HLA-A2 restraint tumor antigen peptide originating in SART-1

Details HLA-A2 restraint tumor antigen peptide originating in SART-1 HLA-A2 restraint tumor antigen peptide originating in SART-1

2001-02-26

2003-12-16

Huff, Sheela (Department: 1642)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C530S377000, C530S328000, C514S006900

Reexamination Certificate

active

06664232

ABSTRACT:

TECHNICAL FIELD
The present invention relates to HLA-A2 restricted tumor antigen peptide originated fom SART-1. More particularly, the present invention relates to an HLA-A2 restricted tumor antigen peptide originated from SART-1, derivatives thereof having characteristics functionally equivalent thereto, compositions for treating, preventing or diagnosing tumors which utilize the tumor antigen peptide or its derivative in vivo or in vitro.
BACKGROUND ART
It is known that the immune system, particularly T cells, plays an important role in uivo in tumor rejection. Indeed, infiltration of lymphocytes having cytotowic effects on tumor cells has been observed in human tumor foci (
Arch. Surg
., 126: 200, 1990), and cytotoxic T lymphocytes (CTILs) recognizing autologous tumor cells have been isolated from melanomas without great difficulties (e.g.,
Immunol. Today
, 8:385, 1987
; J. Immurnol
., 138:989, 1987; and
Int. J. Cancer
, 52: 52, 1992). In addition, the results of clinical treatment of melanomas by CTL introduction also suggest the importance of T cells in tumor rejection (
J. Natl. Cancer. Inst
., 86: 1159, 1994).
Although it has long been unknown about target molecules for CTLs attacking autologous tumor cells, the recent advance in immunology and molecular biology has gradually revealed such target molecules. Specifically, it has been found that using T cell receptors (TCRs), CTL recognizes a complex between a peptide, called tumor antigen peptide, and a major histocompatibility complex class I antigen (MHC class I antigen, and in the case of human, referred to as HLA antigen), and thereby attacks autologous tumor cells.
Tumor antigen peptides are generated from proteins specific for tumors, that is, tumor antigen proteins. Thus, the proteins are intracellularly synthesized and then processed in cytoplasm into the peptides by proteasome. The resultant tumor antigen peptides form a complex with MHC class I antigens (HLA antigens) in endoplasmic reticulum and transported to the cell surface where they are presented as antigen. A tumor-specific CTL recognizes the complex presented as an antigen, and exhibits the anti-tumor effects through the cytotoxc effect or the production of lymphokines. As a consequence of such elucidation of a series of actions, it has become possible to treat tumors by using tumor antigen proteins or tumor antigen peptides as so-called cancer vaccines, which enhance tumor-specific CTLs in a patient.
As such tumor antigen proteins, T. Boon et al. identified a protein named MAGE from human melanoma cells for the first time in 1991 (
Science
, 254: 1643, 1991), and thereafter several additional tumor antigen proteins have been identified from melanoma cells. Examples of melanoma antigens identified so far include melanocyte tissue specific proteins, for instance, gp100 (
J. Em. Med
., 179:1005, 1994), MART-1 (
Proc. Natl. Acad Sci. USA
, 91:3515, 1994), melanosome proteins such as tyrosinase (
J. Ex. Med
., 178:489, 1993); MAGE-related proteins expressed in various tumor cells and normal testis cells as well as melanomas (
J. Em. Med
., 179:921, 1994); those comprising tumor-specific mutations such as &bgr;-catenin (
J. E. Med
., 183:1185, 1996), CDK4 (Science, 269:1281, 1995) and the like. Further, tumor antigen proteins other than melanomas, which have been identified so far, include oncogene products such as HER2
eu (
J. Ekg. Med
., 181: 2109, 1995), p53 (mutant) (
Pror Natl. Acad. Sci. USA
, 93: 14704, 1996) and the like; tumor markers such as CEA (
J. Natl. Cancer. Inst
., 87: 982, 1995), PSA (
J. Natl. Cancer. Inst
., 89: 293, 1997); viral proteins such as HPV (
J. Immunol
., 154: 5934, 1995), EBV (
Int. Immunol
., 7: 653, 1995), and the like. The detail of these tumor antigens is provided in reviews (
Immunol. Today
, 18: 267, 1997
; J. Exp. Med
., 183: 725, 1996
; Curr. Opin. Immunol
