Human GM-CSF receptor component

Details Human GM-CSF receptor component Human GM-CSF receptor component

1993-01-07

1998-01-06

Ulm, John

Chemistry: natural resins or derivatives; peptides or proteins;

Proteins, i.e., more than 100 amino acid residues

435 691, 536 235, C07K 14705, C12N 1512

Patent

active

057056110

DESCRIPTION:

BRIEF SUMMARY
FIELD OF THE INVENTION

The invention relates generally to the human granulocyte-macrophage colony stimulating factor (GM-CSF) receptor, and more particularly, to the synthesis of a human GM-CSF receptor component and to the use of the receptor component for screening agonists and antagonists of human GM-CSF.


BACKGROUND

Circulating blood cells are constantly replaced by newly developed cells. Replacement blood cells are formed in a process termed hematopoiesis which involves the production of at least eight mature blood cell types within two major lineages: (1) the myeloid lineage which includes red blood cells (erythrocytes), macrophages (monocytes), eosinophilic granulocytes, megakaryocytes (platelets), neutrophilic granulocytes, basophilic granulocytes (mast cells); and (2) the lymphoid lineage which includes T Cells (Academic Press, New York, 1983)!. Much of the control of blood-cell formation is mediated by a group of interacting glycoproteins termed colony stimulating factors (CSFs). These glycoproteins are so named because of the in vivo and in vitro assays used to detect their presence. Techniques for the clonal culture of hematopoietic cells in semisolid culture medium have been especially important in the development of in vitro assays. In such cultures, individual progenitor cells (i.e., cells developmentally committed to a particular lineage, but still capable of proliferation) are able to proliferate to form a colony of maturing progeny in a manner which is believed to be essentially identical to the comparable process in vivo. The role of CSFs in hematopoiesis is the subject of many reviews, and is of great interest to clinical investigators who must treat blood diseases or deficiencies; e.g. Metcalf, The Hemopoietic Colony Stimulating Factors (Elsevier, N.Y., 1984); Clark and Kamen, Science, Vol. 236, pgs. 1229-1237 (1987); Sachs, Science, Vol. 238, pgs. 1374-1379 (1987); Dexter et al., eds., Colony Stimulating Factors (Dekker, N.Y., 1990); and Morstyn et al., Cancer Investigation, Vol. 7, pgs. 443-456 (1989).
CSFs are believed to play a role in the development and progression of myeloid leukemias; e.g., Metcalf, Hamatol, Bluttransfus., Vol. 31, pgs. 16-25 (1987). Myeloid leukemias are clonal neoplasms of granulocyte-macrophage precursor cells, which fall into two major groups: chronic myeloid leukemia (CML) and acute myeloid leukemia (AML). CML is characterized by expansion in the marrow of the granulocyte-monocyte population at all stages of maturation, with massive enlargement of hematopoietic populations in the spleen and blood. Whereas chemotherapy is successful in reducing the excessive size of the leukemic cell populations, conventional regimens have not succeeded in preventing terminal acute transformation (of progressively higher proportions of cells into immature or abnormal forms) or in extending the life spans of afflicted patients (Metcalf, cited above, 1984). AML is characterized by an accumulation of immature granulocyte-monocyte blast cells with often little or no evidence of maturing granulocyte-monocyte cells. The disease primarily involves the bone marrow, and spleen enlargement usually is only moderate. Total blood nucleated cells may or may not be elevated, but there is a high proportion of immature blast cells associated with relatively few mature cells. There is usually an associated anemia, thrombocytopenia and a relative absence in the marrow and peripheral blood of mature granulocytes and monocytes. Death usually results from uncontrollable hemorrhage or overwhelming infections (Metcalf, cited above, 1984).
It is believed that both forms of leukemia are driven by abnormal production of, or responsiveness to, colony stimulating factors, particularly GM-CSF. In particular, it has been shown that leukemic cells from some AML patients are capable of autonomous proliferation in vitro because they express GM-CSF constitutively, and that such autonomous proliferation can be inhibited by the addition of GM-CSF neutralizing believed that myeloid leukemias, in particular A

REFERENCES:
Clark et al., Science, vol. 236, pp.1229-1237, 1989.
Gearing et al., The EMBO Journal, vol. 8, No. 12, pp. 3667-3676, 1989.
Morstyn et al., Cancer Investigation, vol. 7, pp. 443-456, 1989.
Sachs, Science, vol. 238, pp. 1374-1379, 1987.
Young et al., Blood, vol. 68, pp. 1178-1181, 1986.
Hyashida et al., Proc. Natl. Acad. Sci. USA, 87 (Dec. 1990), 9655-9659.
Kitamura et al., Proc. Natl. Acad. Sci. USA, 88 (Jun. 1991), 5082-5086.

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