Identification of potential CTL epitopes of tumor-associated antigen MAGE-1 for five common HLA-A alleles.
Identification of CTL epitopes for tumor-specific responses is important for the development of immunotherapies to treat cancer patients. We have developed a strategy to identify potential CTL epitopes based on screening of sequences of target proteins for presence of specific motifs recognized by the most common HLA-A alleles, and identification of high affinity binding peptides using in vitro quantitative assays. A systematic analysis using the sequence of the product of the tumor-associated MAGE-1 gene has been carried out. All possible peptides of nine and ten residues, containing binding motifs for HLA-A1, -A2.1, A-3.2, -A11 and -A24 were synthesized and tested for binding using a quantitative assay. Out of 237 possible peptide/MHC combinations, 47 cases demonstrated good binding affinity (Kd < or = 500 nM). Several peptides were identified as good MHC binders for each one of the five HLA-A alleles studied (five for HLA-A1, 11 for HLA-A2.1, 10 for HLA-A3.2, 16 for HLA-A11 and five for HLA-A24. Furthermore, eight of these peptides were found to bind well to more than one HLA-A allele. These results have important implications for the development of immunotherapeutic vaccines to treat malignant melanoma.
Celis
E
E
Cytel Corporation, San Diego, CA 92121.
Fikes
J
J
Wentworth
P
P
Sidney
J
J
Southwood
S
S
Maewal
A
A
Del Guercio
M F
MF
Sette
A
A
Livingston
B
B
D000595:Amino Acid Sequence; D000951:Antigens, Neoplasm / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D018604:Epitope Mapping; D015234:HLA-A Antigens / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D058950:Melanoma-Specific Antigens; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins; D010455:Peptides / Q000737:chemistry / Q000276:immunology; D011485:Protein Binding; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D013329:Structure-Activity Relationship; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
D000951:Antigens, Neoplasm; D015234:HLA-A Antigens; D008024:Ligands; C072011:MAGEA1 protein, human; D058950:Melanoma-Specific Antigens; D009363:Neoplasm Proteins; D010455:Peptides; D011948:Receptors, Antigen, T-Cell