EP0896584A2 - BIOLOGICALLY ACTIVE PROTEIN (COLLAGEN FRAGMENT HF-COLL-18/514cf) FOR INHIBITING THE GROWTH OF TUMOURS AND CAPILLARY PROFILERATIONS - Google Patents
BIOLOGICALLY ACTIVE PROTEIN (COLLAGEN FRAGMENT HF-COLL-18/514cf) FOR INHIBITING THE GROWTH OF TUMOURS AND CAPILLARY PROFILERATIONSInfo
- Publication number
- EP0896584A2 EP0896584A2 EP97921682A EP97921682A EP0896584A2 EP 0896584 A2 EP0896584 A2 EP 0896584A2 EP 97921682 A EP97921682 A EP 97921682A EP 97921682 A EP97921682 A EP 97921682A EP 0896584 A2 EP0896584 A2 EP 0896584A2
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- EP
- European Patent Office
- Prior art keywords
- ser
- ala
- leu
- coll
- arg
- 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.)
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- 108010028295 histidylhistidine Proteins 0.000 description 1
- 108010085325 histidylproline Proteins 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 230000008105 immune reaction Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000036512 infertility Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000003978 infusion fluid Substances 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 108010044311 leucyl-glycyl-glycine Proteins 0.000 description 1
- 238000011866 long-term treatment Methods 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 238000000816 matrix-assisted laser desorption--ionisation Methods 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 108010051242 phenylalanylserine Proteins 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108010031719 prolyl-serine Proteins 0.000 description 1
- 108010090894 prolylleucine Proteins 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 230000017854 proteolysis Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 108010061238 threonyl-glycine Proteins 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 108010084932 tryptophyl-proline Proteins 0.000 description 1
- 238000000108 ultra-filtration Methods 0.000 description 1
- 210000002229 urogenital system Anatomy 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/78—Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin or cold insoluble globulin [CIG]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Definitions
- the present invention relates to a peptide (protein) with the ability to influence the growth of cells.
- the collagen fragment HF-C0LL-18 / 514cf, as well as fragments and / or derivatives derived from it, and a medicinal product containing the natural and synthetic peptides can be used for diagnostic or therapeutic purposes.
- the invention relates to a method for obtaining a protein in pure or partially purified form from human body fluids, which has the ability to influence the growth of cells in a surprising manner and thus to inhibit vascular and tumor growth.
- a similar substance has recently been detected in the mouse (O'Reilly et al., 1997, Cell Vol.88, page 277).
- This substance is characterized in that it can be obtained in particular from hemofiltrate or hemodialysate, which is filtered off from human blood.
- the substance is referred to as HF-COLL-18 / 514cf and can be used for the purpose of (1) the analysis of diseases, (2) for medical and commercial use as a drug.
- the substance HF-COLL-18 / 514cf was first obtained from the hemofiltrate of kidney patients after ultrafiltration on the hemodialysis machine and was classified according to its molecular mass and 60 amino acids. the N-terminus.
- a patented process (Forssmann, 1988; published application DE 36 33 707 AI) was refined, which was previously invented for the extraction of proteins from hemofiltrate.
- the fractions containing the HF-COLL-18 / 514cf can surprisingly be recognized by mass spectrometry from the molecules of a molecular weight below 20 kilodaltons obtained by this method, which are filtered off in the case of veno-venous or arterio-venous shunt connections.
- this substance could surprisingly be purified in such a way until a uniform protein substance was finally identified and its structure was clarified.
- the substance is a fragment of a protein, the protein being hitherto known only at the cDNA level (Oh et al., 1994, Genomics Vol. 19, page 494).
- the value of this invention is characterized by the fact that this substance can be purified from the hemofiltrate previously considered worthless in order to be used as an economically usable substance.
- the substance HF-COLL-18 / 514cf mentioned can be obtained by chemical synthesis and by genetic engineering production and can be used for numerous other purposes, including analysis in human blood as a pathognomonic diagnostic feature of diseases of vascular growth and growth of tumors and metastases.
- the present invention thus relates to a new peptide, the HF-COLL-18 / 514cf, its production, medicaments containing it, and preparations containing it and its use therefor, and also its natural and pharmacologically contractual 1 -
- a mean molecular weight of 18494 u daltons could be determined by mass spectrometry.
