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Serpentine transmembrane antigens expressed in human cancers and uses thereof

a technology of serpentine and human cancer, applied in the direction of depsipeptides, peptide/protein ingredients, fusion polypeptides, etc., can solve the problems of ineffective treatment of many patients, undesirable consequences, and still no effective treatment for metastatic prostate cancer, and achieve excellent markers

Inactive Publication Date: 2006-01-26
AGENSYS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention is about a new family of cell surface antigens called STEAP (Six Transmembrane Epithelial Antigen of the Prostate). These antigens are exclusively or predominantly expressed in the prostate and prostate cancer cells, and they show no significant structural homology to any known human proteins. The invention provides polynucleotides, mRNAs, and coding sequences of the STEAP gene, as well as means for isolating and expressing the STEAP gene products. The invention also provides antibodies that bind to STEAP proteins and polypeptide fragments thereof, and methods for detecting and treating prostate and other cancers expressing STEAP.

Problems solved by technology

Despite the magnitude of these figures, there is still no effective treatment for metastatic prostate cancer.
Unfortunately, these treatments are ineffective for many and are often associated with undesirable consequences.
On the diagnostic front, the lack of a prostate tumor marker that can accurately detect early-stage, localized tumors remains a significant limitation in the management of this disease.
Although the serum PSA assay has been a very useful tool, its specificity and general utility is widely regarded as lacking in several important respects.

Method used

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  • Serpentine transmembrane antigens expressed in human cancers and uses thereof
  • Serpentine transmembrane antigens expressed in human cancers and uses thereof
  • Serpentine transmembrane antigens expressed in human cancers and uses thereof

Examples

Experimental program
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Effect test

example 1

SSH-Generated Isolation of cDNA Fragment of the STEAP Gene

Materials and Methods

LAPC Xenografts:

[0232] LAPC xenografts were obtained from Dr. Charles Sawyers (UCLA) and generated as described (Klein et al 1997, Nature Med. 3: 402-408; Craft et al., 1999, Cancer Res. 59: 5030-5036). Androgen dependent and independent LAPC-4 xenografts (LAPC-4 AD and AI, respectively) and LAPC-9 xenografts (LAPC-9 AD and AI, respectively) were grown in intact male SCID mice or in castrated males, respectively, and were passaged as small tissue chunks in recipient males. LAPC-4 AI xenografts were derived from LAPC-4 AD tumors and LAPC-9AI xenografts were derived from LAPC-9 AD tumors. To generate the AI xenografts, male mice bearing LAPC AD tumors were castrated and maintained for 2-3 months. After the LAPC tumors re-grew, the tumors were harvested and passaged in castrated males or in female SCID mice.

[0233] LAPC-4 AD xenografts were grown intratibially as follows. LAPC-4 AD xenograft tumor tissu...

example 2

Isolation of Full Length STEAP-1 Encoding cDNA

[0251] The 436 bp 8P1D4 gene fragment (Example 1) was used to isolate additional cDNAs encoding the 8P1D4 / STEAP-1 gene. Briefly, a normal human prostate cDNA library (Clontech) was screened with a labeled probe generated from the 436 bp 8P1D4 cDNA. One of the positive clones, clone 10, is 1195 bp in length and encodes a 339 amino acid protein having nucleotide and encoded amino acid sequences bearing no significant homology to any known human genes or proteins (homology to a rat Kidney Injury Protein recently described in International Application WO98 / 53071). The encoded protein contains at least 6 predicted transmembrane motifs implying a cell surface orientation (see FIG. 1A-B, predicted transmembrane motifs underlined). These structural features led to the designation “STEAP”, for “Six Transmembrane Epithelial Antigen of the Prostate”.

[0252] Subsequent identification of additional STEAP proteins led to the re-designation of the 8P1...

example 3

STEAP-1 Gene and Protein Expression Analysis

[0253] In order to begin to characterize the biological characteristics of STEAP-1, an extensive evaluation of STEAP-1 mRNA and STEAP-1 protein expression across a variety of human tissue specimens was undertaken. This evaluation included Northern blot, Western blot and immunohistochemical analysis of STEAP-1 expression in a large number of normal human tissues, human prostate cancer xenografts and cell lines, and various other human cancer cell lines.

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Abstract

Described is a novel family of cell surface serpentine transmembrane antigens. Two of the proteins in this family are exclusively or predominantly expressed in the prostate, as well as in prostate cancer, and thus members of this family have been termed “STEAP” (Six Transmembrane Epithelial Antigen of the Prostate). Four particular human STEAPs are described and characterized herein. The human STEAPs exhibit a high degree of structural conservation among them but show no significant structural homology to any known human proteins. The prototype member of the STEAP family, STEAP-1, appears to be a type IIIa membrane protein expressed predominantly in prostate cells in normal human tissues. Structurally, STEAP-1 is a 339 amino acid protein characterized by a molecular topology of six transmembrane domains and intracellular N- and C-termini, suggesting that it folds in a “serpentine” manner into three extracellular and two intracellular loops. STEAP-1 protein expression is maintained at high levels across various stages of prostate cancer. Moreover, STEAP-1 is highly over-expressed in certain other human cancers.

Description

[0001] This application is related to U.S. patent application No. 60 / 087,520, filed Jun. 1, 1998, 60 / 091,183, filed Jun. 30, 1998, Ser. No. 09 / 323,873, filed Jun. 1, 1999, and Ser. No. 09 / 455,486, filed Dec. 6, 1999, and, also to PCT / US99 / 12157 (WO 99 / 62941), filed Jun. 1, 1999, and PCT / US00 / 33040, filed Dec. 6, 2000, the entire contents of each of which is incorporated herein by reference.FIELD OF THE INVENTION [0002] The invention described herein relates to a family of novel genes and their encoded proteins and tumor antigens, termed STEAPs, and to diagnostic and therapeutic methods and compositions useful in the management of various cancers, particularly including prostate cancer, colon cancer, bladder cancer, lung cancer, ovarian cancer and pancreatic cancer. BACKGROUND OF THE INVENTION [0003] Cancer is the second leading cause of human death next to coronary disease. Worldwide, millions of people die from cancer every year. In the United States alone, cancer causes the death ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K39/395C07K14/705C07H21/04A61K38/00A61K39/00C07K16/28C07K16/30C12Q1/68G01N33/574
CPCA61K38/00C07K2317/34A61K51/1072A61K2039/505C07K14/4748C07K14/705C07K16/28C07K16/3069C07K2319/00C07K2319/30C12Q1/6886C12Q2600/158G01N33/57407G01N33/57419G01N33/57423G01N33/57434G01N33/57438G01N33/57449G01N33/57484G01N33/57492G01N2333/705A61K39/00
Inventor HUBERT, RENERAITANO, ARTHURSAFFRAN, DOUGLASAFAR, DANIELMITCHELL, STEVENFARIS, MARYJAKOBOVITS, AYA
Owner AGENSYS