Melanoma-associated peptide-HLA-A*02:01 complex (HLA-A*02:01/MAA complex)

Melanoma-associated peptide-HLA-A*02:01 complexes are therapeutic targets consisting of specific intracellular tumor antigens, such as gp100, MART-1, MAGE-A3, or NY-ESO-1, processed into short peptides and presented on the cell surface by the HLA-A*02:01 Major Histocompatibility Complex (MHC) class I molecule (Vigneron, 2015, PMID: 25614325). These complexes allow the immune system to see internal cellular proteins, which are otherwise hidden from traditional antibody-based therapies. In melanoma, these antigens are often overexpressed or aberrantly expressed, providing a window for selective tumor targeting. Drugs like Tebentafusp (Kimmtrak) utilize a bispecific TCR-anti-CD3 format to redirect T cells to kill cells presenting the gp100 peptide in the context of HLA-A*02:01 (Nathan et al., 2021, PMID: 34551227). Similarly, adoptive cell therapies like Afamitresgene autoleucel use engineered TCRs to target NY-ESO-1 peptides presented by the same HLA allele (D'Angelo et al., 2018, PMID: 29592731). Because these targets are HLA-restricted, they are only effective in patients who possess the HLA-A*02:01 allele, and safety concerns primarily involve on-target, off-tumor effects on healthy melanocytes in the skin and eyes.

Other names

pMHC complexMelanoma-associated antigen/HLA-A*02:01gp100/HLA-A*02:01MART-1/HLA-A*02:01NY-ESO-1/HLA-A*02:01MAGE-A3/HLA-A*02:01PRAME/HLA-A*02:01

T-cell redirection and activation via engineered T-cell receptors (TCRs) or bispecific TCR-anti-CD3 fusion proteins (ImmTACs) that bind specifically to the peptide-HLA complex.