Secondary anchor substitutions in an HLA-A*0201-restricted T-cell epitope derived from Her-2/neu.
We investigated analogues of GP2 (IISAVVGIL), an HLA-A*0201-restricted T-cell epitope derived from residues 654-662 in the tumor-associated antigen (TAA) Her-2/neu. One limiting factor of GP2 is its poor affinity for HLA-A*0201. Conformational analysis revealed the P5-P7 region in GP2 appears to be linked to the stability of P9 side chain interaction with the MHC molecule. To identify variants of GP2 with enhanced presentation to HLA-A*0201, we tested V6S, V6T, V6Q, G7P, G7F, T6F7, and Q6F7 for their capacity to stabilize cell surface HLA-A*0201 molecules. Of the mono-substituted variants, V6Q and G7F exhibited superior stabilization as compared to GP2. Molecular dynamics simulations suggest the improved binding can be attributed to concerted motions in the central and C-terminal regions of the peptide. These data support the notion that amino acids in HLA-A*0201 epitopes may be inter-dependent. Priming HLA-A*0201 transgenic mice with G7F-loaded syngeneic dendritic cells stimulated mouse T cells to produce a higher level of INFgamma than mice immunized with GP2.
Joseph
Matthew A
MA
Division of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA 15282, United States.
Mitchell
Megan L
ML
Evanseck
Jeffrey D
JD
Kovacs
Jeffrey R
JR
Jia
Liang
L
Shen
Hongmei
H
Meng
Wilson S
WS
D019943:Amino Acid Substitution; D000818:Animals; D019496:Cancer Vaccines; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D015234:HLA-A Antigens / Q000737:chemistry / Q000235:genetics; D015395:Histocompatibility Antigens Class I / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008958:Models, Molecular; D008968:Molecular Conformation; D011485:Protein Binding; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000737:chemistry / Q000235:genetics; D013601:T-Lymphocytes / Q000737:chemistry / Q000276:immunology
D019496:Cancer Vaccines; D018984:Epitopes, T-Lymphocyte; D015234:HLA-A Antigens; D015395:Histocompatibility Antigens Class I; D018719:Erb-b2 Receptor Tyrosine Kinases