Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1998-07-08
2002-07-09
Carlson, Karen Cochrane (Department: 1653)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S04400A, C514S002600, C514S021800, C530S350000, C530S300000
Reexamination Certificate
active
06417168
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to proteins which lack tyrosine kinase activity and dimerize with members of the erbB family of receptors; to nucleic acid molecules that encode such proteins; to pharmaceutical compositions that comprise such nucleic acid molecules in combination with delivery vehicles which facilitate transfer of the nucleic acid molecule to a cell; and to methods of preventing tumors and treating individuals having tumors by administering such pharmaceutical compositions. The present invention relates to compositions which are useful to convert tumor cells that are resistant to radiation- and/or chemical-induced cell death into cells which are sensitive to radiation. The present invention relates to methods of treating individuals who have tumors by administering such compositions in combination with radiation and/or chemotherapy.
BACKGROUND OF THE INVENTION
The erbB family of receptors includes erbB1 (EGFR), erbB2 (p185), erbB3 and erbB4. Ullrich, et al. (1984)
Nature
309, 418-425, which is incorporated herein by reference, describes EGFR. Schechter, A. L., et al. (1984)
Nature
312, 513-516, and Yamamoto, T., et al. (1986)
Nature
319, 230-234, which are each incorporated herein by reference, describe p185neu/erbB2. Kraus, M. H., et al. (1989)
Proc. Natl. Acad. Sci. USA
86, 9193-9197 which is incorporated herein by reference, describes erbB3. Plowman, G. D., (1993)
Proc. Natl. Acad. Sci. USA
90, 1746-1750, which is incorporated herein by reference, describes erbB4.
The rat cellular protooncogene c-neu and its human counterpart c-erbB2 encode 185 kDa transmembrane glycoproteins termed p185. Tyrosine kinase (tk) activity has been linked to expression of the transforming phenotype of oncogenic p185 (Bargmann et al.,
Proc. Natl. Acad. Sci. USA,
1988, 85, 5394; and Stern et al.,
Mol. Cell. Biol.,
1988, 8, 3969, each of which is incorporated herein by reference). Oncogenic neu was initially identified in rat neuroglioblastomas (Schechter et al.,
Nature,
1984, 312, 513, which is incorporated herein by reference) and was found to be activated by a carcinogen-induced point mutation generating a single amino acid substitution, a Val to Glu substitution at position 664, in the transmembrane region of the transforming protein (Bargmann et al.,
Cell,
1986, 45, 649, which is incorporated herein by reference). This alteration results in constitutive activity of its intrinsic kinase and in malignant transformation of cells (Bargmann et al.,
EMBO J,
1988, 7,2043, which is incorporated herein by reference). The activation of the oncogenic p185 protein tyrosine kinase appears to be related to a shift in the molecular equilibrium from monomeric to dimeric forms (Weiner et al.,
Nature,
1989, 339, 230, which is incorporated herein by reference).
Overexpression of c-neu or c-erbB2 to levels 100-fold higher than normal (i.e.,>10
6
receptors/cell) also results in the transformation of NIH3T3 cells (Chazin et al.,
Oncogene,
1992, 7, 1859; DiFiore et al.,
Science,
1987, 237, 178; and DiMarco et al.,
Mol. Cell. Biol.,
1990, 10, 3247, each of which is incorporated herein by reference). However, NIH3T3 cells or NR6 cells which express cellular p185 at the level of 10
5
receptors/cell are not transformed (Hung et al.,
Proc. Natl. Acad. Sci. USA,
1989, 86, 2545; and Kokai et al.,
Cell,
1989, 58, 287, each of which is incorporated herein by reference), unless co-expressed with epidermal growth factor receptor (EGFR), a homologous tyrosine kinase (Kokai et al.,
Cell,
1989, 58, 287, which is incorporated herein by reference). Thus, cellular p185 and oncogenic p185 may both result in the transformation of cells.
Cellular p185 is highly homologous with EGFR (Schechter et al.,
Nature,
1984, 312, 513; and Yamamoto et al.,
Nature,
1986, 319, 230, each of which is incorporated herein by reference) but nonetheless is distinct. Numerous studies indicate that EGFR and cellular p185 are able to interact (Stern et al.,
Mol. Cell. Biol.,
1988, 8, 3969; King et al.,
EMBO J.,
1988, 7, 1647; Kokai et al.,
Proc. Natl. Acad. Sci. USA,
1988, 85, 53 89; and Dougall et al.,
J. Cell. Biochem.,
1993, 53, 61; each of which is incorporated herein by reference). The intermolecular association of EGFR and cellular p185 appear to up-regulate EGFR function (Wada et al.,
Cell,
1990, 61, 1339, which is incorporated herein by reference). In addition, heterodimers which form active kinase complexes both in vivo and in vitro can be detected (Qian et al.,
Proc. Natl. Acad. Sci. USA,
1992, 89, 1330, which is incorporated herein by reference).
