BMP-9 compositions

• US 6,287,816 B1
• Filed: 06/06/1994
• Issued: 09/11/2001
• Est. Priority Date: 06/25/1991
• Status: Expired due to Fees

• Current Assignee: Genetics Institute LLC (Pfizer Inc.)
• Original Assignee: Genetics Institute LLC (Pfizer Inc.)
• Inventors: Song, Jeffrey R., Thies, R. Scott, Wozney, John M., Rosen, Vicki A., Celeste, Anthony J.
• Primary Examiner(s): ROMEO, DAVID S
• Application Number:
  US08/254,353
• Time in Patent Office: 2,654 Days
• Field of Search: 530/399, 530/840, 930/120, 514/12, 424/423, 424/426, 424/484, 435/69.4, 435/240.2, 435/320.1, 435/252.3, 435/325, 536/24.31, 536/23.51
• US Class Current: 435/69.4
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 38/1875 Bone morphogenic factor; Osteogenins; Osteogenic factor; Bone-inducing factor
• CPC Class Codes: A61K 38/30 Insulin-like growth factors, i.e. somatomedins, e.g. IGF-1, IGF-2 insulin-like growth factor binding protein A61K38/1754
• CPC Class Codes: A61L 27/227 Other specific proteins or polypeptides not covered by A61L27/222, A61L27/225 or A61L27/24
• CPC Class Codes: A61P 1/02 Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07K 14/51 Bone morphogenetic factor; Osteogenins; Osteogenic factor; Bone-inducing factor
• CPC Class Codes: C07K 2319/02 containing a signal sequence
• CPC Class Codes: Y10S 530/84 Bones; tendons; teeth; cartilage
• CPC Class Codes: Y10S 930/12 Growth hormone, growth factor other than t-cell or b-cell growth factor, and growth hormone releasing factor; related peptides

Abstract

Purified bone morphogenetic protein-9 (BMP-9) proteins and processes for producing them are disclosed. The proteins may be used in the treatment of bone and cartilage defects and in wound healing and related tissue repair.

Claims

1. An isolated DNA molecule which encodes a bone morphogenic protein-9 (BMP-9) comprising a DNA sequence selected from the group consisting of:

(a) nucleotides 124 through 453 of SEQ ID NO;

8;

(b) nucleotides 145 through 453 of SEQ ID NO;

8;

(c) nucleotides 610 through 1893 of SEQ ID NO;

1;

(d) nucleotides 628 through 1893 of SEQ ID NO;

1;

(e) nucleotides encoding amino acids 1 or 8 through 110 of SEQ ID NO;

9; and

(f) nucleotides encoding amino acids 319 or 326 through 428 of SEQ ID NO;

2.

2. A host cell transformed with a DNA molecule of claim 1.

3. A vector comprising a DNA molecule of claim 1 in operative association with an expression control sequence therefor.

4. A host cell transformed with the vector of claim 3.

5. A method for producing a BMP-9, encoded by the DNA molecule according to claim 1 said method comprising the steps of:

(a) culturing a host cell transformed with said DNA molecule; and

(b) recovering said BMP-9.

6. A purified BMP-9 encoded by the DNA molecule of claim 1 produced by the steps of:

(a) culturing a host cell transformed with said DNA molecule; and

(b) recovering said BMP-9.

7. An isolated DNA sequence encoding BMP-9, said DNA sequence comprising nucleotides 124 through 453 of SEQ ID NO:

8.

8. A method for producing a BMP-9 encoded by the DNA molecule according to claim 7, said method comprising the steps of:

(a) culturing a host cell transformed with said DNA molecule; and

(b) recovering said BMP-9.

9. An isolated DNA sequence encoding BMP-9, said DNA sequence comprising nucleotides 145 through 453 of SEQ ID NO:

8.

10. An isolated DNA sequence encoding BMP-9, said DNA sequence comprising nucleotides 610 through 1893 of SEQ ID NO:

1.

11. An isolated DNA sequence encoding BMP-9, said DNA sequence comprising nucleotides 628 through 1893 of SEQ ID NO:

1.

12. A host cell transformed with a DNA of claim 11.

13. An isolated DNA sequence encoding BMP-9, said DNA sequence comprising nucleotides encoding amino acids 1 or 8 through 110 of SEQ ID NO:

9.

14. A host cell transformed with a DNA of claim 13.

15. An isolated DNA sequence encoding BMP-9, said DNA sequence comprising nucleotides encoding amino acids 319 or 326 through 428 of SEQ ID NO:

2.

16. A host cell transformed with a DNA of claim 15.

17. An isolated DNA molecule comprising the DNA sequence of ATCC deposit 75252 encoding BMP-9.

18. A purified BMP-9 comprising an amino acid selected from the group consisting of:

(a) amino acids 1 or 8 through 110 of SEQ ID NO;

9; and

(b) amino acids 319 or 326 through 428 of SEQ ID NO;

2.

19. A purified BMP-9 of claim 18, wherein said BMP is a dimer comprising two subunits wherein each of said subunits comprises an amino acid sequence selected from the group consisting of:

(a) amino acids 1 or 8 through amino acid 110 of SEQ ID NO;

9; and

(b) amino acids 319 or 326 through amino acid 428 of SEQ ID NO;

2.

20. A pharmaceutical composition comprising the BMP-9 of claim 18 in admixture with a pharmaceutically acceptable vehicle.

21. A composition for bone and/or cartilage formation comprising an amount of a BMP-9 of claim 18 effective for inducing the formation of cartilage and/or bone in a pharmaceutically acceptable vehicle.

22. A composition of claim 21 further comprising a matrix for supporting said composition and providing a surface for bone and/or cartilage growth.

23. A method for inducing formation of cartilage tissue in a patient in need of same comprising administering to said patient a composition comprising an amount of a BMP-9 of claim 18 effective to induce the formation of cartilage tissue.

24. The method of claim 23, wherein said patient has osteoarthritis.

25. A method for inducing bone and/or cartilage formation in a patient in need of same comprising administering to said patient an effective amount of a BMP-9 of claim 18 effective to induce the formation of cartilage and/or bone.

26. A method for inducing growth and differentiation of liver cells, comprising administering a composition comprising an amount effective for inducing the growth and differentiation of liver cells of a bone morphogenetic protein-9 (BMP-9) of claim 18 to said liver cells.

27. A method for stimulating proteoglycan synthesis in differentiated articular cartilage tissue comprising administering a composition comprising an amount effective for stimulating proteoglycan synthesis in differentiated articular cartilage tissue of a bone morphogenetic protein-9 (BMP-9) of claim 18 to said articular cartilage tissue.

29. A pharmaceutical composition comprising a BMP of claim 19 or 28 in admixture with a pharmaceutically acceptable vehicle.

28. A purified bone morphogenetic polypeptide (BMP), wherein said BMP is a dimer comprising two subunits wherein one of said subunits comprises an amino acid sequence selected from the group consisting of:

(a) amino acids 1 or 8 through amino acid 110 of SEQ ID NO;

9; and

(b) amino acids 319 or 326 through amino acid 428 of SEQ ID NO;

2; and

wherein one of said subunits is selected from the group consisting of a subunit of a BMP selected from the group consisting of BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, BMP-7, and BMP-8.