Chemistry: natural resins or derivatives; peptides or proteins; – Proteins – i.e. – more than 100 amino acid residues – Blood proteins or globulins – e.g. – proteoglycans – platelet...
Reexamination Certificate
1999-04-15
2004-08-17
Ungar, Susan (Department: 1642)
Chemistry: natural resins or derivatives; peptides or proteins;
Proteins, i.e., more than 100 amino acid residues
Blood proteins or globulins, e.g., proteoglycans, platelet...
C530S387300, C530S388100, C424S009100, C424S130100, C424S185100
Reexamination Certificate
active
06777540
ABSTRACT:
CONTINUATION INFORMATION
This application claims the benefit of Japanese application No. 8/231742 filed on Sep. 2, 1996 and Japanese Application No. 8/271546 filed on Sep. 20, 1996 which are incorporated herein by reference.
FIELD OF THE INVENTION
This invention relates to novel humanized immunoglobulins, and is based on information about a site on Fas ligand which is important to suppress apoptosis which is induced in Fas-expressing cells through the Fas-Fas ligand interaction. Specifically, the invention relates to humanized immunoglobulins or active fragments thereof which are specifically reactive to Fas ligand. Said immunoglobulins and said site are useful in clinical applications to diseases which are provoked by apoptosis induced by the physiological reactions between Fas antigen and Fas ligand, and for example, are useful in elucidation of Fas system in cell death, in immunological therapy and diagnosis, in detection for Fas ligand, or in the related industrial fields.
PRIOR ART
The homeostasis of multicellular organisms is maintained by the growth and death of cells, which are delicately controlled. During the processes of ontogeny, a large number of cells are eliminated through cell death. Organs in adults also maintain their functions by continuously keeping the balance of the growth and death of the organ-constituted cells. Such cell death is referred to as “programmed cell death”, which is a predetermined death, and is discriminated from accidental cell death [Raff, M. C., Nature, vol. 356, p.397-400, 1992].
These two cell deaths are different from each other in process. It has been understood that the programmed cell death is caused by apoptosis process whereas the accidental cell death is caused by necrosis process resulting in cell death [Kerr, J. F., Brit. J. Cancer, vol. 26, p.239-257, 1972].
Fas antigen is a cell surface protein which mediates the programmed cell death, apoptosis, and the cDNA of the antigen has been cloned [Nagata, et al., Cell, vol. 66, p.223-243, 1991]. The structure of the resulting cDNA has revealed that human Fas antigen is a transmembrane type protein which consists of 319 amino acid residues containing one transmembrane domain. The extracellular domain of Fas antigen consists of 157 amino acid residues and is rich in cysteine residues. Mouse Fas antigen consists of 306 amino acid residues, and shows 49.3% homology to human Fas antigen.
The structure of the extracellular domain in Fas antigen which is cysteine-rich has been demonstrated to be a well conservative structure also found in low-affinity receptors for nerve growth factor (NGF) and receptors of tumor necrosis factor (TNF), showing that Fas antigen is a cell surface protein which belongs to a family of NGF/TNF receptor. In 1993, a group of Dr. Nagata, Shigekazu and his coworkers identified the ligand molecule of rat Fas antigen [Nagata, et al., Cell, vol. 75, p.1169-1178, 1993], which had been expected to exist within the living body in the light of the fact that most proteins of this family co-exsit with their ligands in body. Subsequently, the same group identified the molecules of mouse and human Fas ligands [Nagata, et al., Int. Immunol., vol.6, No. 10, p.1567-1574, 19941.
Dr. Nagata et al. showed that Fas ligand is a protein consisting of 278 amino acids with a molecular weight of 31,138, and that it contains four N-glycosidic linkage sites and thus is a glycoprotein [Nagata, et al., Cellular Engineering, vol.13 No. 8, p.738-744, 19941]. Further, it has been shown that a soluble Fas ligand molecule induces apoptosis in target cells expressing Fas antigen on their cell surfaces (Nagata, et al., J. Exp. Med., vol. 179, p.873-879, 1994].
