Antitumor activity of immunotoxins with T-cell receptor-like specificity against human melanoma xenografts.
Antitumor activity of immunotoxins with T-cell receptor-like specificity against human melanoma xenografts.
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DOI：
10.1158/0008-5472.can-08-0928
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发表时间：
2008-08-01
期刊：
影响因子：
11.2
通讯作者：
Reiter Y
中科院分区：
文献类型：
--
作者：
Klechevsky E;Gallegos M;Denkberg G;Palucka K;Banchereau J;Cohen C;Reiter Y
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 TCR-like antibodies that are highly specific for the peptide melanoma-associated antigen MART-126–35 presented by HLA-A201. We also used previously selected TCR-like antibodies specific for the peptide melanoma-associated antigen presented by HLA-A201. The gp100280–288 recombinant immunotoxin constructs were generated by fusing the targeting Fab fragment to a truncated form of Pseudomonas exotoxin (PE): 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 and gp-100 specific immunotoxins bound and killed HLA-A201 melanoma MART-1 and gp-100 positive cell lines that were presented at natural levels, but do not bind to HLA-A201− or to HLA-A201+ MART-1 and gp-100 negative cell lines. In SCID mice MART-1 and gp-100 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.
