Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
2000-02-11
2004-12-21
Epps-Ford, Janet L. (Department: 1635)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C530S350000
Reexamination Certificate
active
06833348
ABSTRACT:
FIELD OF THE INVENTION
The present invention is generally in the field of modulators of apoptopic cell death and uses thereof in therapeutic applications to inhibit or to enhance apoptosis, as desired depending on the disease and whether or not it is desired to kill the diseased cells or to rescue the diseased cells from apoptopic cell death. Specifically, the present invention concerns novel genes encoding novel proteins belonging to the leucine zipper family, which are capable of inhibiting apoptosis mediated by the CD3/TCR system or by the Fas/Fas-L system, and which are also capable of stimulating lymphocyte activation.
In particular, the present invention concerns a new protein and the gene encoding therefor called GILR, preparation and uses thereof, as well as any isoforms, analogs, fragments and derivatives of GILR, their preparation and uses.
BACKGROUND OF INVENTION AND PRIOR ART
Apoptosis (programmed cell death) is an important intracellular process having an important role in normal cell and tissue development as well as in the control of neoplastic growth (Cohen, 1993; Osborne and Schwartz, 1994; Wyllie et al., 1980; Kerr et al., 1972; Bursch et al., 1992).
A number of stimuli can either induce or inhibit programmed cell death through activation of molecules, involved in the signaling and execution of apoptosis, acting at different levels including the cell membrane, cytoplasm and nucleus. Among these, of note are those intracellular molecules, including some transcription factors, that have been shown to regulate cell growth. In particular, leucine zipper family proteins, such as for instance MYC, FOS and JUN, can modulate cell death (Shi et al., 1992; Smeyne et al., 1993; Goldstone and Lavin, 1994).
Apoptosis is also important in T-cell development (Dent et al., 1990; Ju et al., 1995; MacDonald and Lees, 1990). In particular, negative selection is due to apoptosis activated through the antigen (Ag) interaction with the T-cell-receptor(TCR)/CD3 complex (Smith et al., 1989). Engagement of the TCR/CD3 complex, either by APCs presenting antigenic peptide or by anti-CD3 antibody, triggers a series of activation events, such as for example, the expression of the Fas/Fas-Ligand (Fas/Fas-L) system, that can induce apoptosis in thymocytes, mature T cells and T cell hybridoma (Alderson et al., 1995; Dhein et al., 1995; Ju et al., 1995; Jenkinson et al., 1989; Webb et al., 1990; Yang et al., 1995). For example, triggering of such activation events in T cell hybridomas leads to cell cycle arrest, followed by apoptosis. This activation-induced cell death (AICD, Kabelitz et al., 1993) requires the interaction of Fas with Fas-L (Alderson et al., 1995; Itoh et al., 1991; Yang et al., 1995).
It has been shown that other stimuli, such as cytokines and glucocorticoid hormones (GCH), are also critical regulators of T-cell development (Migliorati et al., 1993; Nieto et al., 1990; Nieto and Lopez-Rivas, 1989; Cohen and Duke, 1984; Wyllie, 1980). For example, dexamethasone (DEX), a synthetic GCH which by itself induces apoptosis in T cell hybridomas and in normal T lymphocytes, can inhibit AICD induced by triggering of the TCR/CD3 complex (Zacharchuk et al., 1990). This inhibition may be due to prevention of activation induced expression of Fas and Fas-L (Yang et al., 1995).
With respect to the above noted Fas/Fas-L system, it should be noted that Fas has also been called the FAS receptor or FAS-R as well as CD95. For simplicity, this receptor will be called ‘Fas’ herein throughout and its ligand, as noted above, will be called ‘Fas-L’ herein throughout.