- the blood peptide HF-COLL-18 / 514cf has the amino acid sequence: Val -Ala -Leu -Asn -Ser -Pro-Leu- Ser-Gly-Gly-Met-Arg-Gly-Ile -Arg -Gly- Ala-Asp-Phe -Gln-Cys-Phe-Gln-Gln-Ala-Arg-Ala -Val -Gly-Leu-Ala-Gly- Thr- Phe- Arg- Ala- Phe - Leu - Ser -Ser- Ar Q- Leu-Gin - Asr> -Leu-Tyr- Ser -Ile - Val -Arg -Arg -Ala -Asp- Arg- Ala- Ala - Val - Pro- II e- Val -Asn-Leu-L ⁇ s -Asp- Glu-Leu-Leu- Phe-Pro-Ser-
- HF-COLL-18 / 514cf The peptide provided by the present invention, HF-COLL-18 / 514cf, is now an easily accessible drug with biological and therapeutic activity of a natural analogue of the substance found in the blood.
- the present invention provides a production method for this HF-COLL-18 / 514cf and the use of the HF-COLL-18 / 514cf as a medicament for various therapeutic and diagnostic indications.
- the HF-COLL-18 / 514cf can be used as a highly pure substance or - if sufficient for the particular use - within a partially purified peptide mixture.
- the peptide according to the invention, its derivatives and fragments can be produced by various methods, for example by prokaryotic or eukaryotic expression and, if appropriate, chromatographic purification. Furthermore, it can be isolated from human blood, for example by means of chromatographic methods known per se Finally, are HF-COLL-18 / 514cf or its derivatives or fragments can be prepared by conventional solid-phase and liquid-phase synthesis methods from the protected amino acids contained in the sequence given. After the protective groups have been removed, it can be purified using standard chromatography procedures.
- the pharmaceutical preparation according to the invention contains HF-COLL-18 / 514cf or a physiologically tolerable salt of HF-COLL-18 / 514cf.
- the form and composition of the medicinal product containing the HF-COLL-18 / 514cf depends on the mode of administration.
- the human HF-COLL-18 / 514cf can be administered parenterally, intranasally, orally, intravenously, intramuscularly, intracutaneously, intra-thecally, locally-topically and transpulmonally.
- HF-COLL-18 / '514cf is preferably made up into an injection preparation, either as a solution or as a lyophilisate for dissolution immediately before use.
- the pharmaceutical preparation can also contain auxiliaries that are due to filling technology, contribute to the solubility, stability or sterility of the drug or increase the efficiency of absorption into the body.
- auxiliaries that are due to filling technology, contribute to the solubility, stability or sterility of the drug or increase the efficiency of absorption into the body.
- the use of the lyophilized form taken with mannitol in sterile ampoules for dissolution in physiological saline and / or infusion solutions for repeated single injection and / or continuous infusion in amounts of 30 micrograms to 30 milligrams of pure HF-COLL-18 / 514cf pro Therapy unit is beneficial.
- the daily dose to be administered for HF-COLL-18 / 514cf depends on the indication and use of certain derivatives. At i.v./i.m. Injection is in the range from 100 to 1200 units ( ⁇ g) / day, with daily subcutaneous injection preferably at 300 to 2400 units ( ⁇ g) / day.
- the peptide HF-COLL-18 / 514cf according to the invention is characterized in that it is also particularly suitable for long-term JPherapy for tumor diseases or other diseases which are characterized by uncontrolled vascular growth, and does not trigger an immune reaction in the case of long-term treatment. That invented
- the preparation according to the invention is particularly suitable for combination therapy with chemotherapy or radiation therapy or in connection with chemotherapy or radiation therapy for cancer.
- the preparation according to the invention can also be used as a means of therapy and diagnosis for vascular diseases of the supporting and connective tissue, the respiratory tract, the cardiovascular system and urogenital system, the nervous system and the eye, since it can be used for the production of human-compatible antibodies are suitable for determining or influencing changes in the vascular growth in these organs.
- Such antibodies can in principle be obtained by immunizing animals with the peptide according to the invention and / or its fragments or by using hybridoma technology.
- the present invention also relates to a method for treating patients who need HF-COLL-18 / 514cf or its derivatives or fragments by administering therapeutic amounts of HF-COLL-18 / 514cf.
- Patients who suffer from excessive production of HF-COLL-18 / 514cf or its derivatives or fragments require the administration of therapeutic amounts of an antagonist / inhibitor of HF-COLL-18 / 514cf.
