CA2362496A1 - Polypeptide variants with increased heparin-binding ability - Google Patents
Polypeptide variants with increased heparin-binding ability Download PDFInfo
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- CA2362496A1 CA2362496A1 CA002362496A CA2362496A CA2362496A1 CA 2362496 A1 CA2362496 A1 CA 2362496A1 CA 002362496 A CA002362496 A CA 002362496A CA 2362496 A CA2362496 A CA 2362496A CA 2362496 A1 CA2362496 A1 CA 2362496A1
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- 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
- C07K14/475—Growth factors; Growth regulators
- C07K14/51—Bone morphogenetic factor; Osteogenins; Osteogenic factor; Bone-inducing factor
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
-
- 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
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- 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
-
- 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
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
Abstract
The invention relates to polypeptide variants with raised heparin-binding capacity. Said raised heparin-binding capacity is achieved by the addition, insertion and/or substitution of an amino acid sequence X1, X2, X3, X4, X6 (SEQ ID no. 1 or no. 2). The polypeptide variants provided for in the invention are particularly suitable for the stimulation of chondrogenesis, osteogenesis and wound healing. The invention also relates to nucleic acid molecules coding for said polypeptide variants, host cells containing the nucleic acid molecules and methods for producing the polypeptide variants.</ SDOAB>
Claims (26)
1. A polypeptide variant with increased heparin-binding ability, characterized in that (i) added to the amino acid sequence of a polypeptide is at least one oligopeptide comprising the amino acid sequence X1X2X3X4X5X6;
and/or (ii) inserted into the amino acid sequence of a polypeptide is at least one oligopeptide comprising the amino acid sequence X1X2X3X4X5X6; and/or (iii) at least one oligopeptide sequence naturally occurring within the amino acid sequence of a polypeptide is substituted by an oligopeptide comprising an amino acid sequence X1X2X3X4X5X6, wherein X1 = K, R, or H;
X2 = K, R, or H;
X3 = K, R, H, or no amino acid;
X4 = not K, R, H, but any other amino acid;
X5 = not K, R, H, but any other or no amino acid;
X6 = not K, R, H, but any other or no amino acid (SEQ ID NO: 1), or X1 = K, R, or H;
X2 = not K, R, H, but any other amino acid;
X3 = K, R, or H;
X4 = not K, R, H, but any other amino acid;
and/or (ii) inserted into the amino acid sequence of a polypeptide is at least one oligopeptide comprising the amino acid sequence X1X2X3X4X5X6; and/or (iii) at least one oligopeptide sequence naturally occurring within the amino acid sequence of a polypeptide is substituted by an oligopeptide comprising an amino acid sequence X1X2X3X4X5X6, wherein X1 = K, R, or H;
X2 = K, R, or H;
X3 = K, R, H, or no amino acid;
X4 = not K, R, H, but any other amino acid;
X5 = not K, R, H, but any other or no amino acid;
X6 = not K, R, H, but any other or no amino acid (SEQ ID NO: 1), or X1 = K, R, or H;
X2 = not K, R, H, but any other amino acid;
X3 = K, R, or H;
X4 = not K, R, H, but any other amino acid;
2 X5 = not K, R, H, but any other or no amino acid;
X6 = not K, R, H, but any other or no amino acid (SEQ ID NO: 2), and the polypeptide is selected from among members of the DVR family including the TGF-.beta. superfamily.
2. A polypeptide variant as recited in claim 1, characterized in that one to four copies of said oligopeptide are inserted at one to four positions within the polypeptide.
X6 = not K, R, H, but any other or no amino acid (SEQ ID NO: 2), and the polypeptide is selected from among members of the DVR family including the TGF-.beta. superfamily.
2. A polypeptide variant as recited in claim 1, characterized in that one to four copies of said oligopeptide are inserted at one to four positions within the polypeptide.
3. A polypeptide variant as recited in claim 1 or 2, characterized in said oligopeptide comprises amino acid sequence RKRA (SEQ ID NO: 3) or RKRAKHKQ (SEQ ID NO: 4).
