Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving antigen-antibody binding – specific binding protein...
Reexamination Certificate
2000-08-23
2003-04-29
Spector, Lorraine (Department: 1646)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving antigen-antibody binding, specific binding protein...
C424S143100, C436S501000, C530S350000, C435S069100
Reexamination Certificate
active
06555322
ABSTRACT:
FIELD OF THE INVENTION
This invention relates generally to connective tissue growth factor (CTGF) and to receptors thereof.
BACKGROUND OF THE INVENTION
Growth factors are a class of secreted polypeptides that stimulate target cells to proliferate, differentiate, and organize developing tissues. Typically, a growth factor's activity is dependent on its ability to bind to specific receptors, thereby stimulating a signaling event within the cell. Examples of some well-studied growth factors include platelet-derived growth factor (PDGF), insulin-like growth factor (IGF-I), transforming growth factor beta (TGF-&bgr;), transforming growth factor alpha (TGF-&agr;), epidermal growth factor (EGF), and fibroblast growth factor (FGF). Efforts to characterize the receptors corresponding to these growth factors are ongoing and have met with varying degrees of success.
Low Density Lipoprotein Receptor-Related Protein (LRP)
A low density lipoprotein receptor-related protein (LRP) has been reported previously in the literature. (See, e.g., Kristensen et al., 1990,
FEBS Lett.
276:151-155.) This protein is also known as the &agr;2-macroglobulin receptor. (See, e.g., Strickland, D. K. et al. (1990)
J. Biol. Chem.
265:17401-17404; and Herz et al. (1988)
EMBO J.
7:4119-4127.) LRP is encoded by a protein sequence of about 4544 amino acids in length (human mRNA for LDL-receptor related protein, GenBank Accession No. X13916; human LDL-receptor related precursor protein, GenBank Accession No. CAA32112; Herz et al., id; Myklebost et al. (1989)
Genomics,
5:65-69, each of which references is incorporated by reference herein in its entirety.) The mature protein consists of a 4419 amino acid ectodomain, a twenty-five amino acid transmembrane domain and a 100 amino acid intracellular domain. As reported in the literature, the ectodomain contains a furin cleavage site which is processed during transport from a late Golgi compartment, producing a 510 kDa &agr; subunit that is noncovalently associated with an 85 kDa &bgr; subunit anchored to the membrane through the transmembrane sequence. (See, e.g., Strickland, D. K. et al., supra.)
The &agr;2-macroglobulin receptor has been widely studied and a number of subdomains have been identified within the &agr; and &bgr; subunits. These subdomains include twenty-two EGF-like domains, of which two such domains are Ca
2+
binding, eight are EGF precursor spacer regions, and thirty-one are LDL receptor ligand-binding repeats. Additionally, thirty-one copies of complement-type repeats arranged in four clusters spanning the receptor sequence have been identified. It has been reported that the receptor protein sequence is highly conserved (more than 97% homology) between the human and murine systems. (See, e.g., Van Leuven et al. (1993)
Biochim. Biophys. Acta.,
1173:71-74.)
The cytoplasmic domain of the &agr;2-macroglobulin receptor has no homology with known protein kinase domains. Genetic analysis of the protein function by disruption of the &agr;2-macroglobulin receptor gene in order to create &agr;2-macroglobulin receptor-deficient mice has indicated that the protein is essential during development. A number of ligands have been reported to bind to the &agr;2-macroglobulin receptor, including &agr;2 macroglobulin, activated; apolipoprotein E (apo E); low density lipoprotein, apo E enriched; Pseudomonas exotoxin A; receptor-associated protein (RAP); plasminogen activator inhibitor (PAI) I; thrombin-PAI complex; tissue plasminogen activator (tPA); urokinase plasminogen activator (uPA); thrombospondin I; lipoprotein lipase; hepatic lipase; lactoferrin; pregnancy zone protein; &agr;1-inhibitor-3; &agr;1-inhibitor-3/&agr;1 microglobulin complex; &bgr; amyeloid precursor protein; suramin; and vitellogenin. The adaptor molecule mDab1 has been shown to bind to the cytoplasmic tail of LRP in neuronal cells. (See, e.g., Le, N., and M. A. Simon (1998)
Mol. Cell. Bio.
