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WO1999032620A9 - Fragments de proteine liant le facteur de croissance de substances apparentees a l'insuline et leur utilisation - Google Patents

Fragments de proteine liant le facteur de croissance de substances apparentees a l'insuline et leur utilisation

Info

Publication number
WO1999032620A9
WO1999032620A9 PCT/EP1998/008405 EP9808405W WO9932620A9 WO 1999032620 A9 WO1999032620 A9 WO 1999032620A9 EP 9808405 W EP9808405 W EP 9808405W WO 9932620 A9 WO9932620 A9 WO 9932620A9
Authority
WO
WIPO (PCT)
Prior art keywords
peptides
acid sequence
amino acid
peptide
igfbp
Prior art date
Application number
PCT/EP1998/008405
Other languages
German (de)
English (en)
Other versions
WO1999032620A1 (fr
Inventor
Wolf-Georg Forssmann
Ludger Staendker
Maik Obendorf
Lothar Kling
Hans-Georg Opitz
Hossein Mostafavi
Original Assignee
Forssmann Wolf Georg
Ludger Staendker
Maik Obendorf
Lothar Kling
Opitz Hans Georg
Hossein Mostafavi
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 Forssmann Wolf Georg, Ludger Staendker, Maik Obendorf, Lothar Kling, Opitz Hans Georg, Hossein Mostafavi filed Critical Forssmann Wolf Georg
Priority to EP98965865A priority Critical patent/EP1042476A1/fr
Priority to JP2000525539A priority patent/JP2002508931A/ja
Priority to CA002315974A priority patent/CA2315974A1/fr
Publication of WO1999032620A1 publication Critical patent/WO1999032620A1/fr
Publication of WO1999032620A9 publication Critical patent/WO1999032620A9/fr

