Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Recombinant dna technique included in method of making a...
Patent
1993-04-22
1997-08-26
Walsh, Stephen G.
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Recombinant dna technique included in method of making a...
435325, 4352523, 4353201, 435358, 435360, 435364, 435365, 4353651, 514 12, 530399, 536 2351, 930210, C12N 1512, C12N 1579, C07K 1451, A61K 3818
Patent
active
056610076
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to a novel family of purified proteins designated BMP-9 proteins and processes for obtaining them. These proteins may be used to induce bone and/or cartilage formation and in wound healing and tissue repair.
The marine MBP-9 DNA sequence (SEQ ID NO: 1) and amino acid sequence (SEQ ID NO: 2) are set forth in FIG. 1. Human BMP-9 sequence is set forth in FIG. 3 (SEQ ID NO: 8 and SEQ ID NO: 9). It is contemplated that BMP-9 proteins are capable of inducing the formation of cartilage and/or bone. BMP-9 proteins may be further characterized by the ability to demonstrate cartilage and/or bone formation activity in the rat bone formation assay described below.
Murine BMP-9 is characterized by comprising amino acid #319 to #428 of FIG. (SEQ ID NO: 2 amino acid #1-110). Murine BMP-9 may be produced by culturing a cell transformed with a DNA sequence comprising nucleotide #610 to nucleotide #1893 as shown in FIG. 1 (SEQ ID NO: 1) and recovering and purifying from the culture medium a protein characterized by the amino acid sequence comprising amino acid #319 to #428 as shown in FIG. 1 (SEQ ID NO: 2) substantially free from other porteinanceous materials with which it is co-produced.
Human BMP-9 is expected to be homologous to murine BMP-9 and is characterized by comprising amino acid #1 (Ser, Ala, Gly) to #110 of FIG. 3 (SEQ ID NO: 9) (Arg). The invention includes methods for obtaining the DNA sequences encoding human BMP-9. This method entails utilizing the murine BMP-9 nucleotide sequence or portions thereof to design probes to screen libraries for the human gene or fragments thereof using standard techniques. Human BMP-9 may be produced by culturing a cell transformed with the BMP-9 DNA sequence and recovering and purifying 8MP-9 from the culture medium. The expressed protein is isolated, recovered, and purified from the culture medium. The parodied expressed protein is substantially free from other proteinaceous materials with which it is co-produced, as well as from other contaminants the recovered purified protein is contemplated to exhibit cartilage and/or bone formation activity. The proteins of the invention may be further characterized by the ability to demonstrate cartilage and/or bone formation activity in the rate bone formations assay described below.
Human BMP-9 maybe produced by culturing a cell transformed with a DNA sequence comprising nucleotide #124 to #453 as shown in SEQ ID NO: 8 and recovering and purifying from the culture medium a protein characterized by the amino acid sequence of SEQ ID NO: 9 from amino acid #1 to amino acid #110 substantially free from other proteinaceous materials with which it is co-produced.
Another aspect of the invention provides pharmaceutical compositions containing a therapeutically effective amount of a BMP-9 protein in a pharmaceutically acceptable vehicle or carrier. BMP-9 compositions of the invention may be used in the formation of cartilage. These compositions may further be utilized for the formation of bone. BMP-9 compositions may also be used for wound heading and tissue repair. Compositions of the invention may further include at least one other therapeutically useful agent such as the BMP proteins BMP-1, BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, and BMP-7 disclosed for instance in PCT publications WO88/00205, WO89/10409, and WO90/11366, and BMP-8, disclosed in U.S. application Ser. No. 07/641,204 filed Jan. 15, 1991, Ser. No. 07/525,357 filed May 16, 1990, and Ser. No. 07/800,364 filed Nov. 20, 1991.
The compositions of the invention may comprise, in addition to a BMP-9 protein, other therapeutically useful agents including growth factors such as epidermal growth factor (EGF), fibroblast growth factor (FGF), transforming growth factor (TGF-.alpha. and TGF-.beta.), and insulin-like growth factor (IGF). The compositions may also include an appropriate matrix for instance, for supporting the composition and providing a surface for bone and/or cartilage growth. The matrix may provide slow release of the osteoinductive protein and/or th
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Celeste Anthony J.
Wozney John M.
DesRosier Thomas J.
Genetics Institute Inc.
Kapinos Ellen J.
Walsh Stephen G.
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