Novel serpentine transmembrane antigens expressed in human cancers and uses thereof

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

CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application is a continuation of U.S. patent application Ser. No. 10 / 856,109, filed May 28, 2004, which is a continuation of U.S. patent application Ser. No. 09 / 455,486, filed Dec. 6, 1999, now issued as U.S. Pat. No. 6,833,438 on Dec. 21, 2004, which is a continuation-in-part of U.S. patent application Ser. No. 09 / 323,873, filed Jun. 1, 1999, now issued as U.S. Pat. No. 6,329,503 on Dec. 11, 2001, which claims the benefit of U.S. Provisional Application No. 60 / 091,183, filed Jun. 30, 1998 and U.S. Provisional Application No. 60 / 087,520, filed Jun. 1, 1998. This application relates to U.S. patent application Ser. No. 10 / 408,009, filed Apr. 4, 2003, U.S. patent application Ser. No. 10 / 857,785, filed May 28, 2004, U.S. patent application Ser. No. 10 / 752,421, filed Jan. 5, 2004, U.S. patent application Ser. No. 10 / 407,484, filed Apr. 4, 2003, U.S. Provisional Application No. 60 / 370,387, filed Apr. 5, 2002, U.S. Provisional Application...

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, and have been termed \"STEAP-1\" through \"STEAP-4\". The STEAP-1 protein has a molecular topology of six transmembrane domains and intracellular N- and C-termini, suggesting it folds in a \"serpentine\" manner into three extracellular and two intracellular loops. STEAP-1 is highly over-expressed in various cancers, including prostate, bladder, and colon cancer. The invention provides polynucleotides, means for isolating cDNAs, and recombinant DNA molecules containing STEAP genes. It also provides antibodies that bind to STEAP proteins and polypeptide fragments thereof, as well as methods for detecting and identifying STEAP in biological samples. The invention further provides therapeutic compositions and strategies for treating prostate cancer, including antibody, vaccine, and small molecule therapy."

Problems solved by technology

Generally speaking, the fundamental problem in the management of the deadliest cancers is the lack of effective and non-toxic systemic therapies.

While molecular medicine promises to redefine the ways in which these cancers are managed, progress in this area has been slow despite intensive worldwide efforts to develop novel molecular diagnostics and therapeutics.

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.

Tumors within this zone may not produce any symptoms and, as a result, most men with early-stage prostate cancer will not present clinical symptoms of the disease until significant progression has occurred.

Tumor progression into the transition zone of the prostate may lead to urethral obstruction, thus producing the first symptoms of the disease.

However, these clinical symptoms are indistinguishable from the common non-malignant condition of benign prostatic hyperplasia (BPH).

Both have major limitations which have fueled intensive research into finding better diagnostic markers of this disease.

Accordingly, the lack of a prostate tumor marker that can accurately detect early-stage, localized tumors remains a significant limitation in the management of prostate cancer.

A similar problem is the lack of an effective prognostic marker for determining which cancers are indolent and which ones are or will be aggressive.

PSA, for example, cannot accurately discriminate between these alternatives.

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.

However, none of these methodologies have been able to reproducibly distinguish benign from malignant prostate disease.

Similarly, there is no available marker that can predict the emergence of the typically fatal metastatic stage of prostate cancer.

However, the expression of PSM in small intestine and brain (Israeli et al., 1994, Cancer Res. 54: 1807), as well its potential role in neuropeptide catabolism in brain, raises concern of potential neurotoxicity with anti-PSM therapies.

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