Pharmaceutical compositions containing anti-Fas antibody

Details Pharmaceutical compositions containing anti-Fas antibody Pharmaceutical compositions containing anti-Fas antibody

2001-11-20

2004-06-08

Housel, James (Department: 1648)

Drug, bio-affecting and body treating compositions

Immunoglobulin, antiserum, antibody, or antibody fragment,...

C424S133100, C424S141100, C514S002600, C514S249000, C530S387100, C530S387300, C530S388100

Reexamination Certificate

active

06746673

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a novel pharmaceutical composition for prophylaxis and/or treatment of an autoimmune disease or rheumatoid arthritis.
2. Background Art
Physiological death of cells as a result of normal alternation of cells in a living organism is called apoptosis, and is distinguished from the pathological death of cells, i.e. necrosis [cf. Kerr et al., (1972), Br. J. Cancer, 26, 239]. Apoptosis is a kind of so-called programmed cell death, which is observed in certain cells that are programmed, in advance, to die in a living organism. Apoptosis is characterized by a curved cell surface, condensed nuclear chromatin and fragmented chromosomal DNA, amongst others.
Apoptosis plays a role in the differentiation of lymphocytes (T cells and B cells) by eliminating cells that recognize an autoantigen. It is believed that a cause of an autoimmune disease is the presence of auto-reactive lymphocytes generated due to failure of apoptosis in differentiation of lymphocytes [cf. Nakayama et al., (1995), Mebio, 12 (10), 79-86].
Various molecules have been identified as being involved in apoptosis, including: Fas [cf. Yonehara. S., et al., (1989), J. Exp. Med., 169, 1747-1756]; tumor necrosis factor receptor [cf. Loetscher. H., et al., (1990), Cell, 61, 351-359]; CD40 [cf. Tsubata, T., et al., (1993), Nature, 364, 645-648]; and perforin/granzyme A [cf. Jenne. D. E., et al., (1988), Immunol. Rev. 103, 53-71]. Fas is a transmembrane protein present on the cellular surface, and binding of its extracellular domain to a protein called the “Fas ligand” induces apoptosis in the cell.
It has been reported that some anti-Fas monoclonal antibodies have a cytotoxic activity and induce apoptosis in a cell in a similar manner as the Fas ligand does, and thus they can be an agent for treating an autoimmune disease, AIDS, and neoplasm [cf. Japanese Patent Application Publication (Kokai) Hei 2-237935 and International application publication in Japan (Kohyo) Hei 5-503281].
On the other hand, rheumatism, especially rheumatoid arthritis is a disease that is accompanied by various abnormalities in immunology caused by internal and external factors, of which a basic pathological change is proliferation of synovial cells, and it is considered that it is a disorder of proliferation of the synovial cells accompanied by inflammatory cell infiltration and bone erosion. Tissue destruction around the joint suffering from rheumatoid arthritis is considered to be caused by abnormalities in the production of cytokines in inflammatory synovial cells. When the state of a joint of a rheumatic patient is investigated, there are observed an unusual proliferation of synovial cells, synovial villus proliferation, multilayered synovial cells and the like (cf. Daniel J. McCarty (1985) in “Arthritis and allied conditions, A textbook of rheumatology” 10
th
Edition, Lea & Febiger). An anti-inflammatory agent or an immunity regulatory agent, such as a steroid or the like is mainly used in pharmacotherapy that is presently carried out for rheumatism. However, if such excrescence of synovial cells can be controlled with a medicine, it is considered that such a medicine would be useful as an agent for treating rheumatism.
Incidentally, it is known that proliferation of the synovial cells in rheumatism is not out of control, but is spontaneously controlled (cf. Daniel J. McCarty (1985) in “Arthritis and allied conditions, A textbook of rheumatology” 10
th