- the medicament according to the invention is suitable for the treatment of diseases of the human organism, in particular in connection with vascular growths, cancer diseases, diseases involving the cardiovascular and nervous systems, diseases involving the intugement and the sensory organs, in particular the eye.
- the medicament according to the invention is suitable for the treatment of acute diseases of the type mentioned above, in that it is used in a corresponding form for the treatment in the intensive care of these diseases.
- a further use of the peptide according to the invention, its fragments or the antibody according to the invention is used to diagnose diseases by producing specific antibodies against synthetic parts or the entire peptide or its derivatives and its fragments and e.g. the blood concentration of the HF-COLL-18 / 514cf is measured by immunoassays.
- a diagnostic agent containing the peptide according to the invention, its fragments or antibodies according to the invention for test systems for checking tissue, plasma, urine and cerebrospinal fluid levels of this substance are thus also the subject of the invention.
- the diagnostic agent according to the invention is particularly suitable as a marker for certain cancers and for functional disorders of blood vessels, bone marrow, lymph organs, the gastrointestinal tract, the immune system and inflammatory and neoplastic processes.
- Example 1 Isolation and characterization of circulating HF-COLL-18 / 514cf from human hemofiltrate
- Hemofiltrate which is obtained in large quantities in the treatment of kidney insufficient patients and all plasma components up to a molecular size of about 20, was used as the starting material. Contains 000 daltons.
- the hemofiltrate was obtained by means of a Sartorius hemofiltration system using cellulose triacetate filters with an exclusion size of 20,000 daltons (type SM 40042, Sartoriu ⁇ , Göttingen, FRG).
- the filtrate came from kidney insufficiency patients who were in a stable metabolic state due to long-term hemofiltration and was protected against proteolytic degradation by acidification and cooling to 4 ° C immediately after it was obtained.
- TSK SP 650 (M) Merck, Darmstadt, DE
- 2860 l of hemofiltrate were processed. 93% of the pooled extracts were successively eluted on the column material mentioned above using different buffers with different pH values. The crude fractions were then freeze-dried.
- Eluent A water with 10MM HC1
- Eluent B methanol with 10 mM HC1 gradient: 0 - 50% eluent B 28.57 min 50 - 95% eluent B 61.43 min 95% eluent B 5.71 min flow rate: 35 ml / min fractions: 50 ml or 1 , 43 min detection: 230 nm and 280 nm
- a mass spectrum was additionally measured from fraction 25 of step V using an electrospray mass spectrometer (Sciex API III, Perkin-Elmer, Langen, DE). Peaks of the eight to eleven times protonated molecule are shown.
- the average molecular mass of HF-COLL-18 / 514cf is determined here at 18494 u + 3 u, the theoretical value is 18496 u (see VIII).
- the first 60 amino acids were determined by means of automated Edman sequencing with an ABI 494 gas-phase amino acid sequencer (Applied Biosystems, Perkin-Elmer, Rothstadt, DE). No amino acid was detected at the 21st position (Xxx), as is customary for cysteine.
- Example 2 Using the method shown in Example 1, a larger amount of material of more than 0.1 mg HF-COLL-18 / 514cf was isolated from human hemofiltrate. The high-purity HF-COLL-18 / 514cf was used to determine the biological function in endothelial cell proliferation assays. For this assay, bovine capillary endothelial cells from the adrenal cortex of freshly slaughtered calves were cultured as described in the literature (Folkman et al., 1979, Proc. Natl. Acad. Sci. Vol. 76, page 5217).
- the proliferation assay was carried out as described in the literature (O'Reilly et al., 1997, Cell Vol.88, page 277).
- the bovine capillary endothelial cells were washed with PBS (phosphate buffer with sodium chloride, pH 7.4) and suspended in a 0.05% trypsin solution.
- the medium was replaced by 0.5 ml DMEM medium containing 5% FCS and 1% GPS as well as different concentrations (from 0 to 1000 ng / ml final concentration) of the isolated, high-purity HF-COLL-18 / 514cf , replaced.
- bFGF basic fibroblast growth factor
- HF-COLL-18 / 514cf added to the bovine capillary endothelial cells inhibited the proliferation of these cells stimulated with bFGF in a concentration-dependent manner.
- Half-maximal inhibition of proliferation in this assay was achieved at a concentration of 200 ng / ml HF-COLL-18 / 514cf.
