Drug – bio-affecting and body treating compositions – Lymphokine – Interleukin
Reexamination Certificate
1997-12-17
2001-07-10
Spector, Lorraine (Department: 1646)
Drug, bio-affecting and body treating compositions
Lymphokine
Interleukin
C530S351000
Reexamination Certificate
active
06258352
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a pharmaceutical composition for treating thrombocytopenia which comprises as an active ingredient human interleukin-15 (to be described hereinafter as “hIL-15”) having activity to promote the differentiation, maturation and/or proliferation of megakaryocyte-thrombocyte cells and the production of platelets through actions on the cells. Since hIL-15 of this invention acts on the megakaryocyte-thrombocyte system to accelerate the differentiation, maturation and/or proliferation thereof to thereby accelerate the formation of thrombocytes, it is useful especially in the field of medical care as an active ingredient of therapeutic and preventive agents for thrombocytopenia and for thrombocytopenic purpura associated with chemotherapy and bone marrow transplantation and for various diseases characterized by the tendency for bleeding attributable to thrombocytopenia and the like.
BACKGROUND OF THE INVENTION
Blood, which is an indispensable medium for somatic cells constituting the living body, contains blood cells such as erythrocytes, leucocytes, lymphocytes, and thrombocytes. These cells have their own functions and contribute to the maintenance of homeostasis of the living body. It has been a longtime subject of research in the field of hematology to clarify the essential features of differentiation, maturation and proliferation of the blood cells in vivo. It has become recently apparent that the various blood cells are differentiated and maturated from hematopoietic stem cells of the bone marrow and various types of humoral factors in vivo participate in the processes of differentiation and maturation.
From these findings, the humoral factors are expected to be used as a medicament for curing diseases with decreases in blood cells, and the like. Until now there were found various humoral factors including erythropoietin (EPO), G-CSF, GM-CSF, M-CSF, and interleukin (IL) and some of them have been used practically as medical agents which are capable of promoting the differentiation and maturation of blood cells such as erythrocyte, leucocyte, lymphocyte lineages, or the like.
Thrombocytes are akaryocytes with diameters of 2-3 &mgr;m present in the blood and one of the tangible components in the blood, which play an important role in arrest of hemorrhage and formation of thrombus in vivo. It has become apparent that megakaryoblasts are formed within the bone marrow from hematopoietic stem cells via progenitor cells to mature to megakaryocytes and the cytoplasm of the megakaryocytes is fragmented to form thrombocytes, which are released into the blood.
Recently various results of researches on megakaryocyte-thrombocyte system have been reported. For example, it has been reported that IL-6 has activity to promote the maturation of megakaryocytes, which is a precursor cell of thrombocyte [Ishibashi T. et al., Proc. Natl. Acad. Sci. USA 86, 5953-5957 (1989), Ishibashi T. et al., Blood 74, 1241-1244 (1989)].
According to the research conducted so far, it is considered that two factors that act differently contribute to the formation of megakaryocyte colonies from bone marrow cells [Williams N. et al., J. Cell. Physiol., 110, 101 (1982)]. The report shows that one is a megakaryocyte colony stimulating factor, Meg-CSF, which forms the megakaryocyte colonies by itself, while the other is a megakaryocyte potentiating factor, Meg-POT, which does not have activity to form megakaryocyte colonies by itself, but has activity to increase the number of megakaryocyte colonies and to promote the maturation of the colonies in the presence of the Meg-CSF.
For example, IL-3 [Teramura M. et al, Exp. Hematol., 16, 843 (1988)] and granulocytes-macrophage colony stimulating factor [Teramura M. et al, Exp. Hematol., 17, 1011 (1989)], and the like were reported as factors having Meg-CSF activity in humans. While IL-6 [Teramura M. and Mizoguthi H., Int. J. Cell Cloning, 8, 245 (1990)], IL-11 [Teramura M. et al, Blood, 79, 327 (1992)] and erythropoietin [Bruno E. et al., Blood, 73, 671 (1989)], and the like were reported as factors having Meg-POT activity in humans.
