Drug – bio-affecting and body treating compositions – Immunoglobulin – antiserum – antibody – or antibody fragment,... – Structurally-modified antibody – immunoglobulin – or fragment...
Reexamination Certificate
2000-08-02
2003-05-13
Mosher, Mary E. (Department: 1648)
Drug, bio-affecting and body treating compositions
Immunoglobulin, antiserum, antibody, or antibody fragment,...
Structurally-modified antibody, immunoglobulin, or fragment...
C424S145100, C424S152100, C424S158100, C424S172100
Reexamination Certificate
active
06562342
ABSTRACT:
TECHNICAL FIELD
This invention relates to preventives and remedies for inflammatory intestinal disease which contain an anti-Fas ligand antibody as their effective component.
BACKGROUND ART
Fas is a cell surface antigen which transmits apoptosis signal to the cell, and Fas is recognized by Fas antibody (Yonehara, S. et al., J. Exp. Med., vol. 169, 1747-1756, 1989) which is a monoclonal antibody produced by immunizing a mouse with human fibroblast. Fas gene was recently cloned by Itoh, N. et al., and it was then found out that Fas is a cell membrane protein of about 45 kD, and from the amino acid sequence, it was revealed that Fas is a member of TNF receptor family (Cell, vol. 66, pages 233-243, 1991). Mouse Fas gene was also cloned (Watanabe-Fukunaga, et al., J. Immunol., vol. 148, pages 1274-1279, 1992), and the expression of Fas mRNA in thymus, liver, lung, heart, ovary was confirmed.
Human Fas ligand is a polypeptide which has been reported by Nagata et al. to be a biological molecule which induces apoptosis of Fas-expressing cells (Takahashi, T. et al., International Immunology, vol. 6, pages 1567-1574, 1994). Human Fas ligand is a glycosilated 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, pages 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, pages 1169-1178, 1993) and mouse Fas ligand (Takahashi, T. et al., Cell, vol. 76, pages 969-976, 1994). The human Fas ligand recognizes not only the human Fas but also the mouse Fas to induce the apoptosis, and vice versa, the rat Fas ligand and the mouse Fas ligand also recognize the human Fas to induce the apoptosis. Shirakawa, K. et al. has produced an anti-Fas ligand antibody, and disclosed an assay method for measuring Fas ligand in human body fluids using the thus produced antibody (International Patent Application Publication No. WO 97/02290).
Considerable researches have also been done on the mechanism of signal transduction in the cell upon the Fas-mediated apoptosis, and identification and cloning of the factors which interacts with the intracellular domain of the Fas, in particular, the region called “death domain” to transmit or block the signal have been reported. Possibility of the involvement of interleukin-1-converting enzyme (ICE)-related thiol proteases in the signal transduction of the Fas-mediated apoptosis has also been indicated.
Possibility of the involvement of the Fas/Fas ligand system in functions other than the apoptosis has also been indicated, for example, the possibility of the function that the Fas/Fas ligand system act with neutrophil to induce inflammation has also been indicated (Kayagaki, N. et al., Rinshou Men-eki (Clinical Immunology), vol. 28, pages 667-675, 1996).
Relationship of the apoptosis, in particular, the Fas-mediated apoptosis with various diseases and physiological phenomena has been recently indicated. For example, possibility has been indicated for involvement of abnormal Fas-mediated apoptosis in the death of hepatocytes in viral fulminant hepatitis, in some types of autoimmune diseases, and the like. Also disclosed is a therapeutic drug for hepatitis containing an anti-human Fas ligand antibody as its effective component (JP-A 1997-124509).