., 8: 628, 1996, etc.)
To apply tumor antigen proteins or peptides to the treatment or diagnosis of tumors, it is important to identify tumor antigens widely applicable to tumors of much higher incidence than melanomas, for example, squamous cell carcinomas (e.g., esophageal cancer, lung cancer). In this connection, the present inventors have conducted cloning of a gene encoding a tumor antigen protein from squamous cell carcinoma cells derived from esophageal cancer. The inventors, for the first time, cloned a gene encoding a novel tumor antigen protein (“SART-1”) from tumor cells other than melanomas, and identified certain tumor antigen peptide portions from said SART-1, which can be presented after binding to HLA-A26 or HLA-A24 antigen (
J. Exp. Med
., 187: 277, 1998, WO97/46676).
However, it has not been known whether said SART-1 comprises tumor antigen peptide portions capable of binding to HLA-A2 antigen and being presented, ie., whether an HLA-A2 restricted tumor antigen peptide originated from SART-1 is present.
DISCLOSURE OF INVENTION
The purpose or the preftnt invention to to provide HLA-A2 restricted tumor antigen peptides of SART-1 origin. Thus, the present invention provides an HLA-A2 restricted tumor antigen peptide originated from SART-1, a derivative thereof having characteristics functionally equivalent thereto, compositions for treating, preventing or diagnosing tumors which make use of the tumor antigen peptide or its derivative in vivo or in vitro. The SART-1-originated HLA-A2 restricted tumor antigen peptides of the present invention are presented when bound to HLA-A2 which about 40% population of Japanese or Caucasian possesses. Accordingly, the tumor antigen peptides of the present invention are useful in the treatment of a large number of patients and expected to be useful as novel anti-tumor agents since they are applicable to squamous cell carcinoma that shows the highest incidence among human cancers. In this connection, esophageal cancer and lung cancer, among squamous cell carcinomas, are known to be relatively resistant to current chemotherapy or radiotherapy. From this viewpoint, the development of the tumor antigen peptides of the present invention was highly demanded.
The present inventors made intensive investigations to elucidate whether an HLA-A2 restricted tumor antigen peptide is contained in SART-1 molecule as will be hereinafter described.
Thus, the present inventors first established an HLA-A2 restricted CTL cell line from tumor invasive lymphocytes (TIL) derived from a specimen surgically obtained from esophageal cancer, which belong to squamous cell carcinomas when classified on the basis of the tissue type, and named YK-EC (Deposition No. FERM BP-6726). The YK-EC was found to be activated to produce IFN-&ggr; when it was reacted with VA-13 cells that had been doubly transfected with recombinant plasmids each containing SART-1 cDNA and HLA-A0201 cDNA. As a result, it was proved for the first time that SART-1 comprises HLA-A2 restricted tumor antigen peptides.
The present inventors then tried to identify SART-1-originated partial peptides capable of binding to HLA-A2 and being presented, and found that peptides having amino acid sequences as set forth in SEQ ID NO: 1 to SEQ ID NO: 6 or the like possess an activity as tumor antigen peptides. The present invention has been established on the basis of the findings above.
Thus, the present invention is related to:
(1) A tumor antigen peptide which is a partial peptide of SART-1 origin and capable of binding to HLA-A2 antigen and being recognized by cytotoxic T lymphocytes, or a derivative thereof having characteristics functionally equivalent thereto;
(2) The tumor antigen peptide described in (1) above, which has an amino acid sequence selected from those each comprising the entire or a partial amino acid sequence(s) of that shown in any one of SEQ ID NO: 1 to SEQ ID NO: 34, or a derivative thereof having characteristics functionally equivalent thereto;
(3) The tumor antigen peptide described in (2) above, which has an amino acid sequence selected from those each comprising the entire or a partial amino acid sequence(s) of that shown in any one of SEQ ID NO: 1 to SEQ ID NO:

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