Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Patent
1993-10-13
1996-07-30
Ulm, John
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
435 72, 435 71, 435 641, 4351523, 4353201, 530350, 536 235, C07K 14705, C12N 1512, C12N 119, C12N 121
Patent
active
055410634
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The invention relates generally to the human interleukin-3-receptor (hlL-3-receptor), and more particularly, to the synthesis of a human IL-3-receptor component and to the use of the receptor component for screening agonists and antagonists of human IL-3.
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 lymphocytes, and B lymphocytes (Burgess and Nicola, Growth Factors and Stem 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), including G-CSF, M-CSF, GM-CSF, and multi-CSF (also known as IL-3). 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 vive. 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).
The biological effects of the CSFs are mediated by specific cell surface receptors, which may consist of one or more components. Recently, several of these have been cloned and characterized, e.g. Gearing et al., EMBO J., Vol. 8, pgs. 3667-3676 (1989) (low affinity .alpha.-chain of human GM-CSF-receptor); Itoh et al., Science, Vol. 247, pgs. 324-327 (1990) (low affinity mouse IL-3-receptor); and Hayashida et al., Proc. Natl. Acad. Sci., Vol. 87, pgs. 9655-9659 (1990) (.beta.-chain of human GM-CSF-receptor). Besides contributing to an understanding of the signal transduction process, many of these receptors will be useful screening tools for agonists and antagonists of the natural ligand. In particular, such tools may lead to the development of non-protein agonists and antagonists which would obviate many of the difficulties associated with protein therapeutics, e.g. intravenous delivery, short serum half-life, and the like.
SUMMARY OF THE INVENTION
The invention is directed to a component of the human IL-3-receptor, referred to herein as the G-chain of the human IL-3-receptor, and to compositions thereof which bind with high affinity to human IL-3. Specifically such compositions include an .alpha.-chain and .beta.-chain of the human IL-3-receptor that can operably associate to form a high affinity receptor for human IL-3. The invention includes allelic and genetically engineered variants of the .alpha.-chain-receptor, and nucleic acids encoding the .alpha.-chain-receptor and its allelic and genetically engineered variants. Preferably, the receptor component of the invention is selected from the group of polypeptides of the open reading frame defined by the amine acid sequence set forth in SEQ. ID. No. 2 (immediately preceding the Claims). Although the listed sequence includes the intracellular domain of the .alpha.-chain of the receptor, it is clear that truncated forms
REFERENCES:
Hayashida et al, P.N.A.S. 87:9655-9659, Dec. 1990.
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Kitamura Toshio
Miyajima Atsushi
Ching Edwin P.
Macevicz Stephen C.
Schering Corporation
Ulm John
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