Inflammatory intestinal disease may be etiologically categorized into specific disease and nonspecific disease. The phanerogenic specific diseases include inflammatory intestinal disease induced by infection, drugs, chemicals and radiation, and ischemic colitis. The nonspecific disease is called idiopathic inflammatory intestinal disease, and typical such diseases are Crohn's disease and ulcerative colitis, both of which are cryptogenic, intractable, chronic intestinal diseases which experience active and remissive stages. Although ulcerative colitis is cryptogenic, involvement of immunopathological mechanisms and psychological factors in the ulcerative colitis have been indicated. The patients of ulcerative colitis are mainly adults of under 30 although infants and adults over 50 occasionally suffer from ulcerative colitis. The ulcerative colitis is an inflammatory disease of intestine, and more specifically, an inflammatory disease of rectum, and mucous membrane and its substratum are the main lesions. This disease is generally associated with hemorrhagic diarrhea and systemic conditions of varying degree, and when the patients suffer from this disease for a prolonged period and the lesion extends to the entire intestine, the lesion is likely to undergo transformation. Crohn's disease is a cryptogenic disease and the patients are mainly young adults. The Crohn's disease is associated with granulomatous inflammation lesion exhibiting edema, fibrosis (myofibrosis), and ulcer, and such lesion may occur in various parts of the digestive tract. Metastatic lesion is occasionally found in places other than the digestive tract (in particular, in skin). The Crohn's disease was previously called terminal ileitis associated with the lesion in the terminal ileum. However, it has been clearly found that this disease may occur at every parts of the digestive tract from oral cavity to anus. The clinical image of the Crohn's disease varies depending on the place of the lesion and its coverage, and the disease is typically associated fever, malnutrition, anemia, arthritis, iritis, liver damage and other systemic complications (Takazoe, M. et al., Naika (Internal Medicine), vol. 77, No.2, pages 257-264, 1996).
With the progress in immunology and molecular biology, etiology of idiopathic inflammatory disease has been widely investigated and gradually clarified from the points of MHC class II of inflammatory cells such as lymphocyte and epithelial cell, cytokines, adhesive molecules, inflammatory substances such as arachidonic acid and leukotriene, active oxygen, etc. The detailed etiology, however, is yet unknown. In view of such uncertainty in the mechanism of its onset, it is impossible to conduct an etiological therapy for the inflammatory intestinal disease as a routine clinical practice, and the therapies presently conducted are nonspecific therapies (Matsuhashi, N. et al., Naika (Internal Medicine), vol. 77, No.2, pages 227-229, 1996). Current standard therapy for the inflammatory intestinal disease is symptomatic treatment using salazosulfapyridine, steroids, and the like (Current Therapy for Disease in Digestive Apparatus, '95-'96, pages 175-182, 1995). Salazosulfapyridine, however, suffers from side effects such as nausea, headache, fever, rash, hemolytic anemia, epidermolysis, granulocytopenia, fibrous alveolitis, headache, pancreatitis, and male infertility (Allegayer et al., Gastrointestinal pharmacology, vol. 24, pages 643-658, 1992). Steroids also suffer from various serious side effects (Kashiwazaki, S. et al., Sogo Rinsho (General Clinical Medicine), vol. 43, 1725-1729, 1994). Thus, salazosulfapyridine and steroids need careful managements in their timing, dose, duration of administration.
Iwamoto et al. has reported expression of Fas/Fas ligand in epithelium of intestinal crypt of the patient suffering from ulcerative colitis (J. Pathology, vol. 180, pages 152-159, 1996). Ruggero De Maria et al. has reported expression of Fas ligand on T cell of tunica propia of human intestinal mucous membrane (J. Clin. Invest. vol. 97, pages 316-317, 1996). Jorn Strater et al. has reported that epithelial cell of intestinal mucous membrane from the patient suffering from ulcerative colitis exhibits resistance to apoptosis by TNF while its exhibits sensitivity to the apoptosis by anti-human Fas antibody, CH-11; that Fas ligand is expressed in interstitial lymphocytes of the intestine; and that increase in apoptosis of colonocyte and expression of the Fas ligand are found in ulcerative colitis (Gastroenterology, vol. 113, 160-167, 1997
Nagata Shigekazu
Suda Takashi
Yatomi Takehiro
Mochida Pharmaceutical Co. Ltd.
Mosher Mary E.
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