Drug – bio-affecting and body treating compositions – Immunoglobulin – antiserum – antibody – or antibody fragment,... – Binds eukaryotic cell or component thereof or substance...
Reexamination Certificate
2001-02-28
2003-05-06
Mosher, Mary E. (Department: 1642)
Drug, bio-affecting and body treating compositions
Immunoglobulin, antiserum, antibody, or antibody fragment,...
Binds eukaryotic cell or component thereof or substance...
C435S455000
Reexamination Certificate
active
06558668
ABSTRACT:
TECHNICAL FIELD OF THE INVENTION
The present invention relates generally to detection and therapy of cancer of the nervous system. The invention is more specifically related to granulin and granulin-related molecules as therapeutic and diagnostic targets. Granulin antibodies and antisense nucleotides can be used in vaccines and pharmaceutical compositions for the treatment of cancers of the central nervous system, as well as in methods of detecting and assessing the malignancy of such cancers. The invention further provides methods for identifying molecules useful in the treatment and detection of neural cancers.
BACKGROUND OF THE INVENTION
Cancer and infectious disease are significant health problems throughout the world. Although advances have been made in detection and therapy of these diseases, no vaccine or other universally successful method for prevention or treatment is currently available. Current therapies, which are generally based on a combination of chemotherapy or surgery and radiation, continue to prove inadequate in many patients.
Cancer is the result of cumulative multiple genetic mutations, which result in the activation of oncogenes and/or the inactivation of tumor suppressor genes. It is the differential expression of these critical genes and their downstream effectors that enables cells to override growth controls and undergo carcinogenesis (1, 2). The pathological changes that arise in cancer, whether caused by a single gene mutation or multiple genetic alterations, are essentially driven by changes in gene expression (1, 2). In the malignant progression of astrocytic cancers, it has been shown that accumulation of multiple genetic lesions underlies the neoplastic process. These lesions include mutations of the genes p53, p16, RB, and PTEN, as well as amplification of CDK4 and EGFR (3, 4). Although these known genetic abnormalities have been well-documented in the formation of the most malignant brain tumor, glioblastoma, recent insight into the extent of gene expression differences underlying malignancy reveals that hundreds of gene transcripts may be expressed at significantly different levels between normal and neoplastic cells (5). Therefore, there is considerable room for the identification of novel genes that are differentially expressed in brain tumor cells to further our understanding of the complex molecular basis of these neurological cancers. Furthermore, this endeavor has direct clinical relevance if combined with the development of innovative rational therapies that specifically target these differentially expressed gene products.
A variety of methods are currently employed to isolate genes associated with particular differential phenotypes. Subtractive hybridization (6), differential display (DD) (7-10), representational difference analysis RDA) (11-14), serial analysis of gene expression (SAGE) (5, 15), and suppression subtractive hybridization (SSH) (16, 17) all allow for the cloning and identification of differentially expressed sequences. While all these techniques identify tissue-enriched mRNAs, none select for tissue-specific proteins. There remains a need for a differential screening technique that provides actual confirmation of the presence of a protein product, not just the capacity to synthesize a protein. In addition, there is a need for proteins with antigenic determinants that may be recognized by the immune system.
SUMMARY OF THE INVENTION
The invention meets these needs by providing methods for the treatment and detection of cancers of the nervous system. In one embodiment, the invention provides a method for inhibiting proliferation of neural cells. The neural cells can be tumor cells, glial cells, neuronal cells, and cells of the central or peripheral nervous systems. Examples of tumor cells include, but are not limited to, glioblastoma, astrocytoma, oligodendroglioma, ependymoma, choroid plexus papilloma, medulloblastoma, Schwannoma, neurofibroma, neurilemmoma cells, as well as neuronal, meningial, pineal or pituitary tumor cells. The method comprises contacting a neural cell with a molecule that disrupts the biological activity of a granulin molecule. In one embodiment, the molecule is an antibody directed against a granulin peptide. In other embodiments, the molecule is an antisense nucleotide directed against a granulin nucleic acid molecule, or a vaccine comprising a granulin peptide or a polynucleotide encoding a granulin peptide. The invention further provides a method for treating cancer of the nervous system in a subject comprising administering to the subject a molecule that disrupts the biological activity of a granulin molecule.
The invention additionally provides a method for detecting cancer in a neural tissue comprising contacting the tissue with a molecule that recognizes and binds a granulin molecule. The molecule can be, for example, an antibody directed against a granulin peptide, or an antisense nucleotide directed against a granulin nucleic acid molecule.
The invention provides a method for identifying a molecule that inhibits proliferation of neural cancer cells. The method comprises contacting a candidate molecule with a granulin molecule and determining whether the candidate molecule disrupts the biological activity of the granulin molecule. Disruption of the biological activity of the granulin molecule is indicative of a molecule that inhibits proliferation of neural cancer cells.
The invention provides a method for identifying differentially expressed gene products that are translated from mRNA species, using antibody-based screening of a cDNA expression library. This method, termed differential immuno-absorption (DIA), can be coupled to cDNA microarray hybridization and used in the identification of genes that play a role in the malignant progression of cancer. The method for identifying proteins differentially expressed in a target tissue comprises linking a target tissue homogenate to a first substrate, and passing an antiserum raised against the target tissue homogenate over the first substrate to elute antibodies that bind the target tissue. The method further comprises linking a control tissue homogenate to a second substrate, and passing the eluted antibodies over the second substrate to obtain target antibodies that bind proteins present in the target tissue and not proteins present in the control tissue. The target antibodies so obtained are then used to screen a nucleic acid expression library containing proteins expressed in the target tissue. Proteins bound by the target antibodies are identified as differentially expressed in the target tissue. The invention thereby provides novel proteins, antibodies and nucleotides identified by this method.
In addition, the invention provides a method of identifying a protein that is differentially expressed in a neural cancer comprising screening a first library of cells associated with neural cancer and a second library of non-tumor neural cells with a nucleic acid molecule encoding a candidate protein. Increased hybridization of the nucleic acid molecule with the first library relative to the second library is indicative of a protein that is differentially expressed in neural cancer. In one embodiment, the screening comprises a cDNA microarray assay.
REFERENCES:
patent: 5476839 (1995-12-01), Scott et al.
Bhandari, et al., 1993, Endocrinology, 133(6):2682-2689.*
He, et al., 1999, Cancer Reseach, 59:3222-3229.*
Bateman, Andrew et al., “Granulins, A Novel Class of Peptide From Leukocytes”,Biochemical and Biophysical Research Communications, vol. 173, No. 3, Dec. 31, 1990, pp. 1161-1168.
Bhandari, Vijay et al., “The Complementary Deoxyribonucleic Acid Sequence, Tissue Distribution, and Cellular Localization of the Rat Granulin Precursor”,Endocrinology, vol. 133, No. 6, 1993, pp. 2682-2689.
Culouscou, Jean-Michel et al., “Biochemical Analysis of the Epithelin Receptor,”The Journal of Biological Chemistry, vol. 268, No. 14, May 15, 1993, pp. 10458-10462.
Dietzmann, Knut et al., “Coexpression of epidermal growth factor receptor protein and c-erbB-2 o
Gates & Cooper LLP
Mosher Mary E.
The Regents of the University of California
Yu Misook
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