Fas antigen derivatives

Details Fas antigen derivatives Fas antigen derivatives

1998-11-02

2001-10-23

Huff, Sheela (Department: 1642)

Drug, bio-affecting and body treating compositions

Antigen, epitope, or other immunospecific immunoeffector

Amino acid sequence disclosed in whole or in part; or...

C424S184100, C424S192100, C424S193100, C435S069100, C435S069300, C435S069700, C435S069800, C514S001000, C514S002600, C514S008100, C514S012200, C530S350000, C530S380000

Reexamination Certificate

active

06306395

ABSTRACT:

TECHNICAL FIELD
This invention provides the field of medicaments with a novel Fas antigen derivative in which its activities and the like are improved and with a novel DNA fragment which encodes the same. The present invention also provides a recombinant DNA molecule which contains said DNA fragment, a transformant and a method for the production of said novel Fas antigen derivative.
BACKGROUND ART
Human Fas antigen is a polypeptide which is distributed in the surface of various cells and considered to be related to a type of the death of cells, called apoptosis. Homeostasis of the living body is skillfully regulated by the growth and differentiation of cells and the death thereof, and apoptosis is a mode of cell death which is discriminated from necrosis among modes of dying cells. It is known that the death of cells required for the maintenance of homeostasis of the living body, namely a case of cell death in which cells unnecessary for the living body are removed or virus-infected cells or tumor cells are attacked and removed by cytotoxic T lymphocytes (CTL) or natural killer (NK) cells, is mainly based on apoptosis.
It has been remained unexplained for a long time about the true character of Fas antigen which is a monoclonal antibody obtained by immunizing mice with human fibroblasts, originally found by Yonehara, S. et al. (
J. Exp. Med
., vol. 169, pp. 1747-1756, 1989) as a cell surface antigen which is recognized by an anti-Fas antibody capable of inducing apoptosis in certain cells (Yonehara, S. et al.) and transfers a signal of apoptosis to the cells.
Recently, a Fas antigen gene has been cloned which revealed that the Fas antigen is a type I transmembrane glycoprotein which, according to its amino acid sequence, belongs to the NGFR (nerve growth factor receptor)/TNFR (TNF receptor) family that constitutes physiologically important cell surface membrane proteins (Itoh, N. et al., Cell, vol. 66, pp. 233-243, 1991). A mouse Fas antigen gene has also been cloned (Watanabe-Fukunaga, R. et al.,
J. Immunol
., vol. 148, pp. 1274-1279, 1992), which confirmed that Fas antigen mRNA is expressed in the thymus, liver, lung, heart and ovary of mouse. Its expression in human has also been reported in various tissues and cells such as lymphocytes, hepatocytes, small intestine epithelial cells, skin keratinocytes and osteoblasts (Leithauser, F. et al.,
Lab. Invest
., vol. 69, pp. 415-429, 1993).
The Fas antigen which was originally assumed to be present on the surface of cells has been detected in blood and culture supernatants, too, and its presence in the form of a soluble type Fas antigen (sFas) has also been found, so that their physiological functions and the like have become of interest in recent years.
Cheng, J. et al. (
Science
, vol. 263, pp. 1759-1762, 1994) have reported that they have found a mRNA molecule coding for a &Dgr;TM type soluble form of Fas antigen, which seemed to encode a secretor molecule by the deletion of exon IV (corresponds to 14 base pairs of the extracellular region and 49 base pairs of the transmembrane region) due to alternative splicing, that concentration of the soluble type Fas antigen was high in sera of systemic lupus erythematosus (SLE) patients and that increase in the autologous mixed lymphocyte reaction was observed, together with increase in the number of splenocytes, when a chimera molecule composed of the extracellular region of mouse Fas antigen and the Fc moiety of human IgG was administered to mice. Also, Cascino, I. et al. (
J. Immunol
