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Enhancing immunogenicity of a CTL epitope from carcinoembryonic antigen by selective amino acid replacements.
Clin Cancer Res. 2002 Jul; 8(7):2336-44.CC

Abstract

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+Show Affiliations

Department of Internal Medicine, University of Navarra, 31008 Pamplona, Spain.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

12114438

Citation

Huarte, Eduardo, et al. "Enhancing Immunogenicity of a CTL Epitope From Carcinoembryonic Antigen By Selective Amino Acid Replacements." Clinical Cancer Research : an Official Journal of the American Association for Cancer Research, vol. 8, no. 7, 2002, pp. 2336-44.
Huarte E, Sarobe P, Lu J, et al. Enhancing immunogenicity of a CTL epitope from carcinoembryonic antigen by selective amino acid replacements. Clin Cancer Res. 2002;8(7):2336-44.
Huarte, E., Sarobe, P., Lu, J., Casares, N., Lasarte, J. J., Dotor, J., Ruiz, M., Prieto, J., Celis, E., & Borrás-Cuesta, F. (2002). Enhancing immunogenicity of a CTL epitope from carcinoembryonic antigen by selective amino acid replacements. Clinical Cancer Research : an Official Journal of the American Association for Cancer Research, 8(7), 2336-44.
Huarte E, et al. Enhancing Immunogenicity of a CTL Epitope From Carcinoembryonic Antigen By Selective Amino Acid Replacements. Clin Cancer Res. 2002;8(7):2336-44. PubMed PMID: 12114438.
* Article titles in AMA citation format should be in sentence-case
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 - 2002/7/13/pubmed PY - 2003/1/22/medline PY - 2002/7/13/entrez SP - 2336 EP - 44 JF - Clinical cancer research : an official journal of the American Association for Cancer Research JO - Clin. Cancer Res. VL - 8 IS - 7 N2 - 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. SN - 1078-0432 UR - https://www.unboundmedicine.com/medline/citation/12114438/Enhancing_immunogenicity_of_a_CTL_epitope_from_carcinoembryonic_antigen_by_selective_amino_acid_replacements_ L2 - http://clincancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=12114438 DB - PRIME DP - Unbound Medicine ER -