Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1999-08-19
2001-07-10
Schwartzman, Robert A. (Department: 1635)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C435S375000, C435S378000, C536S024500
Reexamination Certificate
active
06258790
ABSTRACT:
FIELD OF THE INVENTION
The present invention provides compositions and methods for modulating the expression of integrin &agr;4. In particular, this invention relates to antisense compounds, particularly oligonucleotides, specifically hybridizable with nucleic acids encoding human integrin &agr;4. Such oligonucleotides have been shown to modulate the expression of human integrin &agr;4.
BACKGROUND OF THE INVENTION
Inflammation is a localized protective response elicited by tissues in response to injury, infection, or tissue destruction resulting in the destruction of the infectious or injurious agent and isolation of the injured tissue. A typical inflammatory response proceeds as follows: recognition of an antigen as foreign or recognition of tissue damage, synthesis and release of soluble inflammatory mediators, recruitment of inflammatory cells to the site of infection or tissue damage, destruction and removal of the invading organism or damaged tissue, and deactivation of the system once the invading organism or damage has been resolved. In many human diseases with an inflammatory component, the normal, homeostatic mechanisms which attenuate the inflammatory responses are defective, resulting in damage and destruction of normal tissue.
Cell—cell interactions are involved in the activation of the immune response at each of the stages described above. One of the earliest detectable events in a normal inflammatory response is adhesion of leukocytes to the vascular endothelium, followed by migration of leukocytes out of the vasculature to the site of infection or injury. The adhesion of these leukocytes, or white blood cells, to vascular endothelium is an obligate step in the migration out of the vasculature (Harlan, J. M.,
Blood
1985, 65, 513-525). This response is mediated by the interaction of adhesion molecules expressed on the cell surface of leukocytes and vascular endothelial cells. Very late antigen-4 (also called VLA-4, &agr;4&bgr;1 or CD49d/CD29) is a homodimeric adhesion receptor which is composed of noncovalently linked &agr; and &bgr; subunits and serves to mediate leukocyte adhesion to vascular cell adhesion molecule-1 (VCAM-1) which is expressed on cytokine-stimulated endothelial cells. This interaction between VCAM-1 and VLA-4 contributes to leukocyte extravasation in acute and chronic inflammatory conditions including multiple sclerosis (MS), rheumatoid arthritis, asthma, psoriasis and allergy.
Fibronectin is also a ligand for VLA-4. Fibronectin plays an important role in many processes including embryonic development, wound healing and tumor cell metastasis (Guan, J.-L. and Hynes, R. O.,
Cell
1990, 60, 53-61).
VLA-4 is a heterodimer of an &agr;4 integrin and a &bgr;1 integrin. The &agr;4 integrin can also heterodimerize with a &bgr;7 integrin chain to form integrin &agr;4&bgr;7 which is known as a mucosal homing receptor because its primary ligand is the mucosal vascular addressing MadCAM-1. Integrin &agr;4&bgr;7 identifies a subset of memory T cells with a tropism for the intestinal tract, whereas integrin &agr;4&bgr;1 (VLA-4) is constitutively expressed on most mononuclear leukocytes, but not on circulating neutrophils. The interaction of VCAM-1 with VLA-4 suggests that VLA-4 is a potential therapeutic target for inflammatory diseases, including atherosclerosis, allergy and asthma, arthritis, and tumor cell metastasis (Kassner, P. D., et al,
Adv. Exp. Med. Biol
. 1992, 323, 163-170). VLA-4 has also been found to play a role in promoting adhesion (i.e., retention) of hemopoietic stem cells in the bone marrow (Papayannopoulou and Nakamoto,
Proc. Natl. Acad. Sci. U.S.A
. 1993, 90, 9374-9378).
Asthma is an inflammatory disease associated with eosinophil infiltration into the lung. VLA-4 is expressed on eosinophils. Metzger, W. J. (Springer
Semin. Immunopathol
. 1995, 16, 467-478) used a rabbit model of asthma to demonstrate that both an anti-VLA-4 antibody and a CS-1 peptide could reduce eosinophil infiltration into the lung and reduce the development of asthma.
