206010029113 Neovascularisation Diseases 0.000 claims 1
- 108091028043 Nucleic acid sequence Proteins 0.000 claims 1
- 201000004681 Psoriasis Diseases 0.000 claims 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 claims 1
- 206010039710 Scleroderma Diseases 0.000 claims 1
- 206010043189 Telangiectasia Diseases 0.000 claims 1
- 208000025865 Ulcer Diseases 0.000 claims 1
- 208000027418 Wounds and injury Diseases 0.000 claims 1
- 230000001580 bacterial effect Effects 0.000 claims 1
- 238000004440 column chromatography Methods 0.000 claims 1
- 210000004748 cultured cell Anatomy 0.000 claims 1
- 230000032692 embryo implantation Effects 0.000 claims 1
- 238000005469 granulation Methods 0.000 claims 1
- 230000003179 granulation Effects 0.000 claims 1
- 239000001963 growth medium Substances 0.000 claims 1
- 229960002897 heparin Drugs 0.000 claims 1
- 229920000669 heparin Polymers 0.000 claims 1
- 230000001969 hypertrophic effect Effects 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 230000002107 myocardial effect Effects 0.000 claims 1
- 150000007523 nucleic acids Chemical group 0.000 claims 1
- 206010039073 rheumatoid arthritis Diseases 0.000 claims 1
- 231100000241 scar Toxicity 0.000 claims 1
- 230000037387 scars Effects 0.000 claims 1
- 208000011580 syndromic disease Diseases 0.000 claims 1
- 208000009056 telangiectasis Diseases 0.000 claims 1
- 231100000397 ulcer Toxicity 0.000 claims 1
- 241000701447 unidentified baculovirus Species 0.000 claims 1
- 230000003612 virological effect Effects 0.000 claims 1
- 210000004900 c-terminal fragment Anatomy 0.000 abstract 1
- 239000003112 inhibitor Substances 0.000 abstract 1
Landscapes
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Peptides Or Proteins (AREA)
Abstract
An inhibitor of endothelial cell proliferation, capable of inhibiting angiogenesis and causing tumor regression, that is approximately 20 kDa and corresponds to a C-terminal fragment of collagen type XVIII, and methods of treating angiogenesis-related disease.
Claims (33)
1. Isolated endostatin.
2. The isolated endostatin of Claim 1 comprising, an isolated protein that is approximately 18 kDa as determined by non-reduced gel electrophoresis, and approximately 20 kDa as determined by reduced gel electrophoresis, wherein the protein can be isolated from the murine hemangioendothelioma EOMA cell line, and wherein the protein is further characterized by its ability to specifically inhibit proliferating cultured endothelial cells.
3. The endostatin of Claim 1, wherein the N-terminal amino acid sequence of the protein has substantial sequence homology to Seq ID No: 1.
4. The endostatin of Claim 1, wherein the protein has substantial seuqence homology to a C-terminal peptide fragment of collagen type XVIII.
5. The endostatin of Claim 1 made by a process comprising recombinantly producing the protein of Claim 1 in a recombinant expression system, and isolating the recombinantly produced protein in its un-refolded form.
6. The endostatin of Claim 5, wherein the recombinant expression system is E. coli or baculovirus.
7. A compound comprising, an isolated nucleic acid sequence coding for endostatin protein.
8. The compound of Claim 7, wherein the endostatin protein is approximately 18 kDa as determined by non-reduced gel electrophoresis, and approximately 20 kDa as determined by reduced gel electrophoresis, wherein the protein can be isolated from the murine hemangioendothelioma EOMA, and wherein the protein is further characterized by its ability to specifically inhibit proliferating cultured endothelial cells.
9. The compound of Claim 7, wherein the N-terminal amino acid sequence of the protein has substantial sequence homology to Seq ID No: 1.
10. The compound of Claim 7, wherein the protein has substantial seuqence homology to a C-terminal peptide fragment of collagen type XVIII.
11. A compound comprising, an isolated antibody capable of specifically binding to endostatin protein.
12. The compound of Claim 11, wherein the endostatin protein is approximately 18 kDa as determined by non-reduced gel electrophoresis, and approximately 20 kDa as determined by reduced gel electrophoresis, wherein the protein can be isolated from the murine hemangioendothelioma EOMA, and wherein the protein is further characterized by its ability to specifically inhibit proliferating cultured endothelial cells.
13. The compound of Claim 11, wherein the antibody is a monoclonal antibody.
14. The compound of Claim 11, wherein the N-terminal amino acid sequence of the endostatin protein has substantial sequence homology to Seq ID No: 1.
15. The compound of Claim 11, wherein the endostatin protein has substantial sequence homology to a C-terminal peptide fragment of collagen type XVIII.
