PURPOSE: Many epitopes from tumor antigens recognized by CTLs canbe 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 NH(2)-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.
PURPOSE: Many epitopes from tumor antigens recognized by CTLs canbe 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 NH(2)-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.
Authors: Eduardo Huarte; Agnieszka Rynda-Apple; Carol Riccardi; Jerod A Skyberg; Sarah Golden; Maryclare F Rollins; Andrew G Ramstead; Larissa O Jackiw; Massimo Maddaloni; David W Pascual Journal: J Autoimmun Date: 2011-10-22 Impact factor: 7.094
Authors: He Zhou; Yunping Luo; Jeng-fan Lo; Charles D Kaplan; Masato Mizutani; Noriko Mizutani; Jiing-Dwan Lee; F James Primus; Jürgen C Becker; Rong Xiang; Ralph A Reisfeld Journal: Proc Natl Acad Sci U S A Date: 2005-07-22 Impact factor: 11.205
Authors: He Zhou; Yunping Luo; Masato Mizutani; Noriko Mizutani; Jürgen C Becker; F James Primus; Rong Xiang; Ralph A Reisfeld Journal: J Clin Invest Date: 2004-06 Impact factor: 14.808
Authors: Eduardo Huarte; Jan Fisher; Mary Jo Turk; Diane Mellinger; Cathy Foster; Benita Wolf; Kenneth R Meehan; Camilo E Fadul; Marc S Ernstoff Journal: Cancer Lett Date: 2009-06-06 Impact factor: 8.679