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Screening of HLA-A24-restricted Epitope Peptides from Prostate-specific Membrane Antigen That Induce Specific Antitumor Cytotoxic T Lymphocytes¹

Department of Urology, School of Medicine, Keio University, Tokyo 160-8582, Japan [Y. H., M. M.]; Biotechnology Research Laboratories, Takara Bio Inc., Otsu, Shiga 520-2193, Japan [I. N., K. O., I. K., K. T.]; Department of Urology, Tokyo Medical University, Tokyo 160-0023, Japan [M. T.]; and Epimmune, Inc., San Diego, California 92121 [J. F., A. S.]

Purpose: Prostate-specific membrane antigen (PSMA), which is a transmembrane glycoprotein predominantly expressed in prostate cancer, is an attractive target for tumor-specific immunotherapy. To identify human leukocyte antigen (HLA)-A24-restricted epitope peptides from PSMA for further application of the dendritic cell (DC)-based immunotherapy targeting prostate cancer, we have screened several PSMA-encoded HLA-A24-binding peptides for their capabilities to elicit specific antitumor CTL response in vitro.

Experimental Design: The amino acid sequence of PSMA was screened for peptides consisting of 9 or 10 amino acids, which possess the known HLA-A24-binding motif. Nine candidate peptides were screened for binding to HLA-A24 molecules. Then, each of these nine peptides was studied to determine whether CTL responses could be induced by primary in vitro immunization of CD8⁺ T cells using peptide-pulsed autologous DCs derived from peripheral blood mononuclear cells of HLA-A24⁺ healthy donor as antigen-presenting cells. The antigen specificity of the CTL lines was confirmed using several tumor cell lines as target cells, which were genetically modified to express both HLA-A24 and PSMA.

Results: Two peptides, LYSDPADYF and NYARTEDFF, were demonstrated to elicit CTL lines that lyse peptide-pulsed, HLA-A24⁺ B-lymphoblastoid cells. Each of the CTL lines recognized their specific PSMA-expressing target cells in a HLA-A24-restricted manner. The capability to release IFN- by the CTL lines was specifically inhibited by anti-MHC class I and anti-CD8 monoclonal antibodies but not by anti-MHC class II and anti-CD4 monoclonal antibodies.

Conclusion: Two novel HLA-A24-restricted PSMA-derived epitopes were identified in this study. These epitopes can be used to further evaluate the clinical utility of DC-based immunotherapeutic strategies for treatment of hormone-refractory prostate cancers.

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