Melanoma peptide MART-1(27-35) analogues with enhanced binding capacity to the human class I histocompatibility molecule HLA-A2 by introduction of a beta-amino acid residue: implications for recognition by tumor-infiltrating lymphocytes.
The design of heteroclytic antigens with high MHC binding capacity is of particular interest to overcome the weak immunogenicity of peptide epitopes derived from tissue antigens expressed by tumors. In the present study, double-substituted peptide analogues of the tumor-associated antigen MART-1(27-35) incorporating a substitution at a primary anchor residue and a beta-amino acid residue at different positions in the sequence were synthesized and evaluated for binding to the human histocompatibility class I molecule HLA-A2 and for recognition by tumor-infiltrating lymphocytes. Interestingly, by combining a Leu for Ala substitution at P2 (which alone is deleterious for antigenic activity) with a beta-amino acid substitution at a putative TCR contact residue, recognition by tumor-infiltrating lymphocytes was partially restored. The analogue [Leu(28),beta-HIle(30)]MART-1(27-35) displays both a higher affinity to HLA-A2 and a more prolonged complex stability compared to [Leu(28)]MART-1(27-35). Overall, these results suggest that double-substitution strategies and beta-amino acid replacements at putative TCR contact residues might prove useful for the design of epitope mimics with high MHC binding capacity.
Guichard
G
G
Laboratoire de Chimie Immunologique, Institut de Biologie Moléculaire et Cellulaire, UPR 9021 CNRS, 15 rue Descartes, 67000 Strasbourg, France. G.Guichard@ibmc.u-strasbg.fr
Zerbib
A
A
Le Gal
F A
FA
Hoebeke
J
J
Connan
F
F
Choppin
J
J
Briand
J P
JP
Guillet
J G
JG
D002851:Chromatography, High Pressure Liquid; D019075:Electrophoresis, Capillary; D000939:Epitopes / Q000737:chemistry*; D015789:HLA-A2 Antigen / Q000378:metabolism*; D006801:Humans; D007519:Isoantigens / Q000737:chemistry / Q000378:metabolism; D016246:Lymphocytes, Tumor-Infiltrating / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D008545:Melanoma / Q000737:chemistry*; D009363:Neoplasm Proteins / Q000737:chemistry*; D010446:Peptide Fragments / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D014407:Tumor Cells, Cultured
D000939:Epitopes; D015789:HLA-A2 Antigen; D007519:Isoantigens; C415186:MART-1 antigen (27-35), Leu(28)-beta-HIle(30)-; C105787:MART-1-Melan-A(27-35) epitope; D009363:Neoplasm Proteins; D010446:Peptide Fragments