CA2176942A1 - Bmp-12, bmp-13 and tendon-inducing compositions thereof - Google Patents

Bmp-12, bmp-13 and tendon-inducing compositions thereof

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Publication number
CA2176942A1
CA2176942A1 CA002176942A CA2176942A CA2176942A1 CA 2176942 A1 CA2176942 A1 CA 2176942A1 CA 002176942 A CA002176942 A CA 002176942A CA 2176942 A CA2176942 A CA 2176942A CA 2176942 A1 CA2176942 A1 CA 2176942A1
Authority
CA
Canada
Prior art keywords
bmp
seq
amino acid
protein
tendon
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
Application number
CA002176942A
Other languages
French (fr)
Other versions
CA2176942C (en
Inventor
Anthony J. Celeste
John M. Wozney
Vicki A. Rosen
Neil M. Wolfman
Gerald H. Thomsen
Douglas A. Melton
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.)
Harvard College
Genetics Institute LLC
Original Assignee
Individual
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
Priority claimed from US08/333,576 external-priority patent/US6027919A/en
Application filed by Individual filed Critical Individual
Publication of CA2176942A1 publication Critical patent/CA2176942A1/en
Application granted granted Critical
Publication of CA2176942C publication Critical patent/CA2176942C/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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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
    • C07K14/475—Growth factors; Growth regulators
    • C07K14/51—Bone morphogenetic factor; Osteogenins; Osteogenic factor; Bone-inducing factor
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/18—Growth factors; Growth regulators
    • A61K38/1875—Bone morphogenic factor; Osteogenins; Osteogenic factor; Bone-inducing factor
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/22—Polypeptides or derivatives thereof, e.g. degradation products
    • A61L27/227—Other specific proteins or polypeptides not covered by A61L27/222, A61L27/225 or A61L27/24
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
    • A61L27/38—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix containing added animal cells
    • A61L27/3839—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix containing added animal cells characterised by the site of application in the body
    • A61L27/3843—Connective tissue
    • A61L27/386—Ligaments, tendons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/54—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • 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
    • 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
    • A61P19/04—Drugs for skeletal disorders for non-specific disorders of the connective tissue
    • 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
    • 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
    • A61P5/00—Drugs for disorders of the endocrine system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/01—Fusion polypeptide containing a localisation/targetting motif
    • C07K2319/02—Fusion polypeptide containing a localisation/targetting motif containing a signal sequence

Abstract

Bone morphogenetic proteins BMP-12 and BMP-13 have been cloned. Compositions of these proteins with tendon/ligament-like tissue inducing activity are disclosed. The compositions are useful in the treatment of tendinitis and tendon or ligament defects and in related tissue repair.

Claims (28)