However, it is known that most of these factors are not the factors that specifically act on megakaryocyte-thrombocyte system but to express their effects through actions on other cells of the blood system or cells not belonging to blood cell system. Thus, there is a risk that not only the expected actions but also other actions would be expressed when these factors are administered as medical agents in anticipation of the actions on the megakaryocyte-thrombocyte system. For example, the above-described IL-6 has various actions other than those mentioned above. From the fact that IL-6 is deeply involved in induction of inflammation as an acute phase reactive protein in vivo, there may be a risk of severe side effects if it is used as a medical agent as it is. Recently c-Mpl ligand has been reported to have both weak Meg-CSF and strong Meg-POT activities [dc Sauvage F. J. et al., Nature, 369, 533 (1994), Kaushansky K. et al., Nature, 369, 568 (1994)]. However, because of paucity of findings on the actions of c-Mpl ligand, practicability of this substance as a medical agent is still unknown.
Thus, as far as factors acting on megakaryocyte-thrombocyte system are concerned, it is important to find out biologically active substances that strongly acts on the megakaryocyte-thrombocyte system and have high activity to promote their differentiation, maturation and/or proliferation. The development of such biologically active has been strongly demanded in the art.
“IL-15 is a protein with a molecular weight of ca 140,00; human IL-15 was purified by Grabstein et al. [
Science
, 264, 965, (1994), hereby incorporated by reference] based on the proteins ability to support the proliferation of a mouse T cell line. Isolation of the gene revealed that a mature protein with 114 amino acid residues was formed by cleavage of a precursor with 162 amino acid residues. The genomic sequence of human IL-15 is given in Krause et al. (1996)
Cytokine
8(9):667-674, hereby incorporated by reference. Human IL-15 is expressed well in placenta, monocytes of peripheral blood and skeletal muscle, while it is also expressed weakly in heart, lung, liver, and kidney, and the like. As to the biological activities of IL-15, there is a report describing its actions to support differentiation and proliferation of T and B cells, to activate NK cells, and to induce CTL and LAK activities. Accordingly, IL-15 is considered to be a cytokine involved mainly in immunological processes such as proliferation, differentiation, and activation of lymphocytes.
SUMMARY OF THE INVENTION
The present inventors investigated biologically active substances which act on the megakaryocyte-thrombocyte system, to promote the differentiation, maturation and/or proliferation of cells of the megakaryocyte-thrombocyte system and the formation of thrombocytes. IL-15 was found to have such activity.
Accordingly, an object of the present invention is to provide a pharmaceutical composition for treating or preventing (and in some cases, curing) thrombocytopenia, comprising human IL-15 (hIL-15) as an active ingredient.
Another object of the present invention is to provide a pharmaceutical composition comprising hIL-15 as an active ingredient which is effective for treating, curing or preventing diseases derived from thrombocytopenia and diseases accompanied by thrombocyte dysfunctions.
REFERENCES:
patent: 5552303 (1996-09-01), Grabstein et al.
patent: 5747024 (1998-05-01), Grabstein et al.
patent: 96 90 7755 (1998-02-01), None
Sheeran et al,British J. Anaesthesia, 78(2) 1997 p 201-219. (Abst Only).*
Atamas et al,Life Sciences, 61(12) 1997, p 1105-12 (Abst Only).*
Ishibashi, T. et al., Human Interleukin 6 is a Direct Promoter of Maturation of Megakaryocytes In Vitro, Proc. Natl. Acad. Sci., U.S.A., 86, 5953-5957 (1989).
Ishibashi, T. et al., Interleukin-6 is a Potent Thromb
Chugai Seiyaku Kabushiki Kaisha
Clark & Elbing LLP
Jiang Dong
Spector Lorraine
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