Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Recombinant dna technique included in method of making a...
Reexamination Certificate
1998-10-29
2002-05-14
Saoud, Christine J. (Department: 1647)
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Recombinant dna technique included in method of making a...
C435S069400, C435S325000, C435S358000, C435S243000, C435S252330, C435S255100, C435S320100, C536S023100, C536S023500, C536S023510
Reexamination Certificate
active
06387657
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates generally to the identification and isolation of novel DNA and to the recombinant production of novel polypeptides having homology to connective tissue growth factor, designated herein as Wnt-1-Induced Secreted Proteins (WISPs).
BACKGROUND OF THE INVENTION
Malignant tumors (cancers) are the second leading cause of death in the United States, after heart disease. Boring et al.,
CA Cancer J. Clin.,
43: 7 (1993).
Cancer is characterized by the increase in the number of abnormal, or neoplastic, cells derived from a normal tissue which proliferate to form a tumor mass, the invasion of adjacent tissues by these neoplastic tumor cells, and the generation of malignant cells which eventually spread via the blood or lymphatic system to regional lymph nodes and to distant sites (metastasis). In a cancerous state a cell proliferates under conditions in which normal cells would not grow. Cancer manifests itself in a wide variety of forms, characterized by different degrees of invasiveness and aggressiveness.
Alteration of gene expression is intimately related to the uncontrolled cell growth and de-differentiation which are a common feature of all cancers. The genomes of certain well studied tumors have been found to show decreased expression of recessive genes, usually referred to as tumor suppression genes, which would normally function to prevent malignant cell growth, and/or overexpression of certain dominant genes, such as oncogenes, that act to promote malignant growth. Each of these genetic changes appears to be responsible for importing some of the traits that, in aggregate, represent the full neoplastic phenotype. Hunter,
Cell,
64: 1129 (1991); Bishop,
Cell,
64: 235-248 (1991).
A well-known mechanism of gene (e.g., oncogene) overexpression in cancer cells is gene amplification. This is a process where in the chromosome of the ancestral cell multiple copies of a particular gene are produced. The process involves unscheduled replication of the region of chromosome comprising the gene, followed by recombination of the replicated segments back into the chromosome. Alitalo et al.,
Adv. Cancer Res.,
47: 235-281 (1986). It is believed that the overexpression of the gene parallels gene amplification, i.e., is proportionate to the number of copies made.
Proto-oncogenes that encode growth factors and growth factor receptors have been identified to play important roles in the pathogenesis of various human malignancies, including breast cancer. For example, it has been found that the human ErbB2 gene (erbB2, also known as her2, or c-erbB-2), which encodes a 185-kd transmembrane glycoprotein receptor (p185
HER2
; HER2) related to the epidermal growth factor receptor (EGFR), is overexpressed in about 25% to 30% of human breast cancer. Slamon et al.,
Science,
235:177-182 (1987); Slamon et al.,
Science,
244:707-712 (1989). It has been reported that gene amplification of a protooncogen is an event typically involved in the more malignant forms of cancer, and could act as a predictor of clinical outcome. Schwab et al.,
Genes Chromosomes Cancer,
1: 181-193 (1990); Alitalo et al., supra. Thus, erbB2 overexpression is commonly regarded as a predictor of a poor prognosis, especially in patients with primary disease that involves axillary lymph nodes (Slamon et al., (1987) and (1989), supra; Ravdin and Chamness,
Gene,
159:19-27 (1995); and Hynes and Stern,
Biochim Biophys Acta,
1198:165-184 (1994)), and has been linked to sensitivity and/or resistance to hormone therapy and chemotherapeutic regimens, including CMF (cyclophosphamide, methotrexate, and fluoruracil) and anthracyclines. Baselga et al.,
Oncology,
11(3 Suppl 1):43-48 (1997). However, despite the association of erbB2 overexpression with poor prognosis, the odds of HER2-positive patients responding clinically to treatment with taxanes were greater than three times those of HER2-negative patients. Baselga et al., supra. A recombinant humanized anti-ErbB2 (anti-HER2) monoclonal antibody (a humanized version of the murine anti-ErbB2 antibody 4D5, referred to as rhuMAb HER2 or HERCEPTIN®) has been clinically active in patients with ErbB2-overexpressing metastatic breast cancers that had received extensive prior anticancer therapy. Baselga et al.,
J. Clin. Oncol.,
14:737-744 (1996).