Edition, Lea & Febiger). Furthermore, it has become clear recently that apoptosis is caused in synovial cells of a rheumatic patient and that the Fas antigen appears on a membrane of the synovial cells. Nakajima et al. (cf. Nakajima, T., et al. (1995) Arthritis Rheum. 38, 485-491) and Aono et al. (cf. 38th Japan rheumatic society summary collection (1994), 487 page and Heisei 6 Japan cancer society general meeting reports 1994, 338 page) have studied whether apoptosis is induced in a synovial cell when the anti-human Fas antibody having a cytotoxic activity is added to the abnormally proliferating synovial cells originated from a rheumatic patient, and have found that apoptosis is induced at a higher rate in the abnormally proliferating synovial cells originated from a rheumatic patient, than in synovial cells which are not originated from a rheumatic patient. Accordingly, an anti-human Fas antibody can selectively induce apoptosis, not only in a lymphocyte, but also in the abnormally proliferating synovial cells, and therefore it is considered to be useful as an agent for rheumatism.
Several kinds of anti-human Fas mouse monoclonal antibodies have already been found (cf. Yonehara, S., et al (1989) J. Exp. Med. 1, 1747-1756, (1989); SCIENCE, 245, 301-305 (1989), and the like). Furthermore, as described above, it has been reported that the antibodies induce apoptosis in synovial cells of a rheumatic patient, in-vitro (cf. 38th Japan rheumatic society summary collection (1994), p.487; and Japan cancer society general meeting reports (1994), p.338). Furthermore, some anti-Fas antibodies have been found to be effective and safe for treatment in an autoimmune disease model animal or a rheumatoid arthritis model animal (cf. European patent application publication No. 0909816).
On the other hand, it is known that the effect of treatment for a rheumatoid arthritis patient can be increased by using methotrexate and a monoclonal antibody cA2 against a tumor necrosis factor &agr; (TNF&agr;) together (Carden, the 7th international rheumatism symposium summary (1998) p.12-13). However, a synergistic effect of an anti-Fas antibody and methotrexate was not heretofore known at all.
If there is a compound which reinforces the efficacy of an anti-Fas antibody useful as an agent for the prophylaxis and/or treatment of an autoimmune disease or rheumatoid arthritis, the amount of the anti-Fas antibody to be used can be decreased by using the compound and an anti-Fas antibody together. Thereby, the possibility that a patient becomes tolerant to an anti-Fas antibody as a result of production of antibodies against anti-Fas antibodies in the patient's body or the like can be decreased. Accordingly, there has been a need for a prophylactic or therapeutic agent consisting of a combination of an anti-Fas antibody and a compound reinforcing the efficacy of the anti-Fas antibody, which can be used for a long time.
The “synergy effect” shown in this application means a coordinated or correlated action by an anti-human Fas antibody and a compound having a folate antagonistic activity or dihydrofolate reductase inhibiting activity. The coordinated or correlated action is far stronger than would be expected by a person of ordinary skill in the art.
SUMMARY OF THE INVENTION
The present invention relates to a pharmaceutical composition comprising an anti-human Fas antibody having an apoptosis inducing activity and a compound having a folate antagonist activity or a dihydrofolate reductase inhibiting activity, as active ingredients. Preferably, the anti-human Fas antibody is a monoclonal antibody CH11, anti-human Fas monoclonal antibody HFE7A produced by a mouse-mouse hybridoma HFE7A (FERM BP-5828), or humanized antibodies thereof. Preferably, the above-mentioned compound having a folate antagonist activity or a dihydrofolate reductase inhibiting activity is selected from the group consisting of: methotrexate, edatrexate, epiroprim, iometrexol, pyritrexim, trimetrexate, brodimoprim, MX-68, N-[4-[3-(2,4-diamino-6,7-dihydro-5H-cyclopenta[d]pyrimidin-5-yl)propyl]benzoyl]-L-glutamic acid, N-[[5-[2-(2-amino-1,4,5,6,7,8-hexahydro-4-oxopyrido[2,3-d]-pyrimidin-6-yl)ethyl]-2-thienyl]carbonyl]-L-glutamic acid, (R)-N-[[5-[2-(2-amino-1,4,5,6,7,8-hexahydro-4-oxopyrido[2,3-d]pyrimidin-6-yl)ethyl]-2-thienyl]carbonyl]-L-glutamic acid, N-((2,4-diamino-3,4,5,6,7,8-hexahydropyrido[

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