Human leukocyte antigen A*02:01 presenting Melanoma Antigen Recognized by T cells 1 (26-35, 27L) peptide (HLA-A*02:01/MART-1(27L))

The HLA-A*02:01-MART-1 (26-35/27L) complex is a peptide-major histocompatibility complex (pMHC) that functions as a target for T-cell-based immunotherapies in melanoma. It involves the presentation of a specific epitope from the MART-1 (Melan-A) protein by the HLA-A*02:01 molecule to the T-cell receptor (TCR) (UniProt: Q16655). The 27L variant is a modified heteroclitic peptide where a leucine substitution at position 27 increases binding affinity to the HLA groove compared to the native alanine, enhancing the immunogenicity and stability of the complex (PubMed: 9620648). MART-1 is a lineage-specific antigen highly expressed in melanocytes and melanoma cells, making this pMHC a frequent target for TCR-engineered T cells (TCR-T) and immune mobilizing monoclonal T-cell receptors against cancer (ImmTACs) (PubMed: 16946036). While effective in inducing tumor regression, targeting this complex carries risks of on-target, off-tumor toxicities due to MART-1 expression in healthy melanocytes in the skin, eyes, and ears. Clinical manifestations of these toxicities include vitiligo, uveitis, and sensorineural hearing loss (PubMed: 19380867). This target represents a classic model for developing high-affinity TCRs and understanding the balance between anti-tumor efficacy and autoimmunity.

Other names

HLA-A2/MART-1 complexMelan-A/HLA-A*02:01MART-1 26-35 (A27L) peptide-MHCELAGIGILTV-HLA-A*02:01pMHC MART-1/A2

Recognition of the peptide-MHC complex by engineered or endogenous T-cell receptors (TCRs) triggers T-cell activation, cytokine release, and cytotoxic lysis of the target cell.