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
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
    • C07K14/4743—Insulin-like growth factor binding protein
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • Insulin-like growth factor binding protein fragments and their use
  • the present invention relates to peptides with cell proliferative and cell protective properties, complexes of the peptides with human insulin-like growth factor 1 and II (IGF) and the associated nucleic acids, antisense nucleotides, antibodies and inhibitors.
  • IGF insulin-like growth factor 1 and II
  • Insulin-like growth factor binding proteins are described, inter alia, by Shimasaki, S. and Ling, N. in Prog. Growth Factor Res. 3 (1991) 243-266 and Zapf, J. in Eur. J. Endocrinol. 132 (1995) 645-654.
  • the present invention relates to peptides whose amino acid sequence corresponds in part to the amino acid sequence of insulin-like growth factor binding proteins and to cyclic, glycosylated, phosphorylated, acetylated, amidated and / or sulfated derivatives thereof. These peptides according to the invention are referred to as IGFBP or IBP.
  • Preferred peptides are those that occur naturally and can be isolated, for example, from hemofiltrate.
  • the peptides preferably have a length of 61 to 115 amino acids.
  • Peptides which have sequences which correspond to N- or C-terminal sequences of insulin-like growth factor binding proteins are particularly preferred.
  • Preferred peptides are peptides with the amino acid sequence of the formula
  • R NH 2 , an amino acid or a peptide with an amino acid sequence comprising up to 41 amino acids
  • X a peptide with an amino acid sequence comprising 24 to 31 amino acids
  • X 2 is a peptide with an amino acid sequence comprising 9 amino acids
  • X 3 is a peptide with an amino acid sequence comprising 10 amino acids
  • X 4 is a peptide with an amino acid sequence comprising 18 to 24 amino acids
  • the peptide has cell proliferative and cell protective properties.
  • the peptides according to the invention can have disulfide bridges, so that they have the general formula
  • the peptides have a glycine at one or more of the following positions in the amino acid sequence.
  • X at position 8 is L or V and / or X at position 11 is L or I and / or X 2 at position 1 is D or N and / or X 2 at the position 9 is K or R and / or X 3 at position 3 is S or A and / or at position 8 is R or A.
  • Rj is selected from
  • APSEEDHSILWDAISTYDGSKALHVTNIKKWKEP SEQ ID NO: 1
  • GGKHHLGLEEPKKLRPPPARTP SEQ ID NO: 2
  • GKGGKHHLGLEEPKKLRPPPARTP SEQ ID NO: 3
  • GHAKDSQRYKVDYESQSTDTQNFSSESK ETEYGP SEQ ID NO: 4
  • KVNGAPREDARPVPQGS SEQ ID NO: 5
  • TQSKFVGGAENTAHPRIISAPE RQESEQGP SEQ ID NO: 6
  • PQAGTARPQDVNRRDQQRNPGTSTTPSQPNSAGVQDTEMGP SEQ ID NO: 7
  • NKNGFYHSR SEQ ID NO 14
  • DHRGFYRKR (SEQ ID NO 19) and / or
  • RSSQGQRRGP (SEQ ID NO 25) and / or
  • YP NGKRIPGSPEIRGDPN (SEQ ID NO: 26), NPNTGKLIQGAPTIRGDPE (SEQ ID NO: 27), DKYGQPLPGYTTKGKEDVH (SEQ ID NO: 28), DRKTGVKLPGGLEPKGELD (SEQ ID NO: 29), DKGGGDQSGGDQSGGSGGDQSGGDQGDQGDQGDQGDQGDQGGDQGDQGDQGDQGDQGDQGDQGDQGDQGDQGDQGDQGDQGDQGDQGDQGDQGDQGDQGDQGDQGDQGDQGDQGDQGDQGDQGDQGDQGDQGDQGDQGDQGDQGDQGDQGDQGDQGDQGDQDQDQDQDQDQDQDQDQDQDQDQDQKDQKDQKDKNKDKDKNK ID NO: 31) and / or
  • R 2 selected from
  • Preferred peptides have the following sequences IGFBP-1
  • the peptides according to the invention can be obtained by purification from human blood filtrate or urine, by solid phase peptide synthesis or by expression in recombinant microorganisms.
  • the invention furthermore relates to the complexes of the peptides according to the invention with human insulin-like growth factor-I and / or human insulin-like growth factor-II and their physiologically active fragments and / or derivatives, in particular amidated, acetylated, sulfated, phosphorylated and / or glycosylated derivatives.
  • the invention furthermore relates to nucleic acids which code for the peptides according to the invention, antisense nucleotides which bind under stringent conditions to a nucleic acid which codes for the peptide according to the invention, antibodies which bind to the peptides according to the invention, inhibitors which inhibit the biological activity of the insulin -like growth factor binding proteins, inhibitors that inhibit the expression of insulin-like growth factor binding proteins.
  • the peptides, complexes, nucleic acids, antisense nucleotides, antibodies and inhibitors according to the invention are particularly suitable for the manufacture of a medicament for the treatment of over- or under-expression of insulin-like growth factor binding proteins, for the treatment of muscle loss, osteoporosis, diabetes, amyloidal lateral sclerosis, peripheral - Ren and central neuropathies, inflammatory processes, disturbed inflammatory reactions, tumor diseases, inflammatory and neoplastic diseases, growth disorders, musculoskeletal disorders, diseases of the bone apparatus and / or for wound and bone healing.
  • IGFBP IGF-I or IGF-II are particularly suitable for the treatment of bone diseases.
  • the peptides according to the invention and the complexes of the peptides with insulin-like growth factor have a cell proliferative activity.
  • the peptides according to the invention regulate the release of IGF-I and IGF-II from the complexes at their site of action.
  • the co-administration of the peptides according to the invention with IGF-I or IGF-II extends the biological half-life and thus the availability of the latter.
  • the hypoglycemia induced by injection of free IGF-I or IGF-II is prevented by the co-administration of the peptides according to the invention.
