Tr. Petersen et al., Identification and design of p53-derived HLA-A2-binding peptides with increased CTL immunogenicity, SC J IMMUN, 53(4), 2001, pp. 357-364
The replacement of a suboptimal amino acid in a primary anchor position wit
h an optimal residue improves human leucocyte antigen (HLA) binding and imm
unogenicity, while maintaining cytotoxic T lymphocyte (CTL) specificity. Us
ing a neural network capable of performing quantitative predictions of pept
ide binding to HLA-A2 molecules, we identified three p53 protein-derived no
namer peptides with intermediate binding owing to suboptimal amino acids in
the P2 anchor position. These peptides were synthesized along with the cor
responding analogs, where the natural P2 residue had been replaced with the
optimal leucine residue. All three modified peptides bound to and more eff
iciently stabilized HLA-A2 molecules than the corresponding nonmodified pep
tides. The HLA-A2 transgenic mice were used for immunization. Two of the ep
itopes were more immunogenic in their modified than in their natural versio
ns. The CTLs raised against the modified peptides efficiently killed the ta
rget cells pulsed with the corresponding native peptide. In terms of sensit
izing the targets cells for the CTL killing, the modified peptides were mor
e efficient than native peptides. Finally, the CTLs induced by modified pep
tide killed HLA-A2 transgenic mouse fibrosarcoma cells transfected with hum
an p53 DNA. The data suggest that modified self-peptides derived from overe
xpressed tumour-associated proteins can be used in vaccine development agai
nst cancer, and that quantitative predictions of HLA binding is of value in
the rational selection and improvement of target epitopes recognized by CT
Ls.