Diagnosis of carcinomas

a carcinoma and carcinoma technology, applied in the field of cancer diagnosis, can solve the problems of limited diagnostic screening usefulness, need for early detection and diagnosis, and detection of cell-associated tumor markers

Inactive Publication Date: 2009-04-23
PACIFIC NORTHWEST RES INST
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Because a hallmark of many types of cancer is rapid and unregulated proliferation of malignant cells, an overarching problem in improving approaches to cancer is the need for early detection and diagnosis.
Nevertheless, detection of cell-associated tumor markers such as the mucin antigen recognized by B72.3 following surgical resection of a tumor may be of limited usefulness for diagnostic screening, in which early detection of a malignant condition prior to accumulation of substantial tumor mass is preferred.
Elevated levels of serum CA125 alone or in combination with other known indicators, however, do not provide a definitive diagnosis of malignancy, or of a particular malignancy such as ovarian carcinoma.
Many of the members of the four-disulfide core family are protease inhibitors; however, for some family members, including HE4, no function has yet been definitively identified.
However, overexpression of the gene in transgenic animals impairs development of mammary alveolar cells (Burdon et al, 1991 Mechanisms Dev.

Method used

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  • Diagnosis of carcinomas
  • Diagnosis of carcinomas
  • Diagnosis of carcinomas

Examples

Experimental program
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example 1

Real-Time PCR Detection of HE4a Expression in Human Samples

[0124]One hundred and fifty-eight human tissue biopsies, or RNA samples from biopsies, were obtained according to the procedures approved by the institutional review boards of the University of Washington, Swedish Hospital and Fred Hutchinson Cancer Research Center, all of Seattle, Wash. Samples from normal tissues (adrenal gland, bone marrow, brain, colon, endometrium, stomach, heart, kidney, liver, lung, lung, mammary gland, skeletal muscle, skeletal muscle, myometrium, peripheral nerve, peripheral blood lymphocyte preparations, salivary gland, skin, small intestine, spinal cord, spleen, spleen, trachea, thymus, uterus, peripheral blood lymphocyte cluture, and 40 normal ovaries), from benign ovarian lesions (13 serous cystadenomas), from 2 ovarian tumors of borderline malignancy, from 3 stage I mucinous ovarian carcinomas, 3 stage I serous ovarian carcinomas, 37 stage III serous ovarian carcinomas, 7 stage IV serous ovaria...

example 2

Cloning and Expression of Nucleic Acid Sequences Encoding HE4a

[0131]Amplification of HE4a fusion construct cDNA from high throughput HE4a cDNA clone: The cDNA sequence for HE4 (SEQ ID NO:8) as originally published by Kirchoff et al., (1991) was deposited in GenBank Accession # X63187 and provided the basis for oligonucleotide primer design to clone cDNA encoding HE4a (SEQ ID NO:10), as described herein. The cDNA for HE4a, identified and isolated as a differentially expressed gene product using high throughput cDNA arrays, was cloned in pSPORT as an 840 base pair fragment. This cDNA was used as template in PCR reactions to amplify HE4a in a form appropriate for creating synthetic fusion protein genes, as described in this Example.

[0132]A portion of the HE4 coding sequence (SEQ ID NO:8) appeared to encode a presumed secretory signal peptide; therefore, this native leader peptide was used in initial constructs to preserve as much of the molecule's structure as possible. In addition, be...

example 3

Monoclonal Antibodies Specific for HE4a

[0142]Generation of anti-HE4a Mabs. In initial experiments, several BALB / c mice were immunized with HE4a-hIgG fusion proteins prepared as described above, with and without adjuvant. Although high antibody titers were seen in these mice, the antibodies were not specific for HE4a, since equally high titers were seen against a control fusion protein having the hIgG tail (CTLA4-hIg fusion). Therefore, HE4a-mIgG fusion protein was used for immunization. FIG. 3 illustrates the results from two immunizations that led to high titered antibodies against HE4a in two BALB / c mice (1605 and 1734) that were each twice immunized with HE4a-mIgG plus adjuvant (TiterMax®, CytRx Corp., Norcross, Ga.) according to the manufacturer's instructions, given subcutaneously in the tail. HE4a-specific hybridomas were prepared by standard methodologies using spleen cells from mice exhibiting high HE4a-specific antibody titers. FIG. 4 shows the initial testing, by ELISA, of...

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Abstract

The invention is directed to compositions and methods for the detection of a malignant condition, and relates to the discovery of soluble and cell surface forms of HE4a polypeptides, including HE4a that is overexpressed in ovarian carcinomas. In particular the invention provides a nucleic acid sequence encoding HE4a, and also provides a method of screening for the presence of a malignant condition in a subject by detecting reactivity of an antibody specific for a HE4a polypeptide with a molecule naturally occurring in soluble and / or cell surface form in a sample from such a subject, and by hybridization screening using an HE4a nucleotide sequence, as well as other related advantages.

Description

CROSS-REFERENCE TO RELATED APPLICATION[0001]This application claims the benefit of U.S. Provisional Patent Application No. 60 / 316,537 filed Aug. 29, 2001, which is incorporated herein by reference in its entirety.TECHNICAL FIELD[0002]The present invention relates generally to malignant conditions such as cancer, and in particular to methods and compositions for diagnosing certain carcinomas such as ovarian carcinoma.BACKGROUND OF THE INVENTION[0003]Cancer includes a broad range of diseases, affecting approximately one in four individuals worldwide. The severity of the adverse impact of cancer is profound, influencing medical policy and procedure as well as society generally. Because a hallmark of many types of cancer is rapid and unregulated proliferation of malignant cells, an overarching problem in improving approaches to cancer is the need for early detection and diagnosis. Numerous attempts have been made to develop accurate and reliable criteria for diagnosing the presence of a...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C12N1/16C07K16/00G01N33/53A61K38/00A61K39/395A61P1/18A61P15/00A61P35/00A61P43/00C07K14/81C07K14/82C07K16/18C07K16/30C07K16/32C07K16/40C07K19/00C12N1/15C12N1/19C12N1/21C12N5/10C12N15/09C12P21/02C12P21/08G01N33/574G01N33/577
CPCA61K2039/505C07K14/811C07K16/18C07K16/30G01N33/57488C07K16/40C07K2319/00C07K2319/30C07K16/3069A61P1/18A61P15/00A61P35/00A61P35/02A61P43/00G01N33/57449G01N33/574G01N2333/705
Inventor SCHUMMER, MICHELHELLSTROM, INGEGERDHELLSTROM, KARL ERIKLEDBETTER, JEFFREY A.HAYDEN-LEDBETTER, MARTHA
Owner PACIFIC NORTHWEST RES INST
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