Antisense inhibition of Her-2 expression

Details Antisense inhibition of Her-2 expression Antisense inhibition of Her-2 expression

2000-09-15

2003-09-02

Wang, Andrew (Department: 1635)

Chemistry: molecular biology and microbiology

Animal cell, per se ; composition thereof; process of...

Method of regulating cell metabolism or physiology

C435S006120, C435S091100, C435S325000, C536S023100, C536S023200, C536S024300, C536S024310, C536S024330, C536S024500

Reexamination Certificate

active

06613567

ABSTRACT:

FIELD OF THE INVENTION
The present invention provides compositions and methods for modulating the expression of Her-2. In particular, this invention relates to compounds, particularly oligonucleotides, specifically hybridizable with nucleic acids encoding Her-2. Such oligonucleotides have been shown to modulate the expression of Her-2.
BACKGROUND OF THE INVENTION
One of the principal mechanisms by which cellular regulation is effected is through the transduction of extracellular signals into intracellular signals that in turn modulate biochemical pathways. Examples of such extracellular signaling molecules include growth factors, cytokines, and chemokines. The cell surface receptors of these molecules and their associated signal transduction pathways are therefore one of the principal means by which cellular behavior is regulated. Because cellular phenotypes are largely influenced by the activity of these pathways, it is currently believed that a number of disease states and/or disorders are a result of either aberrant activation or functional mutations in the molecular components of signal transduction pathways. Consequently, considerable attention has been devoted to the characterization of these receptor proteins.
HER2 (also known as Human EGF Receptor 2, c-erbB2, erbB2 and Neu), a member of the EGF family of receptor/tyrosine kinases, is a protein that has been shown to play a complex role in several signal transduction pathways by forming homo- and heterodimers with other members of the EGF family depending on their concentrations and the concentration of particular ligands. The ligands for the EGF family of receptors include six ligands that bind EGFR (ErbB1) including EGF, TGF-alpha, amphiregulin, heparin binding EGF-like growth factor, betacellulin and epiregulin. In addition, there are two groups of ligands specific to HER3 and HER4 collectively termed neuregulins (NRGs) because of their demonstrated role in the nervous system. Although HER2 acts as the most oncogenic member of the family by inhibition ligand dissociation from the dimer, there is no known ligand specific to HER2. HER3 and HER4 function as the binding receptors; and HER2 along with EGFR are considered co-receptors and are recruited as partners to HER3 and HER4 upon ligand binding. (Burden and Yarden, Neuron, 1997, 18, 847-855).
HER2 was first isolated and cloned in 1985 from brain tumors of female mice treated with a carcinogen which resulted in an oncogenic mutation of the receptor. This mutation transformed the receptor from a ligand dependent kinase to a constitutively active kinase which, when expressed early in development, caused brain tumors (Earp et al.,
Breast Cancer Res. Treat
., 1995, 35, 115-132). Since then it has been demonstrated that HER2 plays a role in both neural and cardiac development (Carraway,
BioEssays
, 1996, 18, 263-266).
Cellular transformation and acquisition of the metastatic phenotype are the two main changes normal cells undergo during the progression to cancer. HER2 has been implicated in both processes. The HER2 receptor has been shown to be altered in a number of malignancies including gastric, esophageal, salivary, colon, bladder and lung cancer and overexpression of HER2 in advanced breast cancer has been correlated with the progression of the disease (Earp et al.,
Breast Cancer Res. Treat
., 1995, 35, 115-132).
Currently, there are no known therapeutic agents which effectively inhibit the synthesis of HER2. Consequently, there remains a long felt need for additional agents capable of effectively inhibiting HER2 expression and/or function. To date, strategies aimed at inhibiting HER2 function have involved the use of gene knockouts in mice, receptor antibodies, antisense vectors and oligonucleotides, ribozymes and antigen-activated cytotoxic lymphocytes (Cirisano and Karlan,
