The organ transplantation performed these days encompasses a broad spectrum of tissues, including cardiac, pulmonary, hepatic, pancreatic, small intestinal, renal, corneal, dermal, combined heart-lung and bone marrow transplants. Meanwhile, as drugs essential to such organ transplantations, immunosuppressants such as cyclosporine, azathioprine, mizoribine, OKT3 which is a monoclonal antibody, steroids, antilymphocyte globulins, etc. are in use for prophylactic or therapeutic immunosuppression in such organ transplantations. The advent of these drugs resulted in a marked enhancement of the success rate of transplantation but the massive and prolonged administration of the drugs met with not only severe myelosuppression and the consequent side effects such as leukopenia, thrombopenia, anemia and renal failure due to nephrotoxicity but also the risk of dangerous complications such as increased susceptibility to infection, anemia, bleeding tendency and so on. Therefore, the dosage of such drugs has to be restricted in many cases.
In recent years, for further enhancement of the success rate of transplantation and for the purpose of alleviating side effects, research and development efforts are being made on FK506, RS61443, 15-deoxyspergualin; DSG), adhesion molecule antibodies, etc., but antibody preparations have the disadvantage of being unsuited for maintenance therapy requiring long-term administration because heterologous proteins are injected. Moreover, although combination therapies using the above-mentioned drugs are practiced in GVHD (graft-versus-host disease), a unique disease complicating a homoplastic marrow transplantation, the therapeutic effects have not necessarily been satisfactory. Therefore, the industry needs research and development for a new drug which may be termed a graft rejection inhibitor and can be used in a long-term-maintenance therapy for positive suppression of both acute and chronic rejections with a reduced risk of side effects in cases of the organ transplantations mentioned above.
Meanwhile, a large number of cytokines has been discovered as proteineous factors which inhibit the expression of various physiologic functions such as immune response, inflammatory reaction and hematopoiesis in the host and with the progressive elucidation of their structures and actions, it has become increasing clear that the actions of these cytokines are not only confined to the immune system but extend to various biologic functions, thus being closely associated with the genesis, differentiation, homeostasis and pathophysiology of the body.
Among said cytokines, IL-1 is a proteinaceous factor produced chiefly from monocytes and macrophages and is a polypeptide with a molecular weight of about 12000-18000 [S. B. Mizel et. al., Immunol. Rev., 63, 51-71, 1982]. This IL-1 acts on various kinds of cells, exhibits various biological activities and, hence, plays an important role in nearly all the vital reactions, such as immunity, inflammation, hematopoiesis, endocrine system and cerebral nervous system. IL-1 occurs in two distinct molecular forms as classified by isoelectric point, viz. pI5 and pI7, and whereas the former is known as IL-1.alpha., the latter is known as IL-i1.beta. Oppenheim, J. J., et al., Immunol. Today, 7, 45, 1986: Dinarello, C. A., Adv. Immuno., 44, 153, 1988]. The homology of the amino acid sequence of the respective molecular forms is as high as 60-70% even among different animal species but the two molecular forms show only a low homology of 25% even in the same species. Moreover, both IL-1.alpha. and IL-1.beta. reportedly bind to the same receptor on the cell membrane [Lowenthal, K., et al., J. Exp. Med., 164, 1060, 1986]. It has also been reported that IL-1 exerts direct growth inhibiting and cytocidal actions on various tumor cells [Onozaki, K., et al., J. Immunol., 135, 3962, 1985], thus producing antitumoral effects [Nakamura, S., et al., Jpn. J. Cancer Res., 77, 767, 1986: North, R. J., et al., J. Exp. Med., 168, 2031, 1988]. In addition, with regard to this IL-1, not only the above-mentioned antitumor effect, such other effects have been reported as fever induction, synovial cell proliferation, cartilage destruction, bone destruction, promotion of bone resorption, impairment of vascular endothelial cells, stimulation of mesangial cell proliferation, induction of prostaglandin E.sub.2 (PGE.sub.2) production, inhibition of development of fertilized ova, induction of PGE.sub.2 and PGE2.alpha. production, promotion of granulation, promotion of IL-1-associated autocrine leukemic cell proliferation, IL-1-related inflammation locally induced by crystalline urea, and, as effects on the immune system, stimulation of the differentiation and augmentation of activity of T, B and NK cells, induction of PGE production, induction of production of cytokines such as IL-2, IL-6, TNF, GM-CSF, G-CSF, etc., induction of NGF from fibroblasts, induction of sleep, hyperalgia and anorexia, induction of ACTH production, and an action to increase glucocorticoids [Onozaki, K., Biomedicine & Therapeutics, 24 (1), 27-31, 1990].
Though, as described above, IL-1 plays a critical role in the inhibition of biologic functions such as the expression of immune response, inflammatory reactions and hematopoiesis, an excess production of IL-1 in the body may cause various diseases accompanied by inflammation. Moreover, in view of the biological activities of IL-1, its excess production in vivo may trigger the onset of serious diseases such as rheumatoid arthritis, Lyme disease, osteoporosis, Kawasaki disease, poisoning-shock syndrome, gout, glomerulonephritis, endometritis, premature delivery, abortion, granuloma, acute myelocytic leukemia and so on. For the prevention and treatment of such diseases, drugs capable of inhibiting an excess production of IL-1 in vivo should be effective but no drug possessed of such an action has been developed. Therefore, a keen demand exists for new drug research and development in this segment of the industry.
USPTO Backgrounds
USPTO Backgrounds