Structural features of peptide analogs of human histocompatibility leukocyte antigen class I epitopes that are more potent and immunogenic than wild-type peptide.
Certain peptide analogs that carry substitutions at residues other than the main major histocompatibility complex anchors and are surprisingly much more antigenic than wild-type peptide (heteroclitic analogs). To date, it was unknown how frequently wild-type epitopes could be modified to obtain heteroclitic activity. In this study, we analyzed a large panel of analogs of two different human histocompatibility leukocyte antigen (HLA)-A2.1-restricted epitopes and found that heteroclitic analogs were associated with higher magnitude responses and increased (up to 10(7)-fold) sensitivity to antigen, and corresponded to conservative or semiconservative substitutions at odd-numbered positions in the middle of the peptide (positions 3, 5, or 7). These findings were validated by performing additional immunogenicity studies in murine and human systems with four additional epitopes. The biological relevance of heteroclitic analogs was underlined when predicted analogs of the p53.261 epitope was shown to induce cytotoxic T lymphocytes (CTLs) that recognize low concentrations of peptide (high avidity) in vivo and demonstrate in vitro antitumor recognition. Finally, in vitro immunization of human peripheral blood mononuclear cells with two heteroclitic analogs resulted in recruitment of more numerous CTLs which were associated with increased antigen sensitivity. In conclusion, heteroclitic analogs were identified in each of the six cases studied and structural features were defined which allow identification of such analogs. The strong CTL immunity elicited by heteroclitic epitopes suggest that they could be of significant value in vaccination against tolerant or weakly immunogenic tumor-associated and viral antigens.
Tangri
S
S
Epimmune Incorporated, San Diego, CA 92121, USA.
Ishioka
G Y
GY
Huang
X
X
Sidney
J
J
Southwood
S
S
Fikes
J
J
Sette
A
A
D000818:Animals; D002272:Carcinoembryonic Antigen / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D015684:Gene Products, pol / Q000138:chemical synthesis / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology; D015789:HLA-A2 Antigen / Q000276:immunology; D019073:HT29 Cells; D006512:Hepatitis B Core Antigens / Q000276:immunology*; D006515:Hepatitis B virus / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D016753:Interleukin-10 / Q000378:metabolism; D015848:Interleukin-5 / Q000378:metabolism; D019169:Jurkat Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010452:Peptide Biosynthesis; D010455:Peptides / Q000737:chemistry / Q000276:immunology*; D013329:Structure-Activity Relationship; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014407:Tumor Cells, Cultured
D002272:Carcinoembryonic Antigen; D018984:Epitopes, T-Lymphocyte; D015684:Gene Products, pol; D015789:HLA-A2 Antigen; D006512:Hepatitis B Core Antigens; D015395:Histocompatibility Antigens Class I; D015848:Interleukin-5; D010455:Peptides; D016753:Interleukin-10; D007371:Interferon-gamma