EP0896584A2 - PROTEINE BIOLOGIQUEMENT ACTIVE (FRAGMENT DE COLLAGENE HF-COLL-18/514cf) SERVANT A INHIBER LA CROISSANCE DE TUMEURS ET LES PROLIFERATIONS CAPILLAIRES - Google Patents

PROTEINE BIOLOGIQUEMENT ACTIVE (FRAGMENT DE COLLAGENE HF-COLL-18/514cf) SERVANT A INHIBER LA CROISSANCE DE TUMEURS ET LES PROLIFERATIONS CAPILLAIRES

Info

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
Authority
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.)
Withdrawn
Application number
EP97921682A
Other languages
German (de)
English (en)
Inventor
Wolf-Georg Prof.Dr.Med. Forssmann
Michael Schrader
Ludger STÄNDKER
Manfred Raida
Peter Schulz-Knappe
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Digilab Biovision GmbH
Original Assignee
Biovision AG
FORSSMANN Wolf-Georg Prof Dr med
Haemopep Pharma GmbH
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Biovision AG, FORSSMANN Wolf-Georg Prof Dr med, Haemopep Pharma GmbH filed Critical Biovision AG
Publication of EP0896584A2 publication Critical patent/EP0896584A2/fr
Withdrawn legal-status Critical Current

Links

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.

Landscapes

  • 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

L'invention concerne un peptide provenant du sang humain, le HF-COLL-18/514cf, dont la structure a été identifiée dans le but d'une application diagnostique, médicale ou commerciale en tant que médicament. L'isolation de ce nouveau type de peptide HF-COLL-18/514cf prouve l'existence du HF-COLL-18/514cf. La forme moléculaire du HF-COLL-18/514cf a été mise en évidence par spectrométrie de masse et séquençage aminoterminal. Le HF-COLL-18/514cf constitue un peptide naturel qui devrait pouvoir être utilisé pour le traitement de nombreuses maladies liées à des troubles de la croissance cellulaire, notamment de cellules endothéliales et de vaisseaux, ainsi que par exemple dans le cas du cancer. En outre, le HF-COLL-18/514cf peut être utilisé commercialement sous forme pure ou sous forme d'extrait brut naturel, dans la recherche de nouvelles fonctions cellulaires.
EP97921682A 1996-04-22 1997-04-22 PROTEINE BIOLOGIQUEMENT ACTIVE (FRAGMENT DE COLLAGENE HF-COLL-18/514cf) SERVANT A INHIBER LA CROISSANCE DE TUMEURS ET LES PROLIFERATIONS CAPILLAIRES Withdrawn EP0896584A2 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE19615710 1996-04-22
DE19615710A DE19615710A1 (de) 1996-04-22 1996-04-22 Verfahren zur Gewinnung und Anwendung eines biologisch aktiven Eiweisstoffes - Kollagenfragment HF-COLL-18/514cf - in partiell aufgereinigter und synthetischer Form aus Körperflüssigkeiten zur Beeinflussung des Zellwachstums und der Diagnose von Kollagenerkrankungen sowie der Osteoporose
PCT/EP1997/002012 WO1997040073A2 (fr) 1996-04-22 1997-04-22 PROTEINE BIOLOGIQUEMENT ACTIVE (FRAGMENT DE COLLAGENE HF-COLL-18/514cf) SERVANT A INHIBER LA CROISSANCE DE TUMEURS ET LES PROLIFERATIONS CAPILLAIRES

Publications (1)

Publication Number Publication Date
EP0896584A2 true EP0896584A2 (fr) 1999-02-17

Family

ID=7791888

Family Applications (1)

Application Number Title Priority Date Filing Date
EP97921682A Withdrawn EP0896584A2 (fr) 1996-04-22 1997-04-22 PROTEINE BIOLOGIQUEMENT ACTIVE (FRAGMENT DE COLLAGENE HF-COLL-18/514cf) SERVANT A INHIBER LA CROISSANCE DE TUMEURS ET LES PROLIFERATIONS CAPILLAIRES

Country Status (5)

Country Link
EP (1) EP0896584A2 (fr)
JP (1) JP2000511511A (fr)
AU (1) AU2766597A (fr)
DE (1) DE19615710A1 (fr)
WO (1) WO1997040073A2 (fr)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
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 (fr) * 1998-09-21 2000-03-30 Haemopep Pharma Gmbh Endostatine ncf pour l'inhibition de la croissance des tumeurs et de la proliferation capillaire et pour le diagnostic des maladies vasculaires et tumorales
ITMI20010394A1 (it) * 2001-02-27 2002-08-27 Univ Degli Studi Milano Peptidi ad attivita' antiangiogenica
GB0114419D0 (en) * 2001-06-13 2001-08-08 Mars Uk Ltd Health food
AU2003262277A1 (en) * 2002-12-03 2004-06-23 Koken Co., Ltd. Inhibitor of proliferation and/or infiltration of tumor cells

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3633797C2 (de) * 1986-10-03 1995-08-10 Forssmann Wolf Georg Verfahren zur Gewinnung von biologisch aktiven Eiweissen (Peptiden) aus menschlichem und tierischem Blut (bzw. anderen Körperflüssigkeiten)
WO1993016716A1 (fr) * 1992-02-24 1993-09-02 Northwestern University Procede et composition d'inhibition de l'angiogenese
ES2206602T3 (es) * 1995-10-23 2004-05-16 The Children's Medical Center Corporation Compuestos y metodos terapeuticos inhibidores de angiogenesis.

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9740073A2 *

Also Published As

Publication number Publication date
AU2766597A (en) 1997-11-12
WO1997040073A2 (fr) 1997-10-30
WO1997040073A3 (fr) 1997-12-24
DE19615710A1 (de) 1997-10-23
JP2000511511A (ja) 2000-09-05

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