TY - JOUR
T1 - Enhancing immunogenicity of a CTL epitope from carcinoembryonic antigen by selective amino acid replacements
AU - Huarte, Eduardo
AU - Sarobe, Pablo
AU - Lu, Jun
AU - Casares, Noelia
AU - Lasarte, Juan José
AU - Dotor, Javier
AU - Ruiz, Marta
AU - Prieto, Jesús
AU - Celis, Esteban
AU - Borrás-Cuesta, Francisco
PY - 2002
Y1 - 2002
N2 - Purpose: Many epitopes from tumor antigens recognized by CTLs can be poorly immunogenic. This low immunogenicity can be improved by carrying out amino acid replacements in their sequence. We have applied this strategy to enhance the immunogenicity of the HLA-A2-restricted CTL epitope CEA691 (IMIGVLVGV) from carcinoembryonic antigen (CEA), which is expressed by a wide variety of tumors. Experimental Design: Substituted peptides from CEA691 were synthesized and tested in HLA-A2-binding assays, and in recognition by CEA691-specific CTL. Selected peptides were used to induce CTL responses in vivo in HLA-A2Kb transgenic mice and in vitro with human cells. Results: Our experiments afforded several peptides with enhanced binding and/or recognition by CTL specific of CEA691. However, when HLA-A2Kb mice were immunized with these peptides only a few induced a CTL response that cross-reacted with CEA691. Additional replacement of their NH2-terminal amino acid by Y (tyrosine) afforded peptides YMIGMLVGV and YMIGVLLGV with enhanced in vivo and in vitro immunogenicity than CEA691. Indeed, they activated a greater number of precursor cells that recognized CEA691-pulsed cells and tumor cells expressing CEA. Conclusions: Our results widen the possibility of treating CEA-expressing tumors with enhanced efficacy.
AB - Purpose: Many epitopes from tumor antigens recognized by CTLs can be poorly immunogenic. This low immunogenicity can be improved by carrying out amino acid replacements in their sequence. We have applied this strategy to enhance the immunogenicity of the HLA-A2-restricted CTL epitope CEA691 (IMIGVLVGV) from carcinoembryonic antigen (CEA), which is expressed by a wide variety of tumors. Experimental Design: Substituted peptides from CEA691 were synthesized and tested in HLA-A2-binding assays, and in recognition by CEA691-specific CTL. Selected peptides were used to induce CTL responses in vivo in HLA-A2Kb transgenic mice and in vitro with human cells. Results: Our experiments afforded several peptides with enhanced binding and/or recognition by CTL specific of CEA691. However, when HLA-A2Kb mice were immunized with these peptides only a few induced a CTL response that cross-reacted with CEA691. Additional replacement of their NH2-terminal amino acid by Y (tyrosine) afforded peptides YMIGMLVGV and YMIGVLLGV with enhanced in vivo and in vitro immunogenicity than CEA691. Indeed, they activated a greater number of precursor cells that recognized CEA691-pulsed cells and tumor cells expressing CEA. Conclusions: Our results widen the possibility of treating CEA-expressing tumors with enhanced efficacy.
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M3 - Article
C2 - 12114438
AN - SCOPUS:0035992407
SN - 1078-0432
VL - 8
SP - 2336
EP - 2344
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 7
ER -