Antibodies to Fas-L for treatment of hepatitis

Drug – bio-affecting and body treating compositions – Immunoglobulin – antiserum – antibody – or antibody fragment,... – Monoclonal antibody or fragment thereof

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4241331, 4241521, 5303873, 53038823, A61K 39395, C07K 1618

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active

060688416

DESCRIPTION:

BRIEF SUMMARY
TECHNICAL FIELD

The present invention relates to therapeutic agents for hepatitis, and in particular to therapeutic agents for hepatitis, comprising an antibody against a human Fas ligand (hereinafter may be abbreviated as "FasL"), or an active fragment thereof as an active ingredient. The therapeutic agents for hepatitis according to the present invention are particularly effective for the treatment of hepatitis caused by the death of hepatocytes due to apoptosis among many kinds of hepatitis.


PRIOR ART

Multicellular organisms skillfully control the proliferation and death of cells to maintain their homeostasis. Many cells are removed by cell death in the course of ontogeny. In an adult, organ constituting cells always maintain their functions while well keeping a balance between their proliferation and death. Such cell death is preliminarily programmed death called "programmed cell death". On the other hand, cell death caused by physical or chemical factors is called "accidental cell death" and is distinguished from the programmed cell death.
These two deaths are different from each other in process. In the programmed cell death, cells are considered to die via the process of apoptosis defined by morphological features such as reduction in cell volume, disappearance and pycnosis of nuclear reticular structure, disappearance of microvilli and formation of vesicles on a cell surface, and formation of apoptotic bodies subsequent thereto. In many cases, the apoptosis is accompanied by a fragmentation reaction of a chromosomal DNA. On the other hand, in the accidental cell death, cells are considered to die via a process of necrosis in which cells and nuclei are imbibed and destroyed.
However, cell death by anticancer agents and radiation, cell death by viral infection or the death of target cells by cytotoxic lymphocytes has been known to go through the process of apoptosis though it is by no means considered to be programmed cell death. At present, this fact had led to the thought that the apoptosis is not always identical with the programmed cell death, and so both have come to be distinguished from each other.
At present, many have been known as factors or substances which induce apoptosis. Fas (Fas antigen) is known as a cell-surface protein that mediates apoptosis. The Fas is isolated as a cell-surface protein that mediates a signal of death to cells, and is a type I transmembrane protein belonging to the TNF/NGF receptor family and having a molecular weight of 45 kDa. Most of members of the TNF/NGF receptor family are considered receptors for their specific ligands. The Fas is also considered a receptor or a ligand mediating a signal of apoptosis. Cells in which Fas has been expressed are led to death by switching on apoptosis due to binding of the Fas to its ligand, Fas ligand.
The Fas ligand is a physiological ligand of Fas and is a cell-surface protein of 40 kDa. The Fas ligand is known from its structure to belong to the TNF family. The Fas ligand has activity to induce apoptosis to cells in which Fas has been expressed.
A system of Fas and Fas ligand (namely, Fas system) is a field in which investigations as to the apoptosis have been most evolved to date, and many investigation reports have been made. For example, the fact that Fas plays the role of a switch in apoptosis may go back to a paper by Yonehara, et al. on the production of anti-Fas antibody (J. Exp. Med., Vol. 169, pp. 1747-1756, 1989). After that, the structure of Fas has been clarified by cloning of the Fas gene (Cell, Vol. 66, pp. 233-243, 1991). Further, it has been reported that the expression of Fas is recognized in T cells infected with HIV which is a causative virus of AIDS (Proc. Natl. Acad. Sci., U.S.A., Vol. 87, pp. 9620-9624, 1990), and that when an anti-Fas antibody (Jo-2 antibody) is administered to mice, the mice undergo a phenomenon similar to fulminant hepatitis to die (Nature, Vol. 364, pp. 806-809, 1993). Besides these, various investigation reports have been made. These reports are collected in detail in "Apopto

REFERENCES:
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