  • the peptides according to the invention furthermore have a growth-promoting effect on bone cells and lead to an enhancement or modulation of the action of growth hormones.
  • the peptides, complexes, nucleic acids, antisense nucleotides, antibodies and inhibitors according to the invention are contained in a pharmaceutical in a pharmaceutical dosage form. They are suitable for oral, intravenous, intramuscular, intracutaneous, intrathecal use or as an aerosol for transpulmonary application.
  • the amount of peptide to be administered is 1 ⁇ g to 1 g per administration unit per day.
  • nucleic acids and / or antisense nucleotides according to the invention are also suitable for the manufacture of a medicament for the treatment of somatic or non-somatic genetic diseases.
  • the diagnostic agent according to the invention contains the peptides, complexes, nucleic acids, antisense nucleotides, antibodies and / or inhibitors according to the invention.
  • the diagnostic agent preferably contains poly- or monoclonal antibodies against the peptide according to the invention, it being possible for the antibodies to be fluorescently or radioactively labeled in order to be able to be used in the known ELISA or RIA.
  • the diagnostic agent can also contain nucleic acids, which are used in modified or labeled form in tests known to those skilled in the art, such as PCR or finger printing.
  • the diagnostic agents according to the invention are particularly suitable for the diagnosis of functional disorders of the bones, the muscles, the nervous system, the lymph organs, the gastric Intestinal tract, immune system, diabetes, inflammatory and neoplastic processes as well as a marker for cancer.
  • the simultaneous appearance of several fragments of BP-4 or BP-5 in the plasma, in particular the N- and C-terminal domains, is suitable as a marker for diseases of the bone metabolism.
  • the corresponding peptides can either be detected by mass spectroscopy or, preferably by an immune reaction with the corresponding antibody.
  • FIG. 1 shows an alignment of the consensus sequences of C-terminal fragments of the insulin-like growth factor proteins.
  • FIG. 2 shows the schematic structure of the insulin-like growth factor proteins with the cysteine-rich N- and C-terminal domains.
  • FIG. 3 shows the schematic structure of the insulin-like growth factor proteins and the sequence of the biologically active fragments isolated from hemofiltrate.
  • FIG. 4 shows the isolation of the osteoanabolic factor IGFBP-4-11 from human hemofiltrate (see example 3).
  • Figure 5 shows the sequence and sulfur bridge analysis of the osteoanabolic factor IGFBP-4- 11.
  • the cysteines 153-183, 194-205 and 207-228 are bridged.
  • Figure 6 shows the biological effect of the osteoanabolic factor IGFBP-4-11. After incubation of serum-free primary rat osteoblasts for (A) 24 hours, (B) 48 hours and (C) 72 hours with IGFBP-4-11, the proliferation-promoting effect of IGFBP-4-11 is shown. An increase in the rate of DNA synthesis is found in a dose-dependent manner, measured as the incorporation of bromodeoxyuridine (BrdU).
  • FIG. 7 shows the specific binding to osteoblasts and the possible receptor for the osteoanabolic factor IGFBP-4-11 (referred to as IGFBP-4 136'237 ).
  • A Radioactively labeled IGFBP-4-11 shows a specific binding to primary osteoblast cells that can be displaced by increasing amounts of unlabelled IGFBP-4-11.
  • B Radioactively labeled IGFBP-4-11 could, after binding to osteoblasts, be chemically cross-linked with its putative receptor molecule and then by gel electrophoresis and subsequent authorization. diography can be demonstrated.
  • the ligand-receptor complex has a molecular weight of approximately 120 kDa. The formation of the complex is promoted by saponin, a membrane pore former. The complex formation is prevented by adding an excess of unlabelled IGFBP-4-11 to the incubation batch.
  • the peptides according to the invention can be obtained from a human hemofiltrate by a purification process.
  • This patented process (Forssmann, W.-G. (1988), publication DE 36 33 707 AI), which was developed for the extraction of proteins from hemofiltrate, was also used in a modified form to purify the peptide complex.
  • Hemofiltrate accumulates in large quantities in the ultrafiltration of the blood of kidney patients. 800 to 1,000 1 hemofiltrate are adjusted to a pH of 2.7 with HCl and diluted to a conductivity of 5.5 mS / cm with water and applied to a strong cation exchanger at a flow rate of 3 1 / min.
  • Buffer A Hemofiltrate pH 2.7, conductivity 5.5 mS / cm
  • Buffer B 0.5 M ammonium acetate
  • ammonium acetate eluates of the batch extraction are combined in amounts of 5,000 to 10,000 1 hemofiltrate peptide.
  • the peptide extract is applied to the preparative cation exchanger with the addition of demineralized water with a conductivity of 5.5 mS / cm.
  • the column is rinsed with 0.01 M HCl until the conductivity is below 1 mS / cm.
  • the elution is carried out in several stages using the buffers specified below
  • Eluates 1-7 are referred to as pH pool I-VII. They are collected separately and then rinsed with demineralized water. The elution takes place until a new baseline is reached. never, with elution volumes of 10 to 25 1 being achieved for the individual pH pools I to VII.
  • the individual pH pools are separated for fractionation and simultaneous desalination using a reverse phase chromatography
  • Pillar FineLine 100 (Pharmacia, Freiburg)
  • Buffer B 80% acetonitrile in 10 mM HCl
  • the column is rinsed with buffer A. Fractions of 200 ml are collected during the elution. Aliquots of the fractions are tested in the bioassay. The fractions are freeze-dried and stored at -20EC.
