Antisense modulation of CD40 ligand expression

Chemistry: molecular biology and microbiology – Animal cell – per se ; composition thereof; process of... – Method of regulating cell metabolism or physiology

Reexamination Certificate

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C435S006120, C435S325000, C536S023100, C536S024500

Reexamination Certificate

active

06586245

ABSTRACT:

FIELD OF THE INVENTION
The present invention provides compositions and methods for modulating the expression of CD40 ligand. In particular, this invention relates to compounds, particularly oligonucleotides, specifically hybridizable with nucleic acids encoding CD40 ligand. Such compounds have been shown to modulate the expression of CD40 ligand.
BACKGROUND OF THE INVENTION
The immune system serves a vital role in protecting the body against infectious agents. It is well established, however, that a number of disease states and/or disorders are a result of either abnormal or undesirable activation of immune responses. In general, an immune response is activated as a result of either tissue injury or infection. Both cases involve the recruitment and activation of a number of immune system effector cells (i.e. B- and T-lymphocytes, macrophages, eosinophils, neutrophils) in a process coordinated through a series of complex cell-cell interactions (Schonbeck and Libby,
Cell Mol. Life Sci
., 2001, 58, 4-43).
A typical scenario by which an immune response is mounted against a foreign protein is as follows: Foreign proteins captured by antigen presenting cells (APCs) such as macrophages or dendritic cells are processed and displayed on the cell surface of the APC. Circulating T-helper cells which express an immunoglobulin that recognizes (i.e. binds) the displayed antigen undergo activation by the APC. These activated T-helpers in turn activate appropriate B-cell clones to proliferate and differentiate into plasma cells that produce and secrete humoral antibodies targeted against the foreign antigen. The secreted humoral antibodies are free to circulate and bind to any cells expressing the foreign protein on their cell surface, in effect marking the cell for destruction by other immune effector cells. In each of the stages described above, direct cell-cell contact between the involved cell types is required in order for activation to occur (Schonbeck and Libby,
Cell Mol. Life Sci
., 2001, 58, 4-43).
In recent years, a number of cell surface receptors that mediate these cell-cell contact dependent activation events have been identified. Among these cell surface receptors is CD40 and its physiological ligand, CD40 ligand (also known as CD40L, CD154, T-BAM, gp39 and tumor necrosis factor-related activation protein; TRAP).
CD40 was first characterized as a receptor expressed on B-lymphocytes (Schonbeck and Libby,
Cell Mol. Life Sci
., 2001, 58, 4-43). It was later found that engagement of B-cell CD40 with CD40L expressed on activated T-cells is essential for T-cell dependent B-cell activation (i.e. proliferation, immunoglobulin secretion, and class switching (Schonbeck and Libby,
Cell Mol. Life Sci
., 2001, 58, 4-43). It was subsequently revealed that functional CD40 is expressed on a variety of cell types other than B-cells, including hematopoietic progenitor cells, T lymphocytes, basophils, eosinophils, monocytes/macrophages, dendritic cells, epithelial cells, endothelial cells, smooth muscle cells, keratinocytes, fibroblasts and carcinomas (Schonbeck and Libby,
Cell Mol. Life Sci
., 2001, 58, 4-43).
The CD40 ligand was cloned in 1993 (Gauchat et al.,
FEBS Lett
., 1993, 315, 259-266), and mapped to chromosome Xq26.3-q27.1 (Graf et al.,
Eur. J. Immunol
., 1992, 22, 3191-3194) thus confirming prior studies implicating CD40 ligand gene defects in X-linked hyper-IgM syndrome (Allen et al.,
Science
, 1993, 259, 990-993).
CD40 ligand is a type II transmembrane protein belonging to the tumor necrosis factor superfamily (Schonbeck and Libby,
Cell Mol. Life Sci
., 2001, 58, 4-43). The human CD40 ligand gene is composed of five exons and four intervening introns and encodes a 2.3 kb mRNA which, upon transcription, yields a polypeptide consisting of 261 amino acids (Schonbeck and Libby,
Cell Mol. Life Sci
., 2001, 58, 4-43).
