Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Recombinant dna technique included in method of making a...
Patent
1994-09-08
1999-02-02
Spector, Lorraine
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Recombinant dna technique included in method of making a...
435 697, 435325, 4352523, 4353201, 536 235, 536 2431, 935 12, C12N 1512, C07H 2104
Patent
active
058663720
DESCRIPTION:
BRIEF SUMMARY
This application is the U.S. National stage of PCT/DE92/00956, filed Nov. 16, 1992.
The invention relates to the lymphoid surface antigen CD30 occurring in Hodgkin's disease, its protein sequence and associated nucleotide sequence, manufacture thereof by genetic engineering, means for diagnosis and investigation of Hodgkin's disease and use of the nucleotide sequences, more particularly for producing transgenic animals.
The pathogenesis of Hodgkin's disease (HD) is as yet poorly understood, although in Central Europe it is numbered among the frequent human lymphomas. After the surface antigen CD30 had been described, identification of the tumour cells of Hodgkin's disease, i.e. the Hodgkin (H) and the Reed-Sternberg (RS) cells, became much easier or possible for the first time (Schwab et al (1982), Nature 299, 65-67; Stein et al (1982) Int. J. Cancer 30, 445-449; McMichael, publisher (1987): Leucocyte Typing III, Oxford University Press, Oxford). The appearance of the CD30 surface antigen is associated with activation of the lymphocytes, as shown by research on in vitro stimulated or virally (by HTLV-I, HTLV-II, EBV) transformed T and B cells (Stein et al, (1985) Blood, 66, 848-858; Andreesen et al. (1984) Blood, 63, 1299-1302). It is assumed that Hodgkin and Reed-Sternberg cells are malignant transformed T or B cells and that the histological variants in Hodgkin's disease are due to secretion of different cytokines (Stein et al. (1989) Recent Results Cancer Res.117, 15-26). The CD30 antigen therefore seems to be important as regards the intracellular signal system and the genesis of tumours.
Histological investigation of tumour tissues has also shown that the CD30 antigen is suitable for identification of large-cell anaplastic neoplasms, which are therefore also called CD30 or Ki-1-positive anaplastic large-cell lymphomas (ALCL; in English, Ki-1.sup.+ anaplastic large cell lymphomas). These tumours, which occur particularly in children and young people, constitute a separate species of lymphomas and are called true histiocytic lymphomas or malignant histiocytosis. The simultaneous occurrence of re-arranged Ig and T-cell receptor genes in most CD30 positive ALCLs shows that these tumour cells are lymphoid. Accordingly, CD30-positive ALCLs are not only a phenotypic but also a genotypic unit. CD30-positive ALCLs are classified as primary and secondary; they originate mainly from T-cells and neutral cells, or to a lesser extent from B-cells. Morphologically, ALCLs are classified as a) common; b) Hodgkin-related; c) giant cell-rich and d) lymphohistiocytic.
Hitherto, by definition, the CD30 antigen has been detectable only by monoclonal antibodies, more particularly the monoclonal antibodies Ki-1 and Ber-H2 (Schwab et al. (1982) Nature 299, 65-67; Schwarting et al (1989) Blood 74, 1678-1689). One disadvantage, however, is that they only recognise a respective epitope on the antigen; they are also unsuitable for detecting and investigating the associated nucleic acids. A diagnosis based only on individual epitopes is also sensitive to artifacts and is not comprehensive. Finally, the recognisability of an isotope depends on how the sample is fixed and prepared; also the epitopes can alter with the state of the cell. For example an epitope can be blocked by glycosylation of neighbouring N- or O-glycosylation sites, and also phosphorylation, more particularly tyrosine phosphorylation, etc., bring about conformation changes which cause an epitope to disappear, particularly if it is made up of a number of peptide-chain portions. Such changes in cell state occur particularly often during the progress of the tumour.
Hitherto also it has been impossible to make a detailed investigation of the properties of the CD30 antigen as a receptor or binding protein with regard to other growth or hormonal factors--partly because of the small quantities available and also because the antigen is a membrane protein with functionally different cytosolic, transmembrane and extracellular protein portions, hereinafter also called domain
REFERENCES:
M.A. Frohman et al., PNAS 85:8998-9002, Dec. 1988.
H. Durkop et al., Cell 68:421-427, Feb. 7, 1992.
P. Froese et al., J. Immunology 139(6):2081-2087, Sep. 15, 1987.
O. Josimovik-Alasevik et al., Eur. J. Immunol. 19:157-162, 1989.
A. Aruffo et al., PNAS 84:8573-8577, 1987.
R.A. Young et al., PNAS 80:1194-1198, 1983.
Durkop Horst
Latza Ute
Stein Harald
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