Similarly, p185 interactions with other erbB family members have been reported (Carraway et al.,
Cell
1994, 78, 5-8; Alroy et al.,
FEBS Lett.
1997, 410, 83-86; Riese et al.,
Mol. Cell. Biol.
1995, 15, 5770-5776; Tzahar et al.,
EMBO J.
1997, 16, 4938-4950; Surden et al.,
Neuron
1997, 18, 847-855; Pinkas-Kramarski et al.,
Oncogene
1997, 15, 2803-2815; each of which is incorporated herein by reference). Human p185 forms heterodimers with either erbB3 or erbB4 under physiologic conditions, primarily in cardiac muscle and the nervous system, particularly in development.
Cellular p185 proteins are found in adult secretory epithelial cells of the lung, salivary gland, breast, pancreas, ovary, gastrointestinal tract, and skin (Kokai et al.,
Proc. Natl. Acad. Sci. USA,
1987, 84, 8498; Mori et al.,
Lab. Invest.,
1989, 61, 93; and Press et al.,
Oncogene,
1990, 5, 953; each of which is incorporated herein by reference). Recent studies have found that the amplification of c-erbB2 occurs with high frequency in a number of human adenocarcinomas such as gastric (Akiyama et al.,
Science,
1986, 232, 1644, which is incorporated herein by reference), lung (Kern et al.,
Cancer Res.,
1990, 50, 5184, which is incorporated herein by reference) and pancreatic adenocarcinomas (Williams et al.,
Pathobiol.,
1991, 59, 46, which is incorporated herein by reference). It has also been reported that increased c-erbB2 expression in a subset of breast and ovarian carcinomas is linked to a less optimistic clinical prognosis (Slamon et al.,
Science,
1987, 235, 177; and Slamon et al.,
Science,
1989, 244, 707, each of which is incorporated herein by reference). Heterodimeric association of EGFR and p185 has also been detected in human breast cancer cell lines, such as SK-Br-3 (Goldman et al.,
Biochemistry,
1990, 29, 11024, which is incorporated herein by reference), and transfected cells (Spivak-Kroizman et al.,
J Biol. Chem.,
1992, 267, 8056, which is incorporated herein by reference). Additionally, cases of erbB2 and EGFR coexpression in cancers of the breast and prostate have been reported. In addition, heterodimeric association of p185 and erbB3 as well as heterodimeric association of p185 and erbB4 have also been detected in human cancers. Coexpression of erbB2 and erbB3 has been observed in human breast cancers. Coexpression of EGFR, erbB2, and erbB3 has been seen in prostate carcinoma.
Amplification and/or alteration of the EGFr gene is frequently observed in glial tumor progression (Sugawa, et al. (1990)
Proc. Natl. Acad. Sci.
87: 8602-8606; Ekstrand, et al. (1992)
Proc. Natl. Acad. Sci.
89: 4309-4313), particularly in glioblastoma, the most malignant glial tumor (Libermann, et al Supra; Wong, et al. Supra; James, et al. (1988)
Cancer Res.
48: 5546-5551; Cavenee, W. K. (1992)
Cancer
70: 1788-93; Nishikawa, et al., (1994)
Proc. Natl. Acad. Sci.
91: 7727-7731; Schlegel, et al. (1994)
Int J. Cancer
56: 72-77). A significant proportion of these tumors show EGFr amplification with or without gene alteration (Ekstrand, et al Supra; Libermann, et al. Supra; Wong, et al. (1987)
Proc. Natl. Acad. Sci.
84:6899-6903), and this has been correlated with a shorter interval to disease recurrence and poorer survival (Schlegel, et al. Supra).
EGFr amplification can be associated with aberrant EGFr transcripts along with normal EGFr transcripts (Sugawa, et al Supra). Frequent amplification and subsequent structural a
Greene Mark I.
Murali Ramachandran
O'Rourke Donald M.
Park Byeong-Woo
Carlson Karen Cochrane
Robinson Hope A.
The Trustees of the University of Pennsylvania
Woodcock & Washburn LLP
LandOfFree
Compositions and methods of treating tumors does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Compositions and methods of treating tumors, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Compositions and methods of treating tumors will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2839939