Chemistry: molecular biology and microbiology – Enzyme – proenzyme; compositions thereof; process for... – Oxidoreductase
Reexamination Certificate
2002-02-07
2004-06-01
Andres, Janet (Department: 1646)
Chemistry: molecular biology and microbiology
Enzyme , proenzyme; compositions thereof; process for...
Oxidoreductase
C435S069100, C435S320100, C435S325000, C536S023500, C530S350000
Reexamination Certificate
active
06743613
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to novel Bone Morphogenic proteins (BMPS). More specifically, isolated nucleic acid molecules are provided encoding novel BMP polypeptides. Novel BMP polypeptides and antibodies that bind to these polypeptides are provided. Also provided are vectors, host cells, and recombinant and synthetic methods for producing human BMP polynucleotides and/or polypeptides. The invention further relates to diagnostic and therapeutic methods useful for diagnosing, treating, preventing and/or prognosing disorders related to these novel BMP polypeptides. The invention further relates to screening methods for identifying agonists and antagonists of polynucleotides and polypeptides of the invention. The present invention further relates to methods and/or compositions for inhibiting the production and function of the polypeptides of the present invention.
BACKGROUND OF THE INVENTION
The present invention relates to Bone Morphogenic Proteins (BMPs) which are responsible for the formation and repair of bone, cartilage, tendon and other tissues present in bone. Members of the bone morphogenetic protein family are useful for induction of cartilage and bone formation. For example, BMP-2 is able to induce the formation of new cartilage and/or bone tissue in vivo in a rat ectopic implant model (See, e.g., U.S. Pat. No. 5,013,649); in mandibular defects in dogs (See, e.g., Toriumi et al., Arch. Otolaryngol Head Neck Surg., 117:1101-1112 (1991)); in femoral segmental defects in sheep (see Gerhart et al., Trans Orthop Res Soc, 16:172 (1991)). Other members of the BMP family also have osteogenic activity, including BMP-4, -6 and -7 (See, e.g., Wozney, Bone Morphogenetic Proteins and Their Gene Expression, in Cellular and Molecular Biology of Bone, pp. 131-167 (Academic Press, Inc. 1993)). BMP proteins further demonstrate inductive and/or differentiation potentiating activity on a variety of other tissues, including cartilage, tendon, ligament, and neural tissue.
BMPs form part of the large superfamily of TGF-&bgr; (Transforming Growth Factor-&bgr;), a family that includes embryonic morphogens, endocrine function regulators, wide-range regulators, and regulators that are specific for cell proliferation and differentiation. TGF-&bgr; is a prototype of this family. It is a dimer of two identical chains of 112 amino acids held together by disulfide bridges. Each chain is synthesized starting from a longer precursor of about 390 amino acids which has the characteristics of a secretory polypeptide, presenting a hydrophobic sequence in the N-terminal region which should function as a secretory peptide for the secretion of the molecule. The precursor is then processed to its mature form by cleavage by a specific peptidase, which cleaves four basic amino acids immediately prior to the biologically active domain. The precursor region plays an essential role in the correct folding of the mature portion in vivo, to the extent that to date, no mature, biologically active peptides are known to have been produced in
Escherichia coli
by recombinant DNA techniques.
BMPs are known in various animal species from Drosophila to humans, their sequences having been maintained to a great extent throughout evolution. The sequence homology among the various polypeptides is usually high, especially in the C-terminal region. The degree of identity of sequence varies between 25 and 90% among the various family members. In the region of homology, between 7 and 9 cysteines are usually conserved among the members. These are involved in the formation of disulfide bridges between the amino-acid chains. BMPs induce chemotactic, proliferative and differential responses, which culminate in the transient formation of cartilage, followed by the accumulation of bone with hematopoietic marrow.
The activity of BMPs is linked with the demineralized bone matrix, and is extractable with denaturing agents. BMPs have been extracted from various species including humans, monkeys, cattle, rats and mice (Sampath, T. K., Reddi, A. H. 1983, PNAS 80,6591-6595; Urist, M. D. et al. 1979, PNAS 76, 1828-1832). Most studies were carried out on BMPs derived from bovine bone, an abundant and easily obtainable source. In 1988 Wozney et al. (Wozney, J. M. et al., 1988, Science 242, 1528-1534) recovered a biologically active protein fraction of about 30 kD from bovine bone that could be detected by polyacrylamide gel electrophoresis under nonreducing conditions. Following reduction of the disulfide bridges by chemical methods, polypeptides of 30, 18 and 16 kD were obtained (Wang, E. A. et al., 1988, PNAS 85, 9484-9488). This protein fraction was digested with trypsin, and the peptides obtained were separated by HPLC and sequenced. This information was used in the synthesis of DNA probes which were used to identify the bovine genome sequences encoding the various factors. Using portions of these sequences as probes, the human sequences coding for the homologous factors were obtained. Much is now known about these factors (Wozney, J. M. et al., 1990, J. Cell. Sci. Suppl. 13, 149-156; Wozney, J. M., 1989, Progress in Growth Factor Research, 1, 267-280). Some were obtained via recombinant DNA techniques. Some examples of references on growth factors belonging to the above said classes, obtained by recombinant DNA techniques, include EP 409472, WO 9011366, WO 8800205, EP 212474, WO 9105863, and U.S. Pat. No. 4,743,679.
Thus there exists a clear need for identifying and exploiting novel BMP proteins. Although structurally related, such proteins may possess diverse and multifaceted functions in a variety of cell and tissue types. The purified BMP polypeptides of the invention are research tools useful for the identification, characterization and purification of additional proteins involved in inductive or differentiation potentiating activity on a variety of other tissues, including cartilage, tendon, ligament, and/or neural tissue. Furthermore, the identification of new BMP polypeptides permits the development of a range of derivatives, agonists and antagonists at the nucleic acid and protein levels which in turn have applications in the treatment and diagnosis of a range of conditions such as cancer, inflammation, neurological disorders and aberrant cell growth, amongst many other conditions.
SUMMARY OF THE INVENTION
The present invention includes isolated nucleic acid molecules comprising, or alternatively, consisting of a polynucleotide sequence disclosed in the sequence listing and/or contained in a human cDNA plasmid described in Table 1 and deposited with the American Type Culture Collection (ATCC). Fragments, variants, and derivatives of these nucleic acid molecules are also encompassed by the invention. The present invention also includes isolated nucleic acid molecules comprising, or alternatively, consisting of, a polynucleotide encoding BMP polypeptides. The present invention further includes BMP polypeptides encoded by these polynucleotides. Further provided for are amino acid sequences comprising, or alternatively, consisting of, BMP polypeptides as disclosed in the sequence listing and/or encoded by the human cDNA plasmids described in Table 1 and deposited with the ATCC. Antibodies that bind these polypeptides are also encompassed by the invention. Polypeptide fragments, variants, and derivatives of these amino acid sequences are also encompassed by the invention, as are polynucleotides encoding these polypeptides and antibodies that bind these polypeptides.
DETAILED DESCRIPTION
Tables
Table 1 summarizes ATCC Deposits, Deposit dates, and ATCC designation numbers of deposits made with the ATCC in connection with the present application. Table 1 further summarizes the information pertaining to each “Gene No.” described below, including cDNA clone identifier, the type of vector contained in the cDNA clone identifier, the nucleotide sequence identifier number, nucleotides contained in the disclosed sequence, the location of the 5′ nucleotide of the start codon of the disclosed sequence, the amino acid se
Ni Jian
Ruben Steven M.
Shi Yanggu
Andres Janet
Human Genome Sciences Inc.
Human Genome Sciences Inc.
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