4. A polypeptide variant as recited in any one of claims 1 to 3, characterized in said oligopeptide is added to the N-terminus and/or inserted into the N-terminal region, and/or substitutes a part of the N-terminal region.
5. A polypeptide variant as recited in any one of claims 1 to 4, characterized in that the amino acid sequence of said polypeptide variant further contains a sequence of relevance to recombinant expression at the N-terminus, said sequence of relevance to recombinant expression being M or MZ, where M stands for methionine and Z stands for one or more amino acids.
6. A polypeptide variant as recited in any one of claims 1 to 5, characterized in that said polypeptide variant further contains a His-tag.
7. A polypeptide variant as recited in any one of claims 1 to 6, characterized in that said polypeptide is altered by addition, substitution, insertion, inversion, and/or deletion, where said polypeptide altered by addition substitution, insertion, inversion and/or deletion shows at least 10% of the biological activity of the unaltered polypeptide, and/or at least 50% homology to the unaltered polypeptide.
8. A polypeptide variant as recited in any one of claims 1 to 7, characterized in that said polypeptide is BMP-2, BMP-4, BMP-5, BMP-6, BMP-7/OP-1, or BMP-8/OP-2.
9. A polypeptide variant as recited in any one of claims 1 to 8, characterized in that said oligopeptide is inserted before the cysteine knot.
10. A polypeptide variant as recited in claim 8 or 9, characterized in that said polypeptide variant has the amino acid sequence SEQ ID NO: 5 (T3) or SEQ ID
NO: 6 (T4).
NO: 6 (T4).
11. A polypeptide variant as recited in any one of claims 1 to 10, characterized in that said polypeptide variant is a polymer, oligomer, or dimer of said polypeptide variant as recited in any one of claims 1 to 10.
12. A nucleic acid molecule, comprising a nucleic acid sequence encoding a polypeptide variant as recited in any one of claims 1 to 11.
13. A nucleic acid molecule as recited in claim 12, characterized in that said nucleic acid sequence is derived from genomic DNA or cDNA, ar is a synthetic DNA.
14. A nucleic acid molecule as recited in claim 12 or 13, further comprising a promoter suited to control expression, wherein said nucleic acid sequence encoding a polypeptide variant is under the control of said promoter.
15. A nucleic acid molecule as recited in any one of claims 12 to 14, wherein said nucleic acid molecule contains at least part of a vector.
16. Host cell, containing a nucleic acid molecule as recited in any one of claims 12 to 15, wherein said host cell is a prokaryotic or eukaryotic cell suitable for expression of said nucleic acid molecule.
17. A process for producing a polypeptide variant with increased heparin-binding ability as recited in any one of claims 1 to 11, comprising:
addition to the amino acid sequence of a polypeptide of at least one oligopeptide containing an amino acid sequence selected from SEQ ID NO:1 or SEQ ID NO:2;
and/or insertion into the amino acid sequence of a polypeptide of at least one oligopeptide containing an amino acid sequence selected from SEQ ID NO:1 or SEQ ID NO:2; and/or substitution of at least one oligopeptide sequence naturally occurring within the amino acid sequence of a polypeptide by one oligopeptide containing an amino acid sequence selected from SEQ ID NO:1 or SEQ ID NO:2.
addition to the amino acid sequence of a polypeptide of at least one oligopeptide containing an amino acid sequence selected from SEQ ID NO:1 or SEQ ID NO:2;
and/or insertion into the amino acid sequence of a polypeptide of at least one oligopeptide containing an amino acid sequence selected from SEQ ID NO:1 or SEQ ID NO:2; and/or substitution of at least one oligopeptide sequence naturally occurring within the amino acid sequence of a polypeptide by one oligopeptide containing an amino acid sequence selected from SEQ ID NO:1 or SEQ ID NO:2.
18. A process as recited in claim 17, characterized in that said process comprises a chemical and/or enzymatic synthesis process.