Fas is a member of the TNF/NGF superfamily of receptors and it shares homology with a number of cell-surface receptors including the p55-TNF receptor and the NGF receptor (see for example Boldin et al., 1995a and 1995b). Fas mediates cell death by apoptosis (Itoh et al. 1991) and appears to act as a negative selector of autoreactive T cells, i.e. during maturation of T-cells, Fas mediates the apoptopic death of T cells recognizing self-antigens. Mutations in the Fas gene, such as the lpr mutations in mice, have been shown to be responsible for a lymphoproliferation disorder in mice resembling the human autoimmune disease, systemic lupus erythomatosus (SLE; Watanabe-Fukunaga et al., 1992). The Fas-L molecule is apparently a cell surface-associated molecule carried by, amongst others, killer T cells (or cytotoxic T lymphocytes—CTLs), and hence, when such CTLs contact cells carrying Fas, they are capable of inducing apoptopic cell death of the Fas-carrying cells. Further, a monoclonal antibody specific to Fas has been prepared which is capable of inducing apoptopic cell death in cells carrying Fas, including mouse cells transformed by cDNA encoding human Fas (see, for example, Itoh et al, 1991).
While some of the cytotoxic effects of lymphocytes are mediated by interaction of lymphocyte-produced Fas-L with the widely-occurring Fas, it has also been found that various other normal cells besides T lymphocytes, express Fas on their surface and can be killed by the triggering of this receptor. Uncontrolled induction of such a killing process is suspected to contribute to tissue damage in certain diseases, for example, the destruction of liver cells in acute hepatitis. Accordingly, finding ways to restrain the cytotoxic activity of Fas may have therapeutic potential.
Conversely, since it has also been found that certain malignant cells and HIV-infected cells carry Fas on their surface, antibodies against Fas, or Fas-L itself, may be used to trigger Fas-mediated cytotoxic effects in these cells and thereby provide a means for combating such malignant cells or HIV-infected cells (see, for example, Itoh et al. 1991). Finding yet other ways for enhancing the cytotoxic activity of Fas may therefore also have therapeutic potential.
As noted above, Fas is related to one of the TNF receptors, namely, the p55-TNF receptor. TNF (both TNF-&agr; and TNF-&bgr;, and as used throughout, ‘TNF’ will refer to both) has many effects on cells (see, for example, Wallach, D. (1986) In: Interferon 7 (Ion Gresser ed.), p. 83-122, Academic Press, London; and Beutler and Cerami (1987)).
TNF exerts its effects by binding to its receptors, the p55-TNF receptor and the p75-TNF receptor. Some of the TNF-induced effects are beneficial to the organism, such as, for example, destruction of tumor cells and virus-infected cells, and augmentation of antibacterial activities of granulocytes. In this way TNF contributes to the defense of the organism against tumors and infectious agents and contributes to recovery from injury.
Thus, TNF can be used as an anti-tumor and anti-infectious agent.
However, TNF can also have deleterious effects. For example, overproduction of TNF can have a pathogenic role in several diseases, including amongst others, septic shock (Tracey et al., 1986); excessive weight loss (cachexia); tissue damage in rheumatic diseases (Beutler and Cerami, 1987); tissue damage in graft-versus-host reactions (Piquet et al., 1987); and tissue damage in inflammation, to name but a few of the pathogenic effects of TNF.
The above cytocidal effects of TNF is mediated mainly by the p55-TNF receptor in most cells studied so far, which activity is dependent on the integrity of the intracellular domain of this receptor (see, for example, Brakebusch et al., 1992; Tartaglia et al., 1993). In addition, mutational studies indicate that the related Fas and p55 TNF-receptor mediate intracellular signaling processes, ultimately resulting in cell death, via distinct regions within their intracellular domains (see also, for example, Itoh and Nagata, 1993). These regions also designated ‘death domains’ present in both these receptors, have sequence similarity. The “death domains” of Fas and p55-TNF receptor are capable of self-association, which is apparently important for promoting the receptor aggregation necessary for initiating intracellular signaling (see, for example, Song et al. 1994; Wallach et al., 1994; Boldin et al., 1995a, b), and which, at high levels of receptor expression
Applied Research Systems Ars Holding N.V.
Browdy and Neimark PLLC
Epps-Ford Janet L.
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