Drug – bio-affecting and body treating compositions – Conjugate or complex of monoclonal or polyclonal antibody,...
Patent
1997-02-12
1999-06-29
Scheiner, Toni R.
Drug, bio-affecting and body treating compositions
Conjugate or complex of monoclonal or polyclonal antibody,...
4241811, 4241331, 4241741, 4241411, 4241431, 4241441, 435346, 435330, 4353441, 435 723, 5303882, 53038823, 53038885, A61K 39395, C12N 512, G01N 33574, C07K 1628
Patent
active
059165618
DESCRIPTION:
BRIEF SUMMARY
The invention relates to a monoclonal antibody against an epitope which is coded by the variant exon v6 of the CD44 gene, antibody molecules derived therefrom and uses of the antibody or antibody molecules for diagnostic and therapeutic purposes.
Recently it has been shown that the expression of variants of the surface glycoprotein CD44 is necessary and sufficient for causing so-called spontaneous metastatic behaviour of a non-metastasizing rat pancreatic adenocarcinoma cell line as well as a non-metastasizing rat fibrosarcoma cell line (Gunthert et al., 1991). While the smallest CD44 isoform, the standard form CD44s (or CD44std), is ubiquitously expressed in different tissues including epithelial cells, certain CD44splice variants (CD44v, CD44var) are expressed only in a subset of epithelial cells. The CD44variants are generated by alternative splicing in a way that the sequences of ten exons (v1-v10) are completely excised in CD44s but can appear in the bigger variants in different combinations (Screaton et al., 1992; Tolg et al., 1993; Hofmann et al., 1991). The variants differ in that different amino acid sequences are inserted at a certain site of the extracellular part of the protein. Such variants can be detected in various human tumor cells as well as in human tumor tissue. So, the expression of CD44 variants in the course of colorectal carcinogenesis has recently been investigated (Heider et al., 1993a). The expression of CD44variants is absent in normal human colon epithelium, and only a weak expression is detectable in the proliferating cells of the crypts. In later stages of the tumor progression, e.g. in adenocarcinomas, all malignancies express variants of CD44. Tissue expression of variant CD44 on a high level has also been shown in aggressive Non-Hodgkin lymphomas (Koopman et al., 1993).
Exon v6 appears to play a special role especially in the course of metastatic spread, (Rudy et al., 1993). In an animal model, antibodies against v6 specific epitopes could prevent the settlement of metastatic cells and the growth of metastases (Seiter et al., 1993). In colon carcinomas, v6 expression correlates with tumor progression (Wielenga et al., 1993). In gastric carcinomas, v6 expression is an important diagnostic marker to distinguish tumors of the intestinal type from those of the diffuse type (Heider et al., 1993b). In the latter two publications, v6 expression has been determined using antibodies against v6 specific epitopes.
Monoclonal antibodies against epitopes coded by exon v6 are known in the state of the art (Hofmann et al., 1991; Wielenga et al., 1993). Because of the high potential utility such antibodies could have in diagnosis and therapy, there is a great need of antibodies with improved properties.
The present invention has the object of providing an antibody with significantly better properties as compared to the known v6 specific antibodies.
The present invention has succeeded in this aim. It relates to an antibody with the designation VFF-18. The invention further relates to a hybridoma cell line which secretes this antibody and has been deposited on Jun. 7, 1994 under the accession number DSM ACC 2174 with the DSM-Deutsche Sammlung fur Mikroorganismen und Zellkulturen GmbH, Mascheroder Weg 1b, D-38124 Braunschweig, Germany.
The terms "antibody" or "antibody molecules" hereinafter refer not only to complete immunoglobulins but also equivalent substances with regard to binding specificity and affinity as well as the antibody derivatives and recombinant antibody molecules described.
The antibody VFF-18 has been prepared by a process according to example 1. The antibody can also be obtained from the hybridoma cell line deposited. It is within the skills of the average artisan to prepare derivatives of the antibody of the invention or, starting from a sequence analysis of the antibody and/or by use of the hybridoma cell line producing this antibody, to prepare recombinant antibody molecules with the same idiotype, i.e. antibody molecules having the same amino acid sequence in the regi
REFERENCES:
Salmi, Marko et al., in Journal of Cell Biol. vol. 122: 431-442, Jul. 1993. (see *1449).
Heider, Karl-Heinz et al., "Differential Expression of CD44 Splice Variants in Intestinal-and Diffuse-Type Human Gastric Carcinomas and Normal Gastric Mucosa," Cancer Research 53, 4197-4203, Sep. 15, 1993.
Jackson, D.G., et al., "Expression of Alternatively Spliced Forms of the CD44 Extracellular-Matrix Receptor on Human Lung Carcinomas," Int. J. Cancer: Supplement 8, 110-115 (1994).
Kreitman, Robert J., et al., "Pseudomonas Exotoxin-based Immunotoxins Containing the Antibody LL2 or LL2-Fab' Induce Regression of Subcutaneous Human B-Cell Lymphoma in Mice," Cancer Research 53, 819-825, Feb. 15, 1993.
Salmi Marko, et al., "Expression of Domain 3 Containing Isoforms of CD44 in Man," 8th International Congress of Immunology, p. 274, abstract W-47/I-34 (1992).
Salmi, Marko, et al., "Regulated Expression of Exon v6 Containing Isoforms of CD44 in Man: Downregulation During Malignant Transformation of Tumors of Squamocellular Origin," The Journal of Cell Biology, vol. 122, No. 2, 431-442, Jul. 1993.
Wielenga, Vera J.M., et al., "Expression of CD44 Variant Proteins in Human Colorectal Cancer Is Related to Tumor Progression," Cancer Research 53, 4754-4756, Oct. 15, 1993.
Adolf Gunther R.
Patzelt Erik
Bansal Geetha P.
Boehringer Ingelheim International GmbH
Scheiner Toni R.
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