Cytokines have been implicated in the pathogenesis of a number of brain diseases in which neurological dysfunction has been attributed to a change in amino acid neurotransmitter metabolism. In particular, members of the transforming growth factor-&bgr; (TGF-&bgr;) family have been implicated. TGF peptides are small polypeptides that were first identified by their ability to induce proliferation and transformation in noncancerous cells in culture. Although initially defined as a growth factor, TGF-&bgr; also inhibits proliferation of epithelial, endothelial, lymphoid, and hematopoietic cells. This cytokine is thought to play an important role in regulating the duration of the inflammatory response, allowing the healing process to proceed. It is also a potent immunomodulator, which has many pleiotrophic effects, including regulating many other cytokines.
The TGF-&bgr; superfamily includes bone morphogenetic proteins (BMP-2, BMP-4, BMP-5, BMP-6, BMP-7), activins A & B, decapentaplegic (dpp), 60A, OP-2, dorsalin, growth differentiation factors (GDFs), nodal, MIS, Inhibin-&agr;, TGF-&bgr;1, TGF-&bgr;2, TGF-&bgr;3, TGF-&bgr;5, and glial-derived neurotrophic factor (GDNF). Atrisano, et al.,
J. Biochemica et Biophysica Acta,
1222:71-80 (1994). Of particular interest are the growth differentiation factors, for as their name implies, these factors are implicated in the differentiation of cells.
Connective tissue growth factor (CTGF) is a growth factor induced in fibroblasts by many factors, including TGF-&bgr;, and is essential for the ability of TGF-&bgr; to induce anchorage-independent growth (AIG), a property of transformed cells. CTGF was discovered in an attempt to identify the type of platelet-derived growth factor (PDGF) dimers present in the growth media of cultured endothelial cells, and is related immunologically and biologically to PDGF. See U.S. Pat. No. 5,408,040. CTGF also is mitogenic and chemotactic for cells, and hence growth factors in this family are believed to play a role in the normal development, growth, and repair of human tissue.
Seven proteins related to CTGF, including the chicken ortholog for Cyr61, CEF10, human, mouse, and Xenopus laevis CTGF, and human, chicken, and Xenopus laevis Nov have been isolated, cloned, sequenced, and characterized as belonging to the CTGF gene family. Oemar and Luescher,
Arterioscler. Thromb. Vasc. Biol.,
17: 1483-1489 (1997). The gene encoding Cyr61 has been found to promote angiogenesis, tumor growth, and vascularization. Babic et al.,
Proc. Natl. Acad. Sci. USA,
95: 6355-6360 (1998). The nov gene is expressed in the kidney essentially at the embryonic stage, and alterations of nov expression, relative to the normal kidney, have been detected in both avian nephroblastomas and human Wilms' tumors. Martinerie et al.,
Oncoaene,
9: 2729-2732 (1994). Wt1 downregulates human nov expression, which downregulation might represent a key element in normal and tumoral nephrogenesis. Martinerie et al.,
Oncogene,
12: 1479-1492 (1996). It has recently been proposed that the CTGF, nov, and cyr61 genes, which encode secreted proteins that contain conserved sequences and IGFBP motifs in their N-termini and bind IGFs with low affinity, represent more members of the IGFBP superfamily, along with the low-affinity mac25/IGFBP-7 (Yamanaka et al.,
J. Biol. Chem.,
272: 30729-30734 (1997)) and the high-affinity IGFBPs 1-6. CTGF under this proposal would be designated IGFBP-8. Kim et al.,
Proc. Natl. Acad. Sci. USA,
94: 12981-12986 (1997).
Recently, a protein was found in the mouse designated ELM1 that is expressed in low metastatic cells. Hashimoto et al.,
J. Exp. Med.,
187: 289-296 (1998). The elm1 gene, a mouse homologue of WISP-1 disclosed below, is a
Botstein David A.
Cohen Robert L.
Goddard Audrey D.
Gurney Austin L.
Hillan Kenneth J.
Genentech Inc.
Marschang Diane L.
Saoud Christine J.
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