  • the bioactive fractions 11 and 12 from pH pool V in the assay were separated using a semi-preparative reverse-phase column. Fractions 21 to 25 contained the substance according to the invention.
  • Buffer B 0.1% TFA, 80% acetonitrile
  • Buffer A 0.1% TFA, 20% methanol
  • Buffer B 0.1% TFA, 100% methanol
  • Buffer A 20 mM sodium phosphate, pH 3.0
  • Buffer B 20 mM sodium phosphate, pH 3.0, 1.5 M NaCl
  • Fraction 56 contained the substance according to the invention.
  • Buffer B 0.1% TFA, 80% acetonitrile
  • the bioactive fraction 56 from the previous separation step was further purified on an analytical reverse phase column.
  • Filling material YMC RP-C18, 5 ⁇ m, 300 ⁇
  • Buffer B 0.1% TFA, 80% acetonitrile
  • bioactive fraction 45 from the previous separation step was subjected directly to the mass and sequence analysis. Another portion was reduced and alkylated (as described in Example 2) and then further purified on an analytical reverse phase column.
  • Filling material Zorbax RP-C3, 5 ⁇ m, 300 ⁇ analytics is used, clearly.
  • IGF-II 7471 Da; IGFBP-2, 12,681 Da; IGFBP-2, 12 865 Da
  • Cysteines can be detected in peptide sequencing after prior chemical derivatization, for example after reduction with ß-mercaptoethanol and carboxamidomethylation with iodoacetamide. After derivatization, desalting is preferably followed by analytical reverse phase chromatography with a Vydac RP-C18 column (4.6 mm x 25 cm). Some of the peptides modified in this way are fed to the sequence analysis, with the other part the mass determinations give a corresponding molecular weight. From the mass difference to the native peptide, it is concluded that the peptides from hemofiltrate contain six cysteines, which are also connected to one another with three disulfide bridges.
  • IGFBP-2-13 MW 12681
  • IGFBP-2-13 MW 12865
  • the peptide sequences are 100% identical to the amino acids of human IGFBP-2 derived from the cDNA or to the amino acid sequence of IGF-II.
  • IGFBP-2 has so far been described as a 34 kD binding protein. whose complete sequence analysis was carried out by analyzing the associated cDNA (Binkert, C. et al., EMBO Journal Vol. 8 (1989), pages 2497 to 2502).
  • IGF-II and IGF-I which also binds to IGFBP-2, have been extensively described in their structure at the protein and DNA sequence level (as a review: Rechler, MM, & Nissley, SP (1990) insulin-like growth factors In: Peptide growth factors and their receptors (Spori, MB, Roberts, AB eds.), pages 263 to 367, Springer-Verlag, Berlin).
  • the IGF / IGFBP-2-13 was isolated on the basis of its biological activity in a survival assay of the PC-12 (pheochromocytoma cells) cell line. For this purpose, aliquots of the individual chromatography steps described in Example 1 were freeze-dried and then fed to the biological assay. The fractions, which each gave a positive signal, were subjected to further purification.
  • the assay measures cell survival after being serum-free by determining mitochondrial enzyme activity 24 hours after serum deprivation.
  • Nerve growth factor (NGF) or fetal calf serum (FCS) is used as a positive control in this assay.
  • 10,000 PC-12 cells per hole are sown in 96-well plates in serum-free medium. Aliquots (approx. 100 ml equivalent of the starting material) are added to the wells. 20 hours later, the survival rate of the cells is measured using a Wst-1 substrate. This substrate is converted by mitochondrial enzymes. The resulting dye intensity is measured at 405 nm in an ELISA reader, the reference wavelength is over 600 nm.
  • the IGF / IGFBP-2-13 complex has a dose-dependent, survival-promoting effect on PC-12 cells. These cells correspond to neuronal progenitor cells, so that it can be assumed that IGF / IGFBP-2-13 is a neuroprotective factor.
  • the bioactive fraction 33 from pH pool IV in the assay was separated on an analytical reverse phase column. Fraction 34 contained the substance according to the invention.
  • Buffer B 0.1% TFA, 80% acetonitrile
  • Mass determinations The mass determinations were carried out on an electrospray mass spectrometer. The molecular weight of the peptide was as
  • the C-terminus was determined by comparing the measured molecular mass with the mass calculated from the sequence. The agreement of these masses lies in the measuring accuracy of the electrospray mass spectrometer of 0.1% of the total mass.
  • the peptide sequence is 100% identical to the amino acids of human IGFBP-4 derived from the cDNA.
  • the sulfur bridge linkage was analyzed by cleaving the native peptide IGFBP-4-11 in parallel in two different batches with the endoproteases chymotrypsin and Arg-C. The cleavage fragments obtained were then separated from one another by means of analytical reverse phase chromatography and subjected to the molecular mass and sequence analysis. The following fragments, each containing two cysteines and a sulfur bridge, were obtained: HPKQCHPALDGQRGKCW, MW 1960
  • the IGFBP-4-11 was isolated on the basis of its biological activity in a proliferation assay with primary bone cells (osteoblasts), which are initially isolated from the skullcap of rat embryos
  • TGF-beta Transforming growth factor-beta
  • FCS fetal calf serum
  • the proliferation rate (DNA synthesis rate) of the cells is measured by adding and incorporating radioactive thymidine.
  • the peptide IGFBP-4-11 has a proliferation-promoting effect on these primary osteoblasts. These cells correspond to typical bone cells, so it can be assumed that IGFBP-4-11 is an osteoanabolic factor.
  • the theoretical mass is 12.5 kD, so it can be assumed that the peptide is glycosylated on serine or theronine.