Shorter soluble forms of the cell-associated full-length 39 kDa form of CD40 ligand have been described with molecular weights of 33, and 18 kDa (Graf et al.,
Eur. J. Immunol
., 1995, 25, 1749-1754; Ludewig et al.,
Eur. J. Immunol
., 1996, 26, 3137-3143; Wykes et al.,
Eur. J. Immunol
., 1998, 28, 548-559). The 18 kDa soluble form generated via intracellular proteolytic cleavage, which lacks the cytoplasmic tail, the transmembrane region and parts of the extracellular domain, but conserves the CD40 binding domain retains the ability to bind to CD40 (Graf et al.,
Eur. J. Immunol
., 1995, 25, 1749-1754).
Disclosed and claimed in U.S. Pat. No. 5,981,724 are DNA sequences encoding CD40 ligand as well as vectors, and transformed host cells for the purpose of producing CD40 ligand polypeptides (Armitage et al., 1999). Disclosed in U.S. Pat. No. 5,962,406 are DNA sequences encoding soluble forms of CD40 ligand (Armitage et al., 1999).
CD40 ligand is expressed on a variety of cell types including T lymphocytes, basophils, eosinophils, monocytes/macrophages, natural killer cells, B-lymphocytes, platelets, mast cells, dendritic cells, endothelial cells, smooth muscle cells and epithelial cells (Schonbeck and Libby,
Cell Mol. Life Sci
., 2001, 58, 4-43).
It is currently believed that the CD40/CD40 ligand partnership plays a broad role in immune regulation. According to Schönbeck and Libby (Schonbeck and Libby,
Cell Mol. Life Sci
., 2001, 58, 4-43), biological functions of the CD40/CD40 ligand pair include regulation of T-cell-dependent humoral immunity via activation of B- and T-lymphocytes, switching of immunoglobulin classes and formation of germinal and memory B-cells (Schonbeck and Libby,
Cell Mol. Life Sci
., 2001, 58, 4-43). The CD40/CD40 ligand pair is also responsible for regulation of inflammatory mediators including cytokines, chemokines, adhesion molecules, matrix degrading enzymes, procoagulant factors, prostaglandin E
2
, and nitric oxide synthase.
Finally, the CD40/CD40 ligand pair has been implicated in anti-apoptotic functions in B-lymphocytes, CD4+ thymocytes, monocytes, dendritic cells and fibroblasts (Schonbeck and Libby,
Cell Mol. Life Sci
., 2001, 58, 4-43). On the other hand, the CD40/CD40 ligand pair has been found to induce apoptosis in neuronal cells and hepatocytes and has been observed to induce expression of caspase family members (Schonbeck and Libby,
Cell Mol. Life Sci
., 2001, 58, 4-43).
In addition, elevated expression of the CD40/CD40 ligand pair has been correlated with a number of human disorders and diseases including autoimmune disease, graft rejection, cardiovascular disease, cancer and lung disorders (Schonbeck and Libby,
Cell Mol. Life Sci
., 2001, 58, 4-43).
Animal models have revealed evidence for the therapeutic potential of anti-CD40 ligand antibodies in treating graft rejection (Parker et al.,
Proc. Natl. Acad. Sci. U.S.A
., 1995, 92, 9560-9564) autoimmune disease such as lupus-like nephritis (Early et al.,
J. Immunol
., 1996, 157, 3159-3164) and cardiovascular disease such as atherosclerosis (Mach et al.,
Nature
, 1998, 394, 200-203).
In addition, animals deficient in CD40 ligand have been found to be resistant to experimental allergic encephalomyelitis (Grewal et al.,
Science
, 1996, 273, 1864-1867) and atherosclerosis (Lutgens et al.,
Nat. Med
., 1999, 5, 1313-1316).
Elevated expression of the CD40/CD40 ligand pair is associated with the progression of many prevalent human diseases. Accordingly, animal models have revealed evidence for the therapeutic potential of modulation of CD40 ligand.
Due to the pivotal role that the CD40/CD40 ligand pair plays in humoral immunity, the potential exists that therapeutic strategies aimed at downregulating signaling by the CD40/CD40 ligand pair via selective inhibition of CD40 ligand may provide a novel class of agents useful in treating a number of immune associated disorders, including, but not limited to, graft rejection, autoimmune diseases such as multiple sclerosis (MS), systemic lupus erythematosus (SLE), certain forms of arthritis, inflammatory and allergic conditions such as asthma, rheumatoid arthritis, inflammatory bowel disease, various dermatological conditions,

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