., vol. 154, pp. 2706-2713, 1995) have reported that at least three Fas antigen-encoding mRNA molecules exist, including the just described Fas antigen mRNA. Though their physiological functions, expression regions and the like are still unclear, it has been shown that the recombinant &Dgr;TM type Fas antigen inhibits the cytotoxic activity of Fas ligand in a concentration-dependent manner and that most of the soluble type Fas antigens existing in sera of healthy people and SLE patients are &Dgr;TM type Fas antigens encoded by splicing variants (Kayagaki, N. et al.,
Igaku
-
no Ayumi
(Advance in Medical Science), vol. 174, pp. 1136-1140, 1995).
In addition, Kimura, K. et al. have recently cloned a rat Fas antigen gene and reported that two types of Fas antigen mRNA can be detected in rat liver mRNA based on the alternative splicing and that a mRNA molecule which encodes a peptide having smaller molecular weight is present in addition to the mRNA of membrane binding type Fas antigen (
Biochemical and Biophysical Research Communications
, vol. 198 (2), pp. 666-674 (1994)) and also have isolated and identified mutants (variants) of corresponding human Fas antigen (Japanese Patent Application Kokai No. 7-289266).
On the other hand, human Fas ligand is a polypeptide that has been reported by Nagata et al. to be a biological molecule that induces apoptosis of Fas antigen-expressing cells (Takahashi, T. et al.,
International Immunology
, vol. 6, pp. 1567-1574, 1994). Human Fas ligand is a Type II membrane protein of TNF family with a molecular weight of about 40 kD. As in the case of TNF, human Fas ligand in the human body is estimated to be in the form of a trimer (Tanaka, M. et al.,
EMBO Journal
, vol. 14, pp. 1129-1135, 1995). The extracellular domain of the human Fas ligand is highly homologous with the extracellular domain of rat Fas ligand (Suda, T. et al.,
Cell
, vol. 75, pp. 1169-1178, 1993) and mouse Fas ligand (Takahashi, T. et al.,
Cell
, vol. 76, pp. 969-976, 1994). The human Fas ligand recognizes not only human Fas antigen but also mouse Fas antigen, and induces the apoptosis. On the other hand, the rat Fas ligand and the mouse Fas ligand recognize the human Fas antigen to induce the apoptosis.
Apoptosis has called attention for its deep involvement in homeostasis of an organism. The homology of the Fas ligands among different species as mentioned above suggests the important role of the apoptosis mediated by the Fas ligand and the Fas antigen in the homeostasis of organism.
Recently, an interesting relation of abnormality of Fas ligand and Fas antigen with an autoimmune disease has been reported. In this report, there is suggested that MRL-lpr/lpr (a strain of model mouse for an autoimmune disease) has mutation in its Fas antigen gene, and apoptosis is not induced in the cells expressing such mutant Fas antigen gene (Watanabe-Fukunaga, R. et al.,
Nature
, vol. 356, pp. 314-317, 1993; Adachi, M. et al.,
Proc. Natl. Acad. Sci. USA
, vol. 90, 1993). In the meanwhile, there has also been reported that C3H-gld/gld (another strain of model mouse for an autoimmune disease)has mutation in its Fas ligand gene, and that the Fas ligand of the gld mouse has no apoptosis-inducing activity. The mutation in the Fas ligand gene of the gld mouse is a point mutation, and as a result of such point mutation, 7th amino acid from the C terminal of the extracellular domain of the Fas ligand is replaced with another amid acid (Tomohiro Takahashi, et al.,
Cell
, vol. 76, pp. 969-976, 1994). The Fas ligand of the gld mouse as described above is incapable of binding with the Fas antigen (Fred Ramsdell, et al.,
Eur. J. Immunol
., vol. 24, pp. 928-933, 1994).
Also, in the case of SLE patients, increase in the level of a soluble type Fas antigen in blood (Cheng J. et al.,
Science
, vol. 263, pp. 1759-1762, 1994) and increase in the expression of a Fas antigen on the surface of lymphocytes (Amasaki T. et al.,
Clin. Exp. Immunol
., vol. 99, pp. 245-250, 1995) have been reported, and it has been suggested about a possibility that abnormality of a Fas antigen gene accompanied by the abnormal expression and function of the Fas antigen is concerned also in lymphocytosis syndrome (Rieux Laucat et al.,
Science
, vol. 268, pp. 1347-1349, 1995, and Fisher G. H. et al.,
Cell
, vol. 81, pp. 935-946, 1995).
The finding as described above resulted in the hypothesis that some autoimmune diseases are induced by the abnormality of the Fas antigen or the Fas ligand, namely, by the autoreactive T cells remaining in the body that

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