18:4844-54; and Trommsdorff, M. et al. (1998)
J. Biol. Chem.
273:33556-60.) When tyrosine-phosphorylated, mDab1 binds non-receptor tyrosine kinases, such as src, fyn, and abl. (See, e.g., Howell, B. W. et al. (1997)
Embo Journal.
16:121-32.) Another member of this family, Dab2, is expressed more widely, and has recently been shown to bind Grb2, an adaptor protein which couples tyrosine kinase receptors to Sos which is part of Ras signaling cascade. (See, e.,g., Xu, X.X. et al. (1998)
Oncogene.
16:1561-9; and Fazili, Z. et al. (1999)
Oncogene.
18:3104-13.) Recent findings indicate broad physiological functions for LRP and other members of the LDL receptor family, suggesting that interfering with any associated signaling cascade would provide methods of modulating activities associated with LRP. (Gotthardt et al. (2000) J. Biol. Chem., 275:25616-25624.)
Connective Tissue Growth Factor (CTGF)
Connective tissue growth factor (CTGF) has been reported and described previously. (See, e.g., U.S. Pat. No. 5,408,040; Bradham et al., 1991,
J. Cell Biology
114:1285-1294.) CTGF is characterized as a polypeptide that exists as a monomer with a molecular weight of approximately 36 to 38 kD. CTGF has been shown to be one of seven cysteine-rich secreted proteins belonging to the CCN family, which includes CTGF, cyr-61, and nov. (See, e.g., Oemar et al. (1997)
Arteriosclerosis, Thrombosis and Vascular Biology
17(8):1483-1489.) CTGF is the product of an immediate early response gene that codes for a protein consisting of four modules and one signal peptide. (See, e.g., Oemar et al. (1997), supra.) The four modules include an insulin-like growth factor (IGF) binding domain, a von Willebrand factor type C repeat most likely involved in oligomerization, a thrombospondin type 1 repeat believed to be involved in binding to the ECM, and a C-terminal module which may be involved in receptor binding. Recent reports suggest that certain fragments of the whole CTGF protein possess CTGF activity. (See, e.g., Brigstock et al. (1997)
J. Bio. Chem.
272(32):20275-282; International Publication No. WO 00/047114; and International Publication No. WO 00/047130, each of which references is incorporated herein by reference in its entirety.) Human, mouse, and rat CTGF are highly conserved, with greater than 90% amino acid homology (Bork (1993)
FEBS Lett.
327:125-130), and a molecular weight of about 38 kDa (Bradham et al. (1991)
J Cell Biol.
114:1285-1294). It was recently shown that the promoter of the CTGF gene contains a novel TGF-&bgr; responsive element. (Grotendorst et al. (1996)
Cell Growth
&
Differentiation
7:469-480.)
CTGF plays a role in the production of collagen and other extracellular matrix proteins. CTGF has mitogenic and chemotactic activity, and its effects have been observed in connective tissue cells, e.g., fibroblasts, as well as in a number of other cell types. The ability of CTGF to effect cell proliferation and motility have led to its implication in a variety of disorders associated with excess growth and increased deposition of extracellular matrix, including disorders such as fibrosis, cancer, angiogenesis, and other proliferative disorders. For example, CTGF appears to be a causal factor in skin fibrosis and in atherosclerosis. (See, e.g., Igarashi et al. (1995)
The Journal of Investigative Dermatology
105:280-284; Igarashi et al. (1996)
The Journal of Investigative Dermatology
106:729-733; Oemar et al. (1997)
Circulation
95:831-839).
CTGF is therefore an attractive target for the development of therapeutic agents useful in the treatment of a number of connective tissue diseases and proliferative disorders. The desirability of modulating, and, preferably, inhibiting, CTGF activity as a method for treating fibrotic diseases and disorders has been previously described. (See, e.g., PCT Application No. PCT/US96/08140.) Various inhibitors of CTGF activity, including peptides, antibodies to CTGF, and the like, have been described and are reported to have potential therapeutic effectiveness in the treatment of fibrotic disease. (Id.) It has also been determined that CTGF is capable of
Carmichael David F.
Nesbitt James E.
Segarini Patricia R.
FibroGen Inc.
FibroGen, Inc.
Jiang Dong
Spector Lorraine
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