Hanabuchi et al. reported that the analysis on mechanism for the cytotoxicity of target cells by killer T cells via Fas antigen reveals that transmission of apoptosis signals via Fas antigen on the target cells may be responsible for the cytotoxicity of the target cells by CD4-positive T cells (CTLs) which does not express perforin, and thereby it was revealed that Fas ligand exists on the cell surface of CD4-positive CTLs [Hanabuchi, et al., Proc. Natl. Acad. Sci. USA, vol.91, No. 11, p.4930-4934, 1994].
As described above, Fas antigen appears to transmit a signal causing “death” to cells, and it has been shown that the inactivation of the proteins mediating apoptosis such as Fas antigen and Fas ligand causes the overgrowth of cells, while, on the contrary, the extraordinary activation of such proteins causes a certain inflammatory reaction.
For example, it has been reported that there is a mutation in the Fas gene of a mice which has lpr (lymphoproliferation) mutation causing an autoimmune disease-like symptom, whereas there is a mutation in Fas ligand itself of a mice which has gld (generalized lymphoproliferative disease) mutation also causing an autoimmune disease-like symptom [Nagata, et al., Cell, vol. 76, p.969-979, 1994].
Further, recent investigations have shown that the physiological reactions between Fas antigen and Fas ligand may cause various diseases.
For example, it has been reported that tat protein derived from HIV, the AIDS-causative virus, expedites the expression of Fas ligand to induce apoptosis of the T cells expressing Fas antigen, via the interaction of Fas-Fas ligand [Westerndrop, M., et al., Nature, vol. 375, p.497-500, 1995], and the expression of Fas on HIV-infected T cells has been actually found [Kobayashi, et al., Proc. Natl. Acad. Sci. USA, vol. 87, p.9620-9624, 1990]. These reports show that apoptosis induced by the interaction of Fas-Fas ligand may be one of the mechanisms of elimination of CD4-positive T cells in AIDS. Further, there are reports, each of which shows that the mice to which anti-Fas antibody (Jo-2) has been administered intra-abdominally develop fulminant hepatitis to lead death [Ogasawara, et al., Nature, vol. 364, p.806-809, 1993], that the Fas expression is observed in viral hepatitis [Hiramatsu, et al., Hepatology, vol. 19, p. 1354-1359, 1994], and that the Fas expression is also observed in diabetes mellitus and autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), and therefore, it is speculated that these diseases as mentioned above would be caused by Fas ligand, which is reactive to Fas antigen.
Under the circumstances, creation of agents exhibiting suppressive (inhibitory) activity against the binding between Fas and Fas ligand to lead to suppression of apoptosis will be extremely significant for advanced exploration of the above studies and in particular, treatment of diseases in a future clinical application.
The inventors of the present invention found the mouse monoclonal antibodies which are specifically reactive to Fas ligand to suppress (inhibit) the physiological reactions between Fas and Fas ligand, and filed a patent application therefor (the Japanese Patent Application No. 303492/1995). abandoned, and to which priority is claimed by PCT Application No. WO96/29350. It has been believed that since the monoclonal antibodies bind to Fas ligand more strongly than Fas, the antibodies may inhibit the physiological reactions of Fas-Fas ligand in vivo.
It is natural that such highly active monoclonal antibodies are desirable in clinical application, but, unfortunately, non-human immunoglobulins such as the aforementioned mouse monoclonal antibodies suffer disadvantages in application to human, which are provided below. The non-human immunoglobulins show the relatively shorter half life in vivo, and require more frequent administrations to maintain the predetermined level in blood compared to human antibody. It should be noted that the non-human immunoglobulins contain an amino acid sequence which may exert antigenicity on the administration to human. Thus, in the case of frequent administration of the non-human immunoglobulins to human, an immune response elicited by the administration eliminates the immunoglobulins admin
Eda Yasuyuki
Higuchi Hirofumi
Maeda Hiroaki
Nakata Motomi
Okumura Ko
Davis Minh Tam
McDermott & Will & Emery
Okumura Ko
Ungar Susan
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