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Clinical Cancer Research Vol. 8, 2336-2344, July 2002
© 2002 American Association for Cancer Research

Experimental Therapeutics, Preclinical Pharmacology

Enhancing Immunogenicity of a CTL Epitope from Carcinoembryonic Antigen by Selective Amino Acid Replacements1

Eduardo Huarte, Pablo Sarobe, Jun Lu, Noelia Casares, Juan José Lasarte, Javier Dotor, Marta Ruiz, Jesús Prieto, Esteban Celis and Francisco Borrás-Cuesta2

Department of Internal Medicine, University of Navarra, 31008 Pamplona, Spain [E. H., P. S., N. C., J. J. L., J. D., M. R., J. P., F. B-C.], and Department of Immunology, Mayo Clinic, 55905 Rochester, Minnesota [J. L., E. C.]

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 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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Copyright © 2002 by the American Association for Cancer Research.