Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1995-06-06
2003-07-01
Kemmerer, Elizabeth (Department: 1646)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S002600, C530S350000
Reexamination Certificate
active
06586395
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to novel proteins with apoptosis-modulating activity, recombinant DNA encoding the proteins, compositions containing the proteins and methods of use thereof.
BACKGROUND OF THE INVENTION
Apoptosis is a normal physiologic process that leads to individual cell death. This process of programmed cell death is involved in a variety of normal and pathogenic biological events and can be induced by a number of unrelated stimuli. Changes in the biological regulation of apoptosis also occur during aging and are responsible for many of the conditions and diseases related to aging. Recent studies of apoptosis have implied that a common metabolic pathway leading to cell death may be initiated by a wide variety of signals, including hormones, serum growth factor deprivation, chemotherapeutic agents, ionizing radiation and infection by human immunodeficiency virus (HIV). Wyllie (1980) Nature, 284:555-556; Kanter et al. (1984)
Biochem. Biophys. Res. Commun.
118:392-399; Duke and Cohen (1986) Lymphokine Res. 5:289-299; Tomei et al. (1988)
Biochem. Biophys. Res. Commun.
155:324-331; Kruman et al. (1991)
J. Cell. Physiol.
148:267-273; Ameisen and Capron (1991)
Immunology Today
12:102; and Sheppard and Ascher (1992)
J. AIDS
5:143. Agents that modulate the biological control of apoptosis thus have therapeutic utility in a wide variety of conditions.
Apoptotic cell death is characterized by cellular shrinkage, chromatin condensation, cytoplasmic blebbing, increased membrane permeability and interchromosomal DNA cleavage. Kerr et al. (1992) FASEB J. 6:2450; and Cohen and Duke (1992)
Ann. Rev. Immunol.
10:267. The blebs, small, membrane-encapsulated spheres that pinch off of the surface of apoptotic cells, may continue to produce superoxide radicals which damage surrounding cell tissue and may be involved in inflammatory processes.
Bcl-2 was discovered at the common chromosomal translocation site t(14:18) in follicular lymphomas and results in aberrant over-expression of bcl-2. Tsujimoto et al. (1984)
Science
226:1097-1099; and Cleary et al. (1986)
Cell
47:19-28. The normal function of bcl-2 is the prevention of apoptosis; unregulated expression of bcl-2 in B cells is thought to lead to increased numbers of proliferating B cells which may be a critical factor in the development of lymphoma. McDonnell and Korsmeyer (1991)
Nature
349:254-256; and, for review see, Edgington (1993)
Bio/Tech.
11:787-792. Bcl-2 is also capable of blocking of &ggr; irradiation-induced cell death. Sentman et al. (1991)
Cell
67:879-888; and Strassen (1991)
Cell
67:889-899. It is now known that bcl-2 inhibits most types of apoptotic cell death and is thought to function by regulating an antioxidant pathway at sites of free radical generation. Hockenbery et al. (1993)
Cell
75:241-251.
While apoptosis is a normal cellular event, it can also be induced by pathological conditions and a variety of injuries. Apoptosis is involved in a wide variety of conditions including but not limited to, cardiovascular disease, cancer regression, immunoregulation, viral diseases, anemia, neurological disorders, gastrointestinal disorders, including but not limited to, diarrhea and dysentery, diabetes, hair loss, rejection of organ transplants, prostate hypertrophy, obesity, ocular disorders, stress and aging.
Bcl-2 belongs to a family of proteins some of which have been cloned and sequenced. Williams and Smith (1993)
Cell
74:777-779. All references cited herein, both supra and infra, are hereby incorporated by reference herein.
SUMMARY OF THE INVENTION
Substantially purified DNA encoding novel bcl-2 homologs, termed cdn-1, cdn-2 and cdn-3, as well as recombinant cells and transgenic animals expressing the cdn-1 and cdn-2 genes are provided. The substantially purified CDN-1 and CDN-2 proteins and compositions thereof are also provided. Diagnostic and therapeutic methods utilizing the DNA and proteins are also provided. Methods of screening for pharmaceutical agents that stimulate, as well as pharmaceutical agents that inhibit cdn-1 and cdn-2 activity levels are also provided.
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Kanter et al., “Epidermal growth factor and tumor promoters prevent DNA fragmentation by different mechanisms”Biochem. Biophys. Res. Commun.(1984) 118:392-399.
Duke et al., “IL-2 addiction: Withdrawal of growth factor activates a suicide program in dependent T cells”Lymphokine Res.(1986) 5:289-299.
Tomei et al., “Inhibition of radiation-induced apoptosis in vitro by tumor promoters”Biochem. Biophys. Res. Commun.(1988) 155:324-331.
Kruman et al., “Apoptosis of murine BW 5147 thymoma cells induced by dexamethasone and &ggr;-irradiation”J. Cell. Physiol.(1991) 148:267-273.
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Tsujimoto et al., “Cloning of the chromosome breakpoint of neoplastic B cells with the t(14;18) chromosome translocation”Science(1984) 226:1097-1099.
Cleary et al., “Cloning and structural analysis of cDNAs for bcl-2 and a hybrid bcl-2/immunoglobulin transcript resulting from the t(14;18) translocation”Cell(1986) 47:19-28.
McDonnell et al., “Progression from lymphoid hyperplasia to high-grade malignant lymphoma in mice transgenic for the t(14;18)”Nature(1991) 349:254-256.
Edgington, “Looking death in the eye: Apoptosis and cancer research”Biotechnol.(1993) 11:787-792.
Sentman et al., “bcl-2 inhibits multiple forms of apoptosis but not negative selection in thymocytes”Cell(1991) 67:879-888.
Strasser, “bcl-2 transgene inhibits T cell death and perturbs thymic self-cencorship”Cell(1991) 67:889-899.
Hockenbery et al., “Bcl-2 functions in an antioxidant pathway to prevent apoptosis”Cell(1993) 75:241-251.
Williams et al., “Molecular regulation of apoptosis: genetic controls on cell death”Cell(1993) 74:777-779.
Zhu et al., “Systemic gene expression after intravenous DNA delivery into adult mice”Science(1993) 261:209-211.
Veis et al., “Bcl-2-deficient mice demonstrate fulminant lymphoid apoptosis, polycystic kidneys, and hypopigmented hair”Cell(1993) 75:229-240.
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Barr Philip J.
Kiefer Michael C.
Kemmerer Elizabeth
Sheridan & Ross P.C.
Tanox, Inc.
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