1. A DNA molecule comprising an isolated DNA sequence encoding a BMP-12 related protein.
2. A DNA molecule according to claim 1, wherein said DNA sequence is selected from the group consisting of:
(a) nucleotides #496, #571 or #577 to #882 of SEQ ID NO:1;
(b) nucleotides #605 or #659 to #964 of SEQ ID NO:25; and (c) sequences which hybridize to (a) or (b) under stringent hybridization conditions and encode a BMP-12 related protein which exhibits the ability to form tendon/ligament-like tissue.
3. A DNA molecule comprising the DNA sequence of claim 1 wherein said DNA sequence is selected from the group consisting of:
(a) nucleotides encoding for amino acids #-25, #1 or #3 to #104 of SEQ ID NO:2;
(b) in a 5' to 3' direction, nucleotides encoding a propeptide selected from the group consisting of native BMP-12 propeptide and a BMP protein propeptides; and nucleotides encoding for amino acids #-25, #1 or #3 to #104 of SEQ ID NO:2; and (c) nucleotides encoding for amino acids #1 or #19 to #120 of SEQ ID
NO:26;
(d) in a 5' to 3' direction, nucleotides encoding a propeptide selected from the group consisting of native BMP-12 propeptide and a BMP protein propeptide; and nucleotides encoding for amino acids #1 or #19 to #120 of SEQ
ID NO:26;
(e) sequences which hybridize to any of (a) through (d) under stringent hybridization conditions and encode a BMP-12 related protein which exhibits the ability to form cartilage and/or bone.
4. A host cell transformed with a DNA molecule according to claim 1.
5. A host cell transformed with the DNA molecule of claim 2.
6. A host cell transformed with the DNA molecule of claim 3.
7. An isolated DNA molecule having a sequence encoding a BMP-12 protein which is characterized by the ability to induce the formation of tendon/ligament-like tissue, said DNA molecule comprising a DNA sequence selected from the group consisting of:
(a) nucleotide #496, #571 or #577 to #882 of SEQ ID NO:1;
(b) nucleotide #605 or #659 to #964 of SEQ ID NO:25: and (c) naturally occurring allelic sequences and equivalent degenerative codon sequences of (a) or (b).
8. A host cell transformed with the DNA molecule of claim 7.
9. A vector comprising a DNA molecule of claim 7 in operative association with an expression control sequence therefor.
10. A host cell transformed with the vector of claim 9.
11. A method for producing a purified BMP-12 protein, said method comprising the steps of:
(a) culturing a host cell transformed with a DNA molecule according to claim 2, comprising a nucleotide sequence encoding a BMP-12 related protein;
and (b) recovering and purifying said BMP-12 related protein from the culture medium.
12. A method for producing a purified BMP-12 related protein said method comprising the steps of:
(a) culturing a host cell transformed with a DNA molecule according to claim 3, comprising a nucleotide sequence encoding a BMP-12 related protein;
and (b) recovering and purifying said BMP-12 related protein from the culture medium.
13. A method for producing a purified BMP-12 related protein said method comprising the steps of:
(a) culturing a host cell transformed with a DNA molecule according to claim 7, comprising a nucleotide sequence encoding a BMP-12 related protein;
and (b) recovering and purifying said BMP-12 related protein from the culture medium.
14. A purified polypeptide comprising an amino acid sequence selected from the following group:
(a) from ammo acid #-25 to amino acid #104 as set forth in SEQ ID
NO:2;
(b) from amino acid #1 to amino acid #104 as set forth in SEQ ID NO:2.
(c) from amino acid #3 to amino acid #104 as set forth in SEQ ID NO:2.
(d) from amino acid #1 to amino acid #120 as set forth in SEQ ID
NO:26; and (d) from amino acid #19 to amino acid #120 as set forth in SEQ ID
NO:26.
15. A purified polypeptide wherein said polypeptide is in the form of a dimer comprised of two subunits, each with the amino acid sequence of claim 14.
16. A purified protein produced by the steps of (a) culturing a cell transformed with a DNA molecule comprising the nucleotide sequence from nucleotide #496, #571 or #577 to #882 as shown in SEQ ID NO:1; and (b) recovering and purifying from said culture medium a protein comprising the amino acid sequence from amino acid #-25, amino acid #1 or amino acid #3 to amino acid #104 as shown in SEQ ID NO:2.
17. A purified BMP-12 related protein characterized by the ability to induce the formation of tendon/ligament-like tissue.
18. A pharmaceutical composition comprising an effective amount of the BMP-12 related protein of claim 17 in admixture with a pharmaceutically acceptable vehicle.
19. A method for inducing tendon/ligament-like tissue formation in a patient in need of same comprising administering to said patient an effective amount of the composition of claim 18.
20. A pharmaceutical composition for tendon/ligament-like tissue healing and tissue repair said composition comprising an effective amount of the proteinof a BMP-12 related protein in a pharmaceutically acceptable vehicle.
21. A method for treating tendinitis. or other tendon or ligament defect in a patient in need of same, said method comprising administering to said patient an effective amount of the composition of claim 20.
22. A chimeric DNA molecule comprising a DNA sequence encoding a propeptide from a member of the TGF-.beta. superfamily of proteins linked in correct reading frame to a DNA sequence encoding a BMP-12 related polypeptide.
23. A chimeric DNA molecule according to claim 22, wherein the propeptide is the propeptide from BMP-2.
24. A heterodimeric protein molecule comprising one monomer having the amino acid sequence of the polypeptide of claim 14, and one monomer having the amino acid sequence of a protein of the TGF-.beta. superfamily.
25. A method for inducing tendon/ligament-like tissue formation in a patient in need of same comprising administering to said patient an effective amount of a composition comprising a protein encoded by a DNA sequence selected from the group consisting of:
(a) nucleotides #496, #571 or #577 to #882 of SEQ ID NO:1;
(b) nucleotides #845 or #899 to #1204 of SEQ ID NO:3;
(c) nucleotides #605 or #659 to #964 of SEQ ID NO:25; and (d) sequences which hybridize to (a), (b) or (c) under stringent hybridization conditions and encode a protein which exhibits the ability to form tendon/ligament-like tissue.
26. A method for inducing tendon/ligament-like tissue formation in a patient in need of same comprising administering to said patient an effective amount of the composition comprising a tendon/ligament-like tissue inducing protein having an ammo acid sequence selected from the group consisting of:
(a) amino acids #-25, #1 or #3 to #104 of SEQ ID NO:2;
(b) amino acids #1 or #19 to #120 of SEQ ID NO:4;
(c) amino acids #1 or #19 to #120 of SEQ ID NO:26; and (d) mutants and/or variants of (a), (b) or (c) which exhibit the ability to form tendon and/or ligament.
27. A pharmaceutical composition for tendon/ligament-like tissue repair, said composition comprising an effective amount of a BMP-12 related protein in a pharmaceutically acceptable vehicle.
28. A method for treating tendinitis, or other tendon or ligament defect in a patient in need of same, said method comprising administering to said patient an effective amount of the composition of claim 27.
CA2176942A 1993-12-07 1994-12-06 Bmp-12, bmp-13 and tendon-inducing compositions thereof Expired - Lifetime CA2176942C (en)