- HF-COLL-18 / 514cf In order to investigate the specificity of the spectrum of activity of HF-COLL-18 / 514cf and thus other possible biological functions, proliferation assays were carried out with non-endothelial cells. In tests with fibroblast cell lines, namely NIH 3T3 cells and LMTK cells, HF-COLL-18 / 514cf showed no significant activity and therefore no antiproliferative activity.
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biophysics (AREA)
- Immunology (AREA)
- Toxicology (AREA)
- Zoology (AREA)
- Gastroenterology & Hepatology (AREA)
- Biochemistry (AREA)
- Engineering & Computer Science (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
Abstract
Description
Claims
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE19615710 | 1996-04-22 | ||
DE19615710A DE19615710A1 (en) | 1996-04-22 | 1996-04-22 | Process for obtaining and using a biologically active protein - collagen fragment HF-COLL-18 / 514cf - in partially purified and synthetic form from body fluids to influence cell growth and the diagnosis of collagen diseases and osteoporosis |
PCT/EP1997/002012 WO1997040073A2 (en) | 1996-04-22 | 1997-04-22 | BIOLOGICALLY ACTIVE PROTEIN (COLLAGEN FRAGMENT HF-COLL-18/514cf) FOR INHIBITING THE GROWTH OF TUMOURS AND CAPILLARY PROFILERATIONS |
Publications (1)
Publication Number | Publication Date |
---|---|
EP0896584A2 true EP0896584A2 (en) | 1999-02-17 |
Family
ID=7791888
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP97921682A Withdrawn EP0896584A2 (en) | 1996-04-22 | 1997-04-22 | BIOLOGICALLY ACTIVE PROTEIN (COLLAGEN FRAGMENT HF-COLL-18/514cf) FOR INHIBITING THE GROWTH OF TUMOURS AND CAPILLARY PROFILERATIONS |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP0896584A2 (en) |
JP (1) | JP2000511511A (en) |
AU (1) | AU2766597A (en) |
DE (1) | DE19615710A1 (en) |
WO (1) | WO1997040073A2 (en) |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU3199999A (en) * | 1998-03-24 | 1999-10-18 | Children's Medical Center Corporation | Endostatin derived peptides with anti-angiogenic and anti-cancer activity |
WO2000017240A1 (en) * | 1998-09-21 | 2000-03-30 | Haemopep Pharma Gmbh | Hmw endostatin for inhibiting the growth of tumours and capillary proliferation and for diagnosing vascular and tumour diseases |
ITMI20010394A1 (en) * | 2001-02-27 | 2002-08-27 | Univ Degli Studi Milano | PEPTIDES WITH ANTIANGIOGENIC ACTIVITY |
GB0114419D0 (en) * | 2001-06-13 | 2001-08-08 | Mars Uk Ltd | Health food |
JPWO2004050125A1 (en) * | 2002-12-03 | 2006-03-30 | 株式会社高研 | Inhibitor of tumor cell growth and / or invasion |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE3633797C2 (en) * | 1986-10-03 | 1995-08-10 | Forssmann Wolf Georg | Process for obtaining biologically active proteins (peptides) from human and animal blood (or other body fluids) |
WO1993016716A1 (en) * | 1992-02-24 | 1993-09-02 | Northwestern University | Method and composition for inhibiting angiogenesis |
KR19990066981A (en) * | 1995-10-23 | 1999-08-16 | 윌리엄 뉴우 | Therapeutic angiogenesis composition and method |
-
1996
- 1996-04-22 DE DE19615710A patent/DE19615710A1/en not_active Withdrawn
-
1997
- 1997-04-22 JP JP09537737A patent/JP2000511511A/en not_active Ceased
- 1997-04-22 EP EP97921682A patent/EP0896584A2/en not_active Withdrawn
- 1997-04-22 AU AU27665/97A patent/AU2766597A/en not_active Abandoned
- 1997-04-22 WO PCT/EP1997/002012 patent/WO1997040073A2/en not_active Application Discontinuation
Non-Patent Citations (1)
Title |
---|
See references of WO9740073A2 * |
Also Published As
Publication number | Publication date |
---|---|
AU2766597A (en) | 1997-11-12 |
JP2000511511A (en) | 2000-09-05 |
WO1997040073A3 (en) | 1997-12-24 |
WO1997040073A2 (en) | 1997-10-30 |
DE19615710A1 (en) | 1997-10-23 |
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