16. An isolated emdostatin made by a process comprising, a. collecting culture media used to grow murine hemangioendothelioma cell line EOMA; and b. fractionating the media by heparin column chromatography, wherein the isolated endostatin is a protein that is approximately 18 kDa as determined by non-reduced gel electrophoresis, and approximately 20 kDa as determined by reduced gel electrophores, and the protein is capable of specifically inhibiting endothelial cell proliferation in cultured cells.
17. A method of treating an angiogenesis-related disease comprising, Administering to a patient in need of such treatment of the endostatin of Claim 1 in an amount sufficient to inhibit angiogenesis.
18. The method of Claim 17, wherein the endostatin is a recombinantly produced protein, and wherein the recombinantly produced protein is administered in its un-refolded form.
19. The method of Claim 18, wherein the recombinantly produced endostatin provides a sustained release of the protein over a period of at least 8 hours.
20. The method of Claim 17, wherein the angiogenesis-related disease is selected from the group consisting of angiogenesis-dependent cancers; benign tumors; rheumatoid arthritis; psoriasis; ocular angiogenesis diseases; Osler-Webber Syndrome; myocardial angiogenesis; plaque neovascularization; telangiectasia; hemophiliac joints; angiofibroma; wound granulation; intestinal adhesions, atherosclerosis, scleroderma, hypertrophic scars, cat scratch disease and Helobacter pylori ulcers.
21. The method of Claim 20, wherein the angiogenesis-related disease is angiogenesis-dependent cancer.
22. A method of treating a patient with an angiogenesis-dependent cancer tumor comprising, administering to a patient in need of such treatment of the endostatin of Claim 1 in an amount sufficient to cause tumor regression.
23. The method of Claim 22, wherein the endostatin is a recombinantly produced protein, and wherein the recombinantly produced protein is administered in its un-refolded form.
24. The method of Claim 23, wherein the recombinantly produced protein provides a sustained release of the protein for a period of at least 8 hours.
25. A method of curing a patient with an angiogenesis-dependent cancer comprising, administering to a patient in need of such a cure an angiogenesis-dependent cancer curing amount of a composition comprising, angiostatin combined with the endostatin of Claim 1, wherein the angiostatin and the endostatin are provided in amounts such that the composition is capable of effectively inhibiting angiogenesis of angiogenesis-dependent cancers when administered to patients with angiogenesis-dependent cancers.
26. The method of Claim 25, wherein at least one of angiostatin and endostatin is a recombinantly produced protein, and wherein the recombinantly produced protein is administered in its unrefolded form.
27. The method of Claim 25, wherein the recombinantly produced protein provides a sustained release of the protein for a period of at least 8 hours.
28. A method of birth control comprising, administering to a female an amount of the endostatin of Claim 1 sufficient to prevent embryo implantation.
29. The method of Claim 28, wherein the endostatin is recombinantly produced protein, and wherein the recombinantly produced protein is administered in its un-refolded form.
30. The method of Claim 29, wherein the recombinantly produced protein provides a sustained release of the protein for a period of at least 8 hours.
31. A composition comprising, angiostatin combined with the endostatin of Claim 1, wherein the angiostatin and the endostatin are provided in amounts such that the composition is capable of effectively regressing the tumor mass of angiogenesis-dependent tumors when administered to patients with an angiogenesis-dependent tumor.
32. A method of making endostatin protein comprising, recombinantly expressing a protein that is approximately 18 kDa as determined by non-reduced gel electrophoresis, and approximately 20 kDa as determined by reduced gel electrophoresis, and which has substantial sequence homology to endostatin, the protein being further characterized by its ability to specifically inhibit proliferating cultured endothelial cells.
33. The method of Claim 32, wherein the endostatin protein is produced in an expression system selected from the group consisting of bacterial expression systems, yeast expression systems and insect viral expression systems.
Applications Claiming Priority (9)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US583595P | 1995-10-23 | 1995-10-23 | |
| US60/005,835 | 1995-10-23 | ||
| US2307096P | 1996-08-02 | 1996-08-02 | |
| US60/023,070 | 1996-08-02 | ||
| US2626396P | 1996-09-17 | 1996-09-17 | |
| US60/026,263 | 1996-09-17 | ||
| US08/740,168 | 1996-10-22 | ||
| US08/740,168 US5854205A (en) | 1995-10-23 | 1996-10-22 | Therapeutic antiangiogenic compositions and methods |
| PCT/US1996/016925 WO1997015666A1 (en) | 1995-10-23 | 1996-10-23 | Therapeutic antiangiogenic compositions and methods |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2235393A1 true CA2235393A1 (en) | 1997-05-01 |
| CA2235393C CA2235393C (en) | 2010-04-06 |
Family
ID=29408123
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA 2235393 Expired - Lifetime CA2235393C (en) | 1995-10-23 | 1996-10-23 | Therapeutic antiangiogenic endostatin compositions and methods of use |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA2235393C (en) |
-
1996
- 1996-10-23 CA CA 2235393 patent/CA2235393C/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| CA2235393C (en) | 2010-04-06 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| MKEX | Expiry |
Effective date: 20161024 |