Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Reexamination Certificate
1996-08-15
2002-04-02
Wang, Andrew (Department: 1635)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
C435S091100, C435S325000, C435S375000, C536S024500
Reexamination Certificate
active
06365345
ABSTRACT:
The present invention is related to an antisense-nucleic acid or effective derivatives thereof hybridizing with an area of the messenger RNA (mRNA) or the DNA, encoding the p185
erbB-2
receptor (also termed c-erbB-2, HER2 or neu), a pharmaceutical composition, comprising an antisense nucleic acid or effective derivatives thereof hybridizing with an area of the messenger RNA (mRNA) or the DNA, encoding the c-erbB-2 receptor as well as the use of said antisense nucleic acids and derivatives thereof for the manufacturing of a pharmaceutical composition for the treatment of neoplasms and/or immune diseases and/or diseases involving pathological angiogenesis.
ErbB-2 is a putative growth factor receptor with an intracellular tyrosine kinase activity that is amplified and/or overexpressed by tumor cells in a variety of neoplasms including breast cancer, lung cancer, esophageal and gastric cancer, bile duct carcinoma, bladder cancer and ovarian cancer.
In breast carcinoma patients, an amplification and overexpression of the c-erbB-2 gene in the tumor tissue has been shown to correlate with a poor clinical prognosis. Overexpression of p185
erbB-2
in non-small-cell lung carcinoma has been shown to impart resistance to a number of chemotherapeutic agents.
WO 93/09788 discloses a method for inhibiting the proliferation of cells which contain an erb B2
eu gene site. The method involves administering a therapeutic dose of an oligonucleotide which is capable of forming a colinear triplex with the promoter region of the erb B2
eu gene.
WO 92/19732 discloses sense and antisense oligonucleotides, namely closed oligonucleotides. These compounds may be used pharmacologically as sense or antisense molecules. It is generally described the therapeutic use of oligonucleotides as sense or antisense agents.
WO 92/13063 discloses a method for effecting expression of growth factors and growth factor receptors in cells or in multicellular animals and methods for testing compounds as effectors of transcription of growth factors and growth factor receptors.
The article “Chemically Modified Oligodeoxynucleotide Analogs as Regulators of Viral and Cellular Gene Expression” in Gene Regulation: Biology of Antisense RNA and DNA discloses in general the use of chemically modified oligonucleotides in the antisense technology.
It is an object of the present invention to provide a compound for the treatment of neoplasms and/or immune diseases and/or diseases involving pathological angiogenesis.
The c-erbB-2 antisense-oligonucleotide of the invention solving the problem addressed above have the sequences as disclosed in the sequence listing under Seq. ID No. 1-105, having a DNA- or RNA-type structure. The control oligonucleotide has the sequence as disclosed in the sequence listing under Seq. ID No 106, having a DNA- or RNA-type structure.
The antisense nucleic acids of the invention, were able to strongly inhibit the expression of the p185
erbB-2
protein, tyrosine kinase activity and cell growth in a variety of tumor cells including breast cancer cells. Untransformed normal fibroblasts were not growth inhibited by the anti-c-erbB-2 antisense compounds. This suggests that p185
erbB-2
plays a pathogenetic role in the growth of the above mentioned tumor cells.
Furthermore, surprisingly, the immune response to a variety of neoplasms was significantly increased by the use of the antisense nucleic acids of the invention. Immune cell growth and activity was stimulated in co-culture assays culturing tumor cells and peripheral blood monocytes together.
Surprisingly, the antisense nucleic acids of the invention, also acted as strong inhibitors of angiogenesis. This suggests, that either the secreted truncated form of the c-erbB-2 protein or the full receptor protein may play a causal role in pathological neoangiogenesis.
According to the invention antisense nucleic acids or effective derivatives thereof which hybridize with an area of the mRNA or DNA coding for p185
erbB-2
can effectively treat the diseases addressed above. The antisense nucleic acid is able to hybridize with regions of p185
erbB-2
mRNA. It is understood by the skilled person that fragments of the antisense nucleic acids and antisense nucleic acids containing these sequences work according to the invention so long as production of p185
erbB-2
is reduced or inhibited.
According to the invention the antisense-oligonucleotides are obtainable by solid phase synthesis using phosphite triester chemistry by growing the nucleotide chain in 3′-5′ direction in that the respective nucleotide is coupled to the first nucleotide which is covalently attached to the solid phase comprising the steps of
cleaving 5′ DMT protecting group of the previous nucleotide,
adding the respective nucleotide for chain propagation,
modifying the phosphite group subsequently cap unreacted 5′-hydroxyl groups and
cleaving the oligonucleotide from the solid support,
followed by working up the synthesis product.
REFERENCES:
patent: 5599704 (1997-02-01), Thompsen et al.
patent: WO 92 13063 (1992-08-01), None
patent: WO 92 19732 (1992-11-01), None
patent: WO 93 09788 (1993-05-01), None
Branch, A good antisense molecule is hard to find, TIBS, vol. 23, pp. 45-50, Feb. 1998.*
Agrawal, Antisense oligonucleotides:towards clinical trials, TIBTECH, vol. 14, pp. 376-387, Oct. 1996.*
Gewirtz et al., Facilitating oligonucleotide delivery: helping antisense deliver on its promise, PNAS, vol. 93, pp. 3161-3163, Apr. 1996.*
Gerwirtz et al. PNAS 93:3161-3163 (1996).*
Rojanasakul et al. Adv. Arag. Delivery Mer. 18:115-131 (1996).*
Proceedings of the American Association for Cancer Research, vol. 32, Mar. 1991, p. 433, Brysch, W. et al. “Inhibiting c-erbB-2 overexpression in human mammary carcinoma cells with phosphorothioate oligodeoxynucleotides”.
Gene Regulation: Biology of Antisens RNA and DNA; K.H. Schlingensiepen & W. Brysch; 1992; pp. 317-328; Phosphorothioate oligomers: Inhibitors of Oncogene Expression in Tumor Cells and Tools for Gene Function Analysis.
Science, vol. 230, Dec. 6, 1985, Lancaster, PA; pp. 1132-1139 Coussens, L. et al.; “Tyrosine Kinase Receptor with Extensive Homology to EGF Receptor Shares Chromosomal Location With Neu Oncogene”.
Brysch Wolfgang
Schlingensiepen Georg-Ferdinand
Schlingensiepen Karl-Hermann
Schlingensiepen Reimar
Biognostik Gesellscahft Für Biomokekulare Diagnostik mbH
Jacobson & Holman PLLC
Wang Andrew
LandOfFree
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