19. A process as recited in claim 17 or 18, characterized in that said process comprises gene technological processes.
20. A process as recited in any one of claims 17 to 19, characterized in that said process comprises:
a) in vitro mutagenesis of a nucleic acid encoding a polypeptide, so that (i) to the nucleic acid encoding said polypeptide is added at least one nucleic acid encoding an oligopeptide containing an amino acid sequence that is selected from SEQ ID No.1 or SEQ ID No. 2; and/or (ii) into the nucleic acid encoding said polypeptide is inserted at least one nucleic acid encoding an oligopeptide containing an amino acid sequence that is selected from SEQ ID No. 1 or SEQ ID No. 2; and/or (iii) at least one nucleic acid sequence naturally occurring within the nucleic acid sequence encoding said polypeptide is substituted by a nucleic acid sequence encoding an oligopeptide containing an amino acid sequence selected from SEQ ID No:1 or SEQ ID No:2;
b) cloning of the mutated nucleic acid into a suitable expression vector;
c) transformation/transfection of a suitable host cell with the expression vector obtained;
d) cultivation of said transformed/transfected host cell under conditions suitable for expression;
e) isolation, and if necessary renaturation, of the expressed polypeptide variant.
a) in vitro mutagenesis of a nucleic acid encoding a polypeptide, so that (i) to the nucleic acid encoding said polypeptide is added at least one nucleic acid encoding an oligopeptide containing an amino acid sequence that is selected from SEQ ID No.1 or SEQ ID No. 2; and/or (ii) into the nucleic acid encoding said polypeptide is inserted at least one nucleic acid encoding an oligopeptide containing an amino acid sequence that is selected from SEQ ID No. 1 or SEQ ID No. 2; and/or (iii) at least one nucleic acid sequence naturally occurring within the nucleic acid sequence encoding said polypeptide is substituted by a nucleic acid sequence encoding an oligopeptide containing an amino acid sequence selected from SEQ ID No:1 or SEQ ID No:2;
b) cloning of the mutated nucleic acid into a suitable expression vector;
c) transformation/transfection of a suitable host cell with the expression vector obtained;
d) cultivation of said transformed/transfected host cell under conditions suitable for expression;
e) isolation, and if necessary renaturation, of the expressed polypeptide variant.
21. A process as recited in any one of claims 17 to 20, characterized in that said process is carried out within a prokaryotic host cell such as preferably E.
coli.
coli.
22. A process as recited in any one of claims 17 to 20, characterized in that said process is carried out within a eukaryotic cell, preferably a yeast, plant or insect cell, CHO or COS cell.
23. A pharmaceutical composition, comprising a polypeptide variant as recited in any one of claims 1 to 11 and, optionally, physiologically compatible additives.
24. Use of a polypeptide variant as recited in any one of claims 1 to 11 to stimulate osteogenesis or wound healing, or to treat inflammation or cancer.
25. A composition for osteoinduction, comprising a polypeptide variant as recited in any one of claims 1 to 11 and a carrier selected from among heparin, hydroxyapatite, hyaluronic acid, synthetic polymers, and collagen.
26. An osteoinductive matrix, characterized in that said matrix contains or is coated with heparin or heparin-like substances and polypeptide variants as recited in any one of claims 1 to 11 are adsorbed to said heparin or heparin-like substances.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19906096.7 | 1999-02-13 | ||
| DE19906096A DE19906096A1 (en) | 1999-02-13 | 1999-02-13 | Protein with a heparin-binding epitope |
| PCT/EP2000/000637 WO2000047736A1 (en) | 1999-02-13 | 2000-01-27 | Polypeptide variants with raised heparin-binding capacity |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2362496A1 true CA2362496A1 (en) | 2000-08-17 |
| CA2362496C CA2362496C (en) | 2011-04-19 |
Family
ID=7897433
