Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Using tissue cell culture to make a protein or polypeptide
Reexamination Certificate
2000-05-09
2003-11-18
Paras, Peter (Department: 1632)
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Using tissue cell culture to make a protein or polypeptide
C435S320100, C435S325000, C536S023100, C536S023500
Reexamination Certificate
active
06649377
ABSTRACT:
INTRODUCTION
1. Field of the Invention
The field of the invention is proteases, particularly proteases that cleave aggrecan.
2. Background of the Invention
Cartilage matrix structure as dry weight of the tissue is made up of 70% collagen and 20-30% proteoglycans. The proteoglycan component confers mechanical flexibility to load bearing tissues and imparts viscoelastic properties to cartilage. Its loss leads to rapid structural damage as is seen most frequently in arthritic joint diseases and joint injury.
Aggrecan is a major cartilage proteoglycan. Aggrecan is a large protein of 210 kDa and has three globular domains: G1, G2, and G3. The G1 and G2 domains of the protein are closer to the amino terminus of the protein and their intervening interglobular domain has sites that are proteolytically sensitive. The region between G2 and G3 is heavily glycosylated and connected to oligosaccharides and glycosaminoglycans (GAGs) to form the mature proteoglycan. In arthritic cartilage, core protein fragments of 55 kDa are observed and believed to be the result of cleavage of the core protein in the G1 and G2 interglobular domain between asparagine 341 and phenylalanine 342. This cleavage can be made by many matrix metalloproteinases e.g. MMP-1, -2, -3, -7, -8, -9, and -13. In addition, 60 kDa aggrecan fragments with a —COOH terminus of glutamic acid are also identified and are indicative of a cleavage site between glutamic acid 373 and alanine 374. Matrix metalloproteinase are unable to cleave at this site. The unique endopeptidase activity responsible for this cleavage has been termed “aggrecanase.”
The G1 domain of the core protein forms a stable ternary complex by binding to hyaluronic acid and link proteins in the matrix. Any enzymatic cleavage in this region destabilizes the cartilage matrix structure, leads to the loss of the major proteoglycan aggrecan and exposes type II collagen to collagenases, causing cartilage loss and the consequent development of joint disease. Since a variety of anti-arthritic drugs do not target aggrecanase and are incapable of blocking cleavage of aggrecan, the aggrecanase site plays a key role in the proteolytic degradation of aggrecan.
As such, aggrecanase is considered to be an important drug target for arthritis. Aggrecan fragments released into the synovial fluid are the primary detectable events in the development of rheumatoid- and osteo-arthritis. Search for this protease has been intense. Despite these intense discovery efforts, identification of human aggrecanase has remained elusive.
As such, there is much interest in the identification of human aggrecanase, as well as the gene encoding this activity.
Relevant Literature
U.S. Patents of interest include: U.S. Pat. Nos. 5,872,209 and 5,427,954. PCT publications of interest include: WO 99/09000; WO 98/55643; WO 98/51665; and WO 97/18207.
Other references of interest include: Vankemmelbeke et al., “Coincubation of bovine synovial or capsular tissue with cartilage generates a soluble ‘Aggrecanase’ activity,” Biochem Biophys Res Commun (Feb. 24, 1999) 255(3):686-91; Arner et al., “Generation and Characterization of Aggrecanase. A soluble, cartilage-derived aggrecan-degrading activity,” J Biol Chem (Mar. 5, 1999) 274(10):6594-6601; Billington et al., “An aggrecan-degrading activity associated with chondrocyte membranes,” Biochem J (Nov. 15, 1998) 336 (Pt 1):207-12; Hughes et al., “Differential expression of aggrecanase and matrix metalloproteinase activity in chondrocytes isolated from bovine and porcine articular cartilage,” J Biol Chem (Nov. 13, 1998) 273(46):30576-82; Sandy et al., “Chondrocyte-mediated catabolism of aggrecan: aggrecanase-dependent cleavage induced by interleukin-1 or retinoic acid can be inhibited by glucosamine,” Biochem J (Oct. 1, 1998) 335 (Pt 1):59-66; Arner et al., “Cytokine-induced cartilage proteoglycan degradation is mediated by aggrecanase,” Osteoarthritis Cartilage (May 1998) 6(3):214-28; Ilic et al., “Characterization of aggrecan retained and lost from the extracellular matrix of articular cartilage. Involvement of carboxyl-terminal processing in the catabolism of aggrecan,” J Biol Chem (Jul. 10, 1998) 273(28):17451-8; and Buttner et al., “Membrane type 1 matrix metalloproteinase (MT1-MMP) cleaves the recombinant aggrecan substrate rAgg1mut at the ‘aggrecanase’ and the MMP sites. Characterization of MT1-MMP catabolic activities on the interglobular domain of aggrecan,” Biochem J (Jul. 1, 1998)333 (Pt 1):159-65.
SUMMARY OF THE INVENTION
Human aggrecanase and polypeptides related thereto, as well as nucleic acid compositions encoding the same, are provided. The subject polypeptide and nucleic acid compositions find use in a variety of applications, including research, diagnostic, and therapeutic agent screening applications, as well as in treatment therapies. Also provided are methods of treating disease conditions associated with aggrecanase activity, e.g. conditions characterized by the presence of aggrecan cleavage products, such as rheumatoid- and osteo-arthritis.
REFERENCES:
patent: 5427954 (1995-06-01), Sandy et al.
patent: 5872209 (1999-02-01), Bartnik et al.
patent: 0 874 050 (1998-10-01), None
patent: WO 97/18207 (1997-05-01), None
patent: WO 98/55643 (1998-10-01), None
patent: WO 98/51665 (1998-11-01), None
patent: WO 9856804 (1998-12-01), None
patent: WO 99/09000 (1999-02-01), None
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Arner et al. (1998). “Cytokine-induced cartilage proteoglycan degradation is mediated by aggrecanase”Osteoarthritis Cartilage, vol. 6(3): 214-228.
Arner et al. (1999). “Generation and Characterization of Aggrecanase. A soluble, cartilage-derived aggrecan-degrading activity”J. Biol. Chem., vol. 274(10): 6594-6601.
Billington et al. (1998). “An aggrecan-degrading activity associated with chondrocyte membranes”Biochem J., vol. 336(Pt 1): 207-212.
Buttner et al. (1998). “Membrane type 1 matrix metalloproteinase (MT1-MMP) cleaves the recombinant aggrecan substrate rAgg1mut at the ‘aggrecanase’ and the MMP sites. Characterization of MT1-MMP catabolic activities on the interglobular domain of aggracan”Biochem J., vol. 333(Pt 1):159-165.
Hughes et al. (1998). “Differential expression of aggrecanase and matrix metalloproteinase activity in chondrocytes isolated from bovine and porcine articular cartilage”J. Biol. Chem., vol. 273(46): 30576-30582.
Ilic et al. (1998). “Characterization of aggrecan retained and lost from the extracellular matrix of atricular cartilage. Involvement of carboxyl-terminal processing in the catabolism of aggrecan”J. Biol. Chem., vol. 273(28): 1751-17458.
Vankemmelbeke et al. (1999). “Coincubation of bovine synovial or
Allard John David
Ileller Renu Anand
Klonowski Paul
VanWart Harold Edgar
Hall Robert C.
Paras Peter
Peries Rohan
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