Melanoma Peptide MART-1(27−35) Analogues with Enhanced Binding Capacity to the Human Class I Histocompatibility Molecule HLA-A2 by Introduction of a β-Amino Acid Residue:  Implications for Recognition by Tumor-Infiltrating Lymphocytes

• Published in: Journal of medicinal chemistry Vol. 43; no. 20; pp. 3803 - 3808
• Main Authors: Guichard, Gilles, Zerbib, Annette, Le Gal, Frédérique-Anne, Hoebeke, Johan, Connan, Francine, Choppin, Jeannine, Briand, Jean-Paul, Guillet, Jean-Gérard
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 05.10.2000; Amer Chemical Soc
• Subjects: Antineoplastic agents; Biological and medical sciences; Chemistry, Medicinal; Chromatography, High Pressure Liquid; Electrophoresis, Capillary; Epitopes - chemistry; HLA-A2 Antigen - metabolism; Humans; Immunotherapy; Isoantigens - chemistry; Isoantigens - metabolism; Life Sciences & Biomedicine; Lymphocytes, Tumor-Infiltrating - metabolism; Magnetic Resonance Spectroscopy; Medical sciences; Melanoma - chemistry; Neoplasm Proteins - chemistry; Peptide Fragments - chemical synthesis; Peptide Fragments - chemistry; Peptide Fragments - metabolism; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Protein Binding; Science & Technology; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Tumor Cells, Cultured; MHC CLASS-I; METASTATIC MELANOMA; IMMUNOGENICITY; REACTIVE CTL; AFFINITY; ANTIGENS; GENERATION; IMMUNODOMINANT PEPTIDE; INDUCTION; VACCINES; Antineoplastic agent; Tumor associated antigen; Antigenic determinant; Peptides; Major histocompatibility system; Molecular interaction; Nonapeptide; Tumor infiltrating lymphocyte; Vaccine; Malignant tumor; Biological activity; Pseudopeptide; Immunogenicity; Peptide fragment; Immunotherapy; Malignant melanoma; Peptide synthesis; Solid phase; Chemical synthesis; Class I histocompatibility antigen; Heterocyclic compound
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm000909s

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 β-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 β-amino acid substitution at a putative TCR contact residue, recognition by tumor-infiltrating lymphocytes was partially restored. The analogue [Leu28,β-HIle30]MART-1(27−35) displays both a higher affinity to HLA-A2 and a more prolonged complex stability compared to [Leu28]MART-1(27−35). Overall, these results suggest that double-substitution strategies and β-amino acid replacements at putative TCR contact residues might prove useful for the design of epitope mimics with high MHC binding capacity.