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Design of Agonistic Altered Peptides for the Robust Induction of CTL Directed towards H-2D^b in Complex with the Melanoma-Associated Epitope gp100

Departments of ¹ Immunohematology and Blood transfusion and ² Clinical Oncology, Leiden University Medical Center, Leiden, the Netherlands; and ³ Center for Infectious Medicine, Department of Medicine, Karolinska University Hospital Huddinge, Karolinska Institutet, Stockholm, Sweden

Requests for reprints: Adnane Achour, Center for Infectious Medicine, Department of Medicine, F59, Karolinska University Hospital Huddinge, Karolinska Institutet, S-141 86, Stockholm, Sweden. Phone: 46-8-52486232; Fax: 46-8-30-42-76; E-mail: adnane.achour{at}ki.se and Thorbald van Hall, Department of Clinical Oncology, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands. E-mail: T.van_Hall{at}LUMC.nl.

Key Words: Modified MHC class I epitope • immunogenicity • cytotoxic T lymphocytes • cancer vaccines

Immunogenicity of tumor-associated antigens (TAA) is often weak because many TAA are autoantigens for which the T-cell repertoire is sculpted by tolerance mechanisms. Substitutions at main anchor positions to increase the complementarity between the peptide and the MHC class I (MHC-I) binding cleft constitute a common procedure to improve binding capacity and immunogenicity of TAA. However, such alterations are tailored for each MHC-I allele and may recruit different CTL specificities through conformational changes in the targeted peptides. Comparative analysis of substituted melanoma-differentiation antigen gp100 in complex with H-2D^b revealed that combined introduction of glycine and proline residues at the nonanchor positions 2 and 3, respectively, resulted in an agonistic altered peptide with dramatically enhanced binding affinity, stability, and immunogenicity of this TAA. Peptide vaccination using the p2Gp3P-altered peptide version of gp100 induced high frequencies of melanoma-specific CTL in the endogenous CD8⁺ repertoire. Crystal structure analysis of MHC/peptide complexes revealed that the conformation of the modified p2Gp3P-peptide was similar to the wild-type peptide, and indicated that this mimotope was stabilized through interactions between peptide residue p3P and the tyrosine residue Y159 that is conserved among most known MHC-I molecules throughout mammalian species. Our results may provide an alternative approach to enhance MHC stabilization capacity and immunogenicity of low-affinity peptides for induction of robust tumor-specific CTL. [Cancer Res 2009;69(19):7784–92]