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Gene differentially expressed in breast and bladder cancer, and encoded polypeptides

a human gene and gene technology, applied in the field of human genes, can solve the problems of unfavorable broad-effect tumor vaccine development, no a priori reason why random mutation and systematic gene deregulation cannot both give rise to new immunogenic expression, and technological challeng

Inactive Publication Date: 2007-04-12
UNIVERSITY OF ROCHESTER
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

This would be unfavorable for development of broadly effective tumor vaccines.
There is, however, no a priori reason why random mutation and systematic gene deregulation could not both give rise to new immunogenic expression in tumors.
The major challenge is technological.
Two major limitations of this approach, however, are that (1) screening requires labor intensive transfection of numerous small pools of recombinant DNA into separate target populations, which themselves often need to be modified to express one or more MHC molecules required for antigen presentation, in order to assay T cell stimulation by a minor component of some pool; and (2) with the possible exception of renal cell carcinoma, tumor-specific CTLs have been very difficult to isolate from either tumor infiltrating lymphocytes (TIL) or PBL of patients with other types of tumors, especially the epithelial cell carcinomas that comprise greater than 80% of human tumors.
Weak antigens may be poorly processed and fail to be presented effectively to T cells.
In contrast, it has, for technical reasons, been more difficult to establish that the frequency of clonal representation in the T cell repertoire is an important mechanism of low responsiveness.
With present day methods, it would be a complex and difficult undertaking to modify the way in which antigenic peptides of a tumor are processed and presented to T cells.
Prior tolerization of T cells specific for immunodominant antigens of a tumor may, therefore, account for the difficulty in developing successful strategies for immunotherapy of cancer.
These observations suggest that T cells specific for immunodominant tumor antigens are less likely to be effective for immunotherapy of established tumors because they are most likely to have been tolerized.

Method used

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  • Gene differentially expressed in breast and bladder cancer, and encoded polypeptides
  • Gene differentially expressed in breast and bladder cancer, and encoded polypeptides
  • Gene differentially expressed in breast and bladder cancer, and encoded polypeptides

Examples

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example 1

Differential Expression of C35 in Human Breast Carcinoma

[0259] The present inventors have characterized a full-length cDNA representing a gene, C35, that is differentially expressed in human breast and bladder cancer (FIG. 1). A 348 base pair DNA fragment of C35 was initially isolated by subtractive hybridization of poly-A RNA from tumor and normal mammary epithelial cell lines derived from the same patient with primary infiltrating intraductal mammary carcinoma. (Band, V. et al., Cancer Res. 50:7351-7357 (1990). Employing primers based on this sequence and that of an overlapping EST sequence (Accession No. W57569), a cDNA that includes the full-length C35 coding sequence was then amplified and cloned from the SKBR3 breast tumor cell line (ATCC, HTB-19). This C35 cDNA includes, in addition to the 348 bp coding sequence, 167 bp of 3′ untranslated region.

[0260] Differential expression of the C35 sequence is demonstrated in FIG. 2 panel A which compares expression levels of clone C35 ...

example 2

C35 Specific CTL are Cytolytic for C35 Positive Breast Tumor Cells

[0262] Although a gene product may be overexpressed in tumor cells, as is the case for C35, it is immunologically relevant only if peptides derived from that gene product can be processed and presented in association with MHC molecules of the tumor cells. It is conceivable that for any given gene product either no peptides are produced during the cellular degradation process that satisfy the requirements for binding to the MHC molecules expressed by that tumor, or, even if such peptides are generated, that defects in transport or competition for MHC molecules by other tumor peptides would preclude presentation of any peptides from that specific gene product. Even if relevant tumor peptides are processed and presented in association with human MHC in the tumor cells, it must in all cases be determined whether human T cells reactive to these peptides are well-represented in the repertoire or whether T cells may have be...

example 3

C35 Expression on the Membrane of Breast Carcinoma Cells

[0265] To determine whether the C35 polypeptide product is expressed on the surface of tumor cells, a C35 specific antiserum was prepared. BALB / c mice were immunized with syngeneic Line 1 mouse tumor cells that had been transduced with retrovirus encoding human C35. Mice were bled following a series of two or more immunizations. The immune sera were employed to detect surface expression of C35 protein by flow cytometry on three breast tumor cell lines representing high (21NT), intermediate (SKBR3), and low (MDA-MB-231 levels of expressionof the C35 transcript in Northern blots (see FIG. 4). 1×105 breast tumor cells were stained with 3.5 microliters of C35 specific antiserum or control, pre-bleed BALB / c serum. After a 30 minute incubation, cells were washed twice with staining buffer (PAB) and incubated with FITC-goat anti-mouse IgG (1 μg / sample) for 30 minutes. Samples were washed and analyzed on an EPICS Elite flow cytometer....

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Abstract

The present invention is directed to antibodies or antigen binding fragments thereof that specifically bind to the cancer specific antigen, C35. This invention also relates to a polynucleotide encoding the antibody or antigen binding fragment thereof as well as vectors and host cells comprising the polynucleotide. The present invention further relates to a composition comprising the antibody or antigen binding fragment thereof or further comprising a chemotherapeutic agent, specifically taxol. The invention is also directed to therapeutic and diagnostic methods of using antibodies against C35, preferably more than one anti-C35 antibody in combination with a chemotherapeutic agent, to treat C35 associated cancer.

Description

[0001] This application is a divisional application of U.S. application Ser. No. 09 / 824,787, filed Apr. 4, 2001, which claims the benefit of U.S. Provisional Application No. 60 / 194,463, filed Apr. 4, 2000, the entire contents of each of which is herein incorporated by reference.BACKGROUND OF THE INVENTION [0002] 1. Field of the Invention [0003] The present invention relates to a novel human gene that is differentially expressed in human breast and bladder carcinoma. More specifically, the present invention relates to a polynucleotide encoding a novel human polypeptide named C35. This invention also relates to C35 polypeptides, as well as vectors, host cells, antibodies directed to C35 polypeptides, and the recombinant methods for producing the same. The present invention further relates to diagnostic methods for detecting carcinomas, including human breast and bladder carcinomas. The present invention further relates to the formulation and use of the C35 gene and polypeptides in imm...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K51/00C07H21/04C12P21/06A61K39/395C07K16/46C12N15/09A61K31/7088A61K35/76A61K38/00A61K48/00A61P35/00A61P43/00C07K14/47C07K14/82C07K16/32C12N1/15C12N1/19C12N1/21C12N5/10C12N15/12C12P21/02C12Q1/02C12Q1/68
CPCC07K14/47A61P35/00A61P43/00
Inventor ZAUDERER, MAURICEEVANS, ELIZABETH E.BORRELLO, MELINDA A.
Owner UNIVERSITY OF ROCHESTER
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