Drug – bio-affecting and body treating compositions – Lymphokine – Interleukin
Patent
1992-07-27
1996-11-05
Sayala, Chhaya D.
Drug, bio-affecting and body treating compositions
Lymphokine
Interleukin
514 8, 514 21, A61K 4505
Patent
active
055715087
DESCRIPTION:
BRIEF SUMMARY
The present invention relates generally to a method for, and pharmaceutical compositions useful in, the treatment of thrombocytopenia in a mammal by the administration of an effective amount of leukaemia inhibitory factor (LIF) and/or its derivatives and optionally in combination with one or more other cytokines.
Leukaemia inhibitory factor (LIF) was purified (1, 2) and cloned (3) on the basis of its capacity to induce differentiation in and suppress clonogenecity of the M1 mouse myeloid leukaemic cell line (see International Patent Application No. PCT/AU88/00093). LIF has comparable effects on human HL60 and U937 cells, particularly when acting in collaboration with colony stimulating factors (4). In conventional semisolid cultures, LIF has no colony stimulating activity for normal murine haemopoietic cells (5) although it stimulates the proliferation of the continuous haemopoietic cell line DA1.1a (6) and erythroid cell lines from myc-transformed mouse fetal liver cells.
Receptors for LIF are present on monocytemacrophages (7) and some non-haemopoietic cells including osteoblasts, placental and liver cells (8). LIF has been shown to possess a remarkable variety of actions: it releases calcium from bone tissue (9), is the factor preventing spontaneous differentiation in normal embryonic stem cells (10, 11), is a molecule stimulating DA1.1a (6) cell proliferation, stimulates liver cells to produce acute phase proteins (12, 13), and is a lipoprotein lipase inhibitor (14).
In initial studies, the consequences of high LIF levels were determined in mice engrafted with FDC-P1 cells producing LIF (International Patent Application No. PCT/U90/00092; 15, 16). Such mice developed a fatal syndrome of body weight loss, osteosclerosis with compensatory splenic and liver extramedullary haemopoiesis, a neutrophil leukocytosis, pancreatitis, calcification in skeletal muscle, heart and liver, liver necrosis and fibrosis, thymus atrophy, adrenal cortex changes and failure of spermatogenesis and corpora lutea formation.
The engrafted model is potentially complex due to the presence of the engrafted FDC-P1 cells. The present invention arose from experiments attempting to overcome this complexity by injecting purified recombinant murine LIF into mice to determine what changes could be induced by injected LIF. Changes inter alia in blood components, marrow, spleen and peritoneal cell components, megakaryocyte and progenitor cell components in the marrow and spleen were analysed and it was surprisingly discovered that LIF caused the enhancement, stimulation and/or increase in the level of formation of megakaryocytes and/or their progenitor cells and led to an increase in platelets. The present invention, therefore, will be beneficial in the treatment of thrombocytopenia occurring in some acute infections, anaphylactic shock, certain haemorrhagic diseases, anaemias, as a result of chemo- or radiotherapy, platelet- function deficient disease, chronic hepatic disorders and renal disorders.
Accordingly, one aspect of the present invention relates to a method for treating thrombocytopenia in a mammal which method comprises administering to said mammal an effective amount of leukaemia inhibitory factor (LIF) for a time and under conditions sufficient to enhance, stimulate and/or increase the level of formation of megakaryocytes and/or their progenitor cells and/or increase the level of platelets.
In another embodiment, LIF is administered simultaneously or sequentially with one or more other cytokines.
Another aspect of the present invention is directed to a pharmaceutical composition for treating thrombocytopenia in a mammal said composition comprising LIF in combination with one or more other cytokines and one or more pharmaceutically acceptable carriers and/or diluents.
Yet another aspect of the present invention relates to the use of LIF alone or in combination with one or more other cytokines and/or their derivatives for the manufacture of a medicament for treating thrombocytopenia by enhancing, stimulating and/or increasing the
REFERENCES:
patent: 5126325 (1992-06-01), Kishimoto et al.
Metcalf et al. (1989) "A Myelosclerotic Syndrome in Mice Engrafted with Cells Producing High Levels of Leukemia Inhibitory Factor (LIF)" Leukemia 3:847-852.
Baumann, et al. (1989) "Hepatocyte-Stimulating Factor III Shares Structural and Functional Identity with Leukemia-Inhibitory Factor", J. Immunol. 143, 1163-1167.
Yamamori et al. (1989) "The Cholinergic Neuronal Differentiation Factor From Heart Cells Is Identical to Leukemia Inhibitory Factor" Science 246, 1412-1416.
McDonald T. P., Magakaryocyte biology and Precursors: in vitro cloning and cellular properties, Eds. Evatt B. L. et al., Elsevier, pp. 39-57, 1981.
Wintrobe et al., Clinical Hemetology, Eighth Edition, Chapter 47, 1981.
Whicher et al., Clin Chem., vol. 36(7), pp. 1269-1281, 1990.
Hamblin, Lymphohines, IRL Press, 1988, pp. 22-23, 32-33, 45-48, 51-52.
Burstein et al., J. Cellular Physiology, vol. 153, pp. 305-312, 1992.
Metcalf et al., Blood, vol. 77(10), pp. 2150-2153, 1991.
Stiles et al., Basic & Clinical Immunology, Seventh Edn., Chapter 7, 1991.
McDonald Advances in Experimental Med. & Biol. vol. 241, 1988, pp. 243-253.
Ishibashi et al. Blood, vol. 74, No. 4 Sep. 1989, pp. 1241-1244.
Amrad Corporation Limited
Sayala Chhaya D.
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