J. Soc. Gynecol. Investig
., 1996, 3, 99-105).
A critical role for HER2 during gestational development was illustrated using HER2 deficient mice which underwent aberrant cardiac development 10 days post-fertilization and died (Alroy and Yarden,
FEBS Lett
., 1997, 410, 83-86). Other studies demonstrated the importance of HER2 in neural development. Mice lacking in either NRG or HER2 expression lacked neural crest-derived cells of cranial sensory ganglia as well as axonal connections to the hindbrain (Carraway,
BioEssays
, 1996, 18, 263-266).
Other studies using an expression vector encoding HER2 in the antisense orientation have shown that the reduction of HER2 levels in various cancer cells may have a beneficial effect. For example, Yoo and Hamburger demonstrated that HER2 expression modulates signal transduction pathways in breast cancer lines (Yoo and Hamburger,
Mol. Cell. Endocrinol
., 1998, 138, 163-171), while Pegues and Stromberg demonstrated that inhibition of HER2 reduced anchorage independent growth of ovarian carcinoma cells (Pegues and Stromberg,
Cancer Letters
, 1997, 117, 73-79). Finally, Casalini et al. have shown that HER2 antisense constructs inhibit tumorigenicity in lung adenocarcinoma cells (Casalini et al.,
Int. J. Cancer
, 1997, 72, 631-636).
Furthermore, Herceptin™, a recombinant humanized anti-HER2 antibody has been approved for treatment of metastatic breast cancer and has been shown to enhance antitumor activity of Paclitaxel and Doxorubicin in breast cancer xenografts (Baselga et al.,
Cancer Res
., 1998, 58, 2825-2831).
Other studies of antisense oligonucleotides targeting HER2 in breast carcinoma cells also demonstrated growth inhibition of the cells using an oligonucleotide targeting the 5′ region of the gene and synergistic effects were seen with treatment of the oligonucleotide in combination with conventional chemotherapeutic agents (Roh et al.,
Surgery
, 1999, 126, 413-421; Roh et al.,
J. Surg. Res
., 1998, 77, 85-90). The same oligonucleotide was subsequently shown to induce apoptosis in cancer cells overexpressing HER2 (Roh et al.,
Cancer Res
., 2000, 60, 560-565). Several studies have also shown the utility of antisense technology in downregulating HER2 expression in cancer cells (Bennett et al., 1999; Bertram et al.,
Biochemical and Biophysical Research Communications
, 1994, 2000, 661-667; Liu and Pogo,
Antisens and Nucleic Acid Drug Development
, 1996, 6, 9-16; Marks et al., 1998; Vaughn et al.,
Proc. Natl. Acad. Sci. U.S.A
., 1995, 92, 8338-8342). Finally, Urbaine et al. showed that cells expressing a certain mRNA preferentially retain the antisense probe targeting that mRNA. These studies concluded that antisense molecules represent a novel class of radiopharmaceutical drugs with unique specificity (Urbain et al.,
Eur. J. Nucl. Med
., 1995, 22, 499-504).
Disclosed in the PCT Publication WO 99/31118 are recombinant adenoviruses which express ribozymes targeting HER2 mRNA for the purpose of inhibiting tumor growth (Czubayko and Wellstein, 1999). Ribozymes are also disclosed in Wiechen et al. for use in downregulating HER2 in ovarian cancers (Wiechen et al.,
Cancer Gene Ther
., 1998, 5, 45-51).
Antisense technology is emerging as an effective means for reducing the expression of specific gene products and may therefore prove to be uniquely useful in a number of therapeutic, diagnostic, and research applications for the modulation of HER2 expression.
The present invention provides compositions and methods for modulating HER2 expression.
SUMMARY OF THE INVENTION
The present invention is directed to compounds, particularly antisense compounds, which are targeted to a nucleic acid encoding Her-2, and which modulate the expression of Her-2. Pharmaceutical and other compositions comprising the antisense compounds of the invention are also provided. Further provided are methods of modulating the expression of Her-2 in cells or tissues comprising contacting said cells or tissues with one or more of the antisense compounds or compositions of the invention. Further provided are methods of treating an animal, particularly a human, suspected of having or being prone to a disease or condition associated with expression of Her-2 by administering a t

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