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Abstract

L'invention concerne des peptides qui se caractérisent en ce que leur séquence d'aminoacide correspond à des parties de la séquence d'aminoacide de la protéine liant le facteur de croissance de substances apparentées à l'insuline. L'invention concerne en outre des dérivés cycliques, glycosylés, phosphorylés, acétylés, amidés et/ou sulfatés.
PCT/EP1998/008405 1997-12-22 1998-12-22 Fragments de proteine liant le facteur de croissance de substances apparentees a l'insuline et leur utilisation WO1999032620A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP98965865A EP1042476A1 (fr) 1997-12-22 1998-12-22 Fragments de proteine liant le facteur de croissance de substances apparentees a l'insuline et leur utilisation
JP2000525539A JP2002508931A (ja) 1997-12-22 1998-12-22 インシュリン様成長因子結合蛋白質フラグメント及びその利用
CA002315974A CA2315974A1 (fr) 1997-12-22 1998-12-22 Fragments de proteine liant le facteur de croissance de substances apparentees a l'insuline et leur utilisation

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19757250A DE19757250A1 (de) 1997-12-22 1997-12-22 Insulin-like growth factor binding protein und seine Verwendung
DE19757250.2 1997-12-22

Publications (2)

Publication Number Publication Date
WO1999032620A1 WO1999032620A1 (fr) 1999-07-01
WO1999032620A9 true WO1999032620A9 (fr) 1999-09-23

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EP (1) EP1042476A1 (fr)
JP (1) JP2002508931A (fr)
CA (1) CA2315974A1 (fr)
DE (1) DE19757250A1 (fr)
WO (1) WO1999032620A1 (fr)

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WO1999032620A1 (fr) 1999-07-01
CA2315974A1 (fr) 1999-07-01

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