Applications Claiming Priority (7)

Application Number Priority Date Filing Date Title
US16410393A 1993-12-07 1993-12-07
US08/164,103 1993-12-07
US21778094A 1994-03-25 1994-03-25
US08/217,780 1994-03-25
US08/333,576 1994-11-02
US08/333,576 US6027919A (en) 1993-12-07 1994-11-02 BMP-12 and BMP-13 proteins and DNA encoding them
PCT/US1994/014030 WO1995016035A2 (en) 1993-12-07 1994-12-06 Bmp-12, bmp-13 and tendon-inducing compositions thereof

Publications (2)

Publication Number Publication Date
CA2176942A1 true CA2176942A1 (en) 1995-06-15
CA2176942C CA2176942C (en) 2011-11-01

Family

ID=27388970

Family Applications (1)

Application Number Title Priority Date Filing Date
CA2176942A Expired - Lifetime CA2176942C (en) 1993-12-07 1994-12-06 Bmp-12, bmp-13 and tendon-inducing compositions thereof

Country Status (15)

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US (5) US5658882A (en)
EP (1) EP0733109B9 (en)
JP (3) JP3717930B2 (en)
KR (1) KR100353182B1 (en)
AT (1) ATE319823T1 (en)
AU (1) AU689184B2 (en)
CA (1) CA2176942C (en)
DE (1) DE69434651T2 (en)
DK (1) DK0733109T3 (en)
ES (1) ES2255059T3 (en)
FI (1) FI119816B (en)
NO (1) NO317801B1 (en)
OA (1) OA10582A (en)
PT (1) PT733109E (en)
WO (1) WO1995016035A2 (en)

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CA2176942C (en) 2011-11-01
US6284872B1 (en) 2001-09-04
AU1301395A (en) 1995-06-27
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US20020160494A1 (en) 2002-10-31
JPH09506261A (en) 1997-06-24
FI962350A (en) 1996-07-16
WO1995016035A2 (en) 1995-06-15
OA10582A (en) 2002-08-23
JP2005312457A (en) 2005-11-10
EP0733109B9 (en) 2006-07-05
JP3717930B2 (en) 2005-11-16
US6984623B2 (en) 2006-01-10
KR100353182B1 (en) 2002-09-28
ES2255059T3 (en) 2006-06-16
JP2007016037A (en) 2007-01-25
FI119816B (en) 2009-03-31
EP0733109B1 (en) 2006-03-08
DE69434651D1 (en) 2006-05-04
EP0733109A1 (en) 1996-09-25
AU689184B2 (en) 1998-03-26
US5658882A (en) 1997-08-19
NO962304L (en) 1996-06-04
DK0733109T3 (en) 2006-07-03
FI962350A0 (en) 1996-06-06
JP3939729B2 (en) 2007-07-04
US20070004005A1 (en) 2007-01-04
US20040146923A1 (en) 2004-07-29
WO1995016035A3 (en) 1995-07-13
NO317801B1 (en) 2004-12-13
NO962304D0 (en) 1996-06-04
ATE319823T1 (en) 2006-03-15
US7365052B2 (en) 2008-04-29
PT733109E (en) 2006-07-31

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