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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]