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2362496A Expired - Fee Related CA2362496C (en) | 1999-02-13 | 2000-01-27 | Polypeptide variants with increased heparin-binding ability |
Country Status (11)
| Country | Link |
|---|---|
| US (1) | US7253254B1 (en) |
| EP (1) | EP1151095B1 (en) |
| JP (3) | JP4155711B2 (en) |
| CN (1) | CN1169959C (en) |
| AT (1) | ATE470713T1 (en) |
| AU (1) | AU762387B2 (en) |
| BR (1) | BR0008785A (en) |
| CA (1) | CA2362496C (en) |
| DE (2) | DE19906096A1 (en) |
| RU (1) | RU2227743C2 (en) |
| WO (1) | WO2000047736A1 (en) |
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| EP1885751B1 (en) * | 2005-05-27 | 2011-11-16 | BBS - Bioactive Bone Substitutes Oy | Bone morphogenetic protein 6 containing a heparin binding site and osteogenic devices and pharmaceutical products containing thereof |
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| US7951384B2 (en) * | 2005-08-05 | 2011-05-31 | University Of Massachusetts | Virus-like particles as vaccines for paramyxovirus |
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| JP2007332106A (en) * | 2006-06-16 | 2007-12-27 | Okayama Univ | Sustained release pharmaceutical composition for osteogenesis |
| US20080206299A1 (en) * | 2007-02-27 | 2008-08-28 | Shimp Lawrence A | Method for Recovering Minerals From Bone and Use of Same |
| US9554920B2 (en) | 2007-06-15 | 2017-01-31 | Warsaw Orthopedic, Inc. | Bone matrix compositions having nanoscale textured surfaces |
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| JP2009045142A (en) * | 2007-08-16 | 2009-03-05 | Okayama Univ | Method of processing base material for inducing bone formation around base material in vivo |
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| JP5799409B2 (en) * | 2008-12-19 | 2015-10-28 | 国立大学法人 新潟大学 | Heparin affinity erythropoietin |
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1999
- 1999-02-13 DE DE19906096A patent/DE19906096A1/en not_active Ceased
-
2000
- 2000-01-27 RU RU2001123926/15A patent/RU2227743C2/en not_active IP Right Cessation
- 2000-01-27 BR BR0008785-8A patent/BR0008785A/en not_active Application Discontinuation
- 2000-01-27 EP EP00901137A patent/EP1151095B1/en not_active Expired - Lifetime
- 2000-01-27 DE DE50015938T patent/DE50015938D1/en not_active Expired - Lifetime
- 2000-01-27 WO PCT/EP2000/000637 patent/WO2000047736A1/en active IP Right Grant
- 2000-01-27 CN CNB008037183A patent/CN1169959C/en not_active Expired - Fee Related
- 2000-01-27 CA CA2362496A patent/CA2362496C/en not_active Expired - Fee Related
- 2000-01-27 AU AU21106/00A patent/AU762387B2/en not_active Ceased
- 2000-01-27 JP JP2000598634A patent/JP4155711B2/en not_active Expired - Fee Related
- 2000-01-27 US US09/913,467 patent/US7253254B1/en not_active Expired - Fee Related
- 2000-01-27 AT AT00901137T patent/ATE470713T1/en not_active IP Right Cessation
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2007
- 2007-10-02 JP JP2007258333A patent/JP2008086319A/en active Pending
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2008
- 2008-08-05 JP JP2008201668A patent/JP2009011323A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| US7253254B1 (en) | 2007-08-07 |
| AU2110600A (en) | 2000-08-29 |
| RU2227743C2 (en) | 2004-04-27 |
| BR0008785A (en) | 2001-11-06 |
| CN1169959C (en) | 2004-10-06 |
| DE50015938D1 (en) | 2010-07-22 |
| WO2000047736A1 (en) | 2000-08-17 |
| DE19906096A1 (en) | 2000-08-17 |
| ATE470713T1 (en) | 2010-06-15 |
| EP1151095B1 (en) | 2010-06-09 |
| JP2008086319A (en) | 2008-04-17 |
| AU762387B2 (en) | 2003-06-26 |
| EP1151095A1 (en) | 2001-11-07 |
| JP4155711B2 (en) | 2008-09-24 |
| JP2009011323A (en) | 2009-01-22 |
| CA2362496C (en) | 2011-04-19 |
| CN1340102A (en) | 2002-03-13 |
| JP2002536016A (en) | 2002-10-29 |
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| Date | Code | Title | Description |
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| EEER | Examination request | ||
| FZDC | Discontinued application reinstated | ||
| MKLA | Lapsed |
Effective date: 20140128 |