Rheumatoid arthritis is another disease associated with inflammation. Müller-Ladner, U., et al., (
J. Rheumatology
1997, 24, 1873-1880) found that the alternatively spliced form of fibronectin containing CS-1 was expressed in the rheumatoid synovium. Additionally, they found that not only did expression of fibronectin result in recruitment of VLA-4 expressing cells, but fibroblasts in the rheumatoid synovium expressed VLA-4. Seiffge, D. (
J. Rheumotology
1996, 23, 2086-2091) used a rat model for arthritis to show that a monoclonal antibody to the &agr;4 chain of VLA-4 resulted in an improvement of symptoms.
VLA-4 also plays a role in a number of autoimmune diseases. Marazuela, M., et al., (
Eur. J. Immunol
. 1994, 24, 2483-2490) found elevated expression of both the VLA-4/VCAM-1 and LFA-1/ICAM-1,3 pathways in Graves' disease and Hashimoto's thyroiditis, suggesting that both play a role in these diseases. VLA-4 may also play a role in multiple sclerosis. Antibodies to VLA-4 have been found to prevent experimental autoimmune encephalomyelitis (EAE), an experimentally induced disease with similarities to multiple sclerosis (Yednock, T. A., et al.,
Nature
1992, 356, 63-66). Elevated expression levels of VLA-4 were detected in a patient with systemic lupus erythematosus (Takeuchi, T., et al.,
Clin. Rheumatology
1995, 14, 370-374). VLA-4 is involved in cellular responses to two surgical procedures, transplantation and vascular reconstructive procedures. Allograft rejection is a common response to transplantation of a foreign tissue. CS-1 peptides have been found to prevent both acute rejection (Coito, A. J., et al.,
Transplantation
1998, 65, 699-706) and chronic rejection (Korom, S., et al.,
Transplantation
1998, 65, 854-859) by blocking VLA-4 binding to fibronectin. During vascular reconstructive surgery, a common cause of failure is intimal hyperplasia which results from the accumulation of monocytes and lymphocytes. In a baboon model, Lumsden, A. B., et al.,(
J. Vasc. Surg
. 1997, 26, 87-93) demonstrated that an anti-VLA-4 antibody reduced intimal hyperplasia.
VLA-4 also plays a role in tumor cell metastasis. In metastasis, tumor cells must cross the extracellular matrix, enter the circulatory system and invade into new tissue. Bao, L. et al., (
Differentiation
1993, 52, 239-246) detected VLA-4 expression of many human tumor cell lines, including a breast carcinoma, melanoma, and renal carcinoma, and found that the presence of VLA-4 correlated well with metastatic potential. Kawaguchi, S. et al., (
Jpn. J. Cancer Res
. 1992, 83, 1304-1316) transfected a cDNA encoding the &agr;4 subunit of VLA-4 into a human fibrosarcoma cell line. These cells overexpressed VLA-4 and showed increased in vitro invasive ability. Augmentation of metastasis by IL-1 (Garofalo, A.,et al.,
Cancer Res
. 1995, 55, 414-419) or TNF-&agr; (Okahara, H., et al.,
Cancer Res
. 1994, 54, 3233-3236) has been shown to involve the interaction between VLA-4 and VCAM-1. These authors suggest that a therapy directed towards inhibiting this interaction would be useful in reducing the risk of metastasis with conditions associated with high serum concentrations of TNF-&agr;, including cachexia, sepsis, surgical stress, or TNF-&agr; therapeutic applications. Because tumor cells often secrete IL-1 and TNF-&agr;, such a therapy may be useful in reducing the risk of metastasis associated with such tumor cells.
VLA-4 is involved in promoting retention of hemopoietic progenitor cells in the bone marrow. Antibodies to integrin &agr;4 (but not integrin &bgr;2) have been found to selectively mobilize progenitor/stem cells into the bloodstream (Papayannopoulou and Nakamoto,
Proc. Natl. Acad. Sci. U.S.A
. 1993, 90, 9374-9378). This mobilization is of clinical relevance in the field of bone marrow transplantion as it obviates the need for marrow harvesting by making hemopoietic progenitor cells available in the circulating blood.
While steroids and other antiinflammatory drugs are effective in treating inflammatory diseases and co
Bennett C. Frank
Condon Thomas P.
Cowsert Lex M.
ISIS Pharmaceuticals Inc.
Larson Thomas G.
Licata & Tyrrell P.C.
Schwartzman Robert A.
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