This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Klechevsky, E. Articles by Reiter, Y. Search for Related Content PubMed PubMed Citation Articles by Klechevsky, E. Articles by Reiter, Y.

Antitumor Activity of Immunotoxins with T-Cell Receptor–like Specificity against Human Melanoma Xenografts

¹ Faculty of Biology, Technion-Israel Institute of Technology, Haifa, Israel and ² Baylor Institute for Immunology Research, Dallas, Texas

Requests for reprints: Yoram Reiter, Faculty of Biology, Technion-Israel Institute of Technology, Technion City, Room 333, Haifa 32000, Israel. Phone: 972-4-8292785; Fax: 972-4-8225153; E-mail: reiter{at}tx.technion.ac.il.

In this study, we have explored the use of Fab-toxin proteins (immunotoxin) to target antigen-specific MHC-peptide complexes of in vitro and in vivo cancer cells. A human phage display library was used to screen for T-cell receptor (TCR)–like antibodies that are highly specific for the peptide melanoma-associated antigen MART-1_26-35 presented by HLA-A201. We also used previously selected TCR-like antibodies specific for the peptide melanoma-associated antigen gp100_280-288 presented by HLA-A201. The recombinant immunotoxin constructs were generated by fusing the targeting Fab fragment to a truncated form of Pseudomonas exotoxin, PE38KDEL. These immunotoxins bound with high affinity to the EBV-transformed JY cell line pulsed with the aforementioned peptides and internalized within 30 min. A significant inhibition of protein synthesis, which resulted in cell death, was detected at 24 h. MART-1–specific and gp100-specific immunotoxins bound and killed HLA-A201 melanoma MART-1⁺ and gp100⁺ cell lines that were presented at natural levels but do not bind to HLA-A201^– or to HLA-A201⁺ MART-1^– and gp100^– cell lines. In severe combined immunodeficient mice, MART-1 and gp100 immunotoxins significantly and discriminately inhibited human melanoma growth. These results show that MHC class I/peptide complexes can serve as a specific target for passive immunotherapy of cancer. [Cancer Res 2008;68(15):6360–7]