HLA-A*02:01 presenting non-MART-1 cross-reactive peptides (HLA-A*02:01/non-MART-1 pMHC)

This target refers to a diverse set of peptide-MHC complexes where the HLA-A*02:01 molecule presents peptides that are not derived from the MART-1 (Melan-A) protein but are nonetheless recognized by MART-1-specific T-cell receptors (TCRs). This phenomenon, known as TCR cross-reactivity or polyspecificity, is a significant challenge in the development of TCR-engineered T-cell therapies (Frontiers in Immunology, 2020). Research has identified specific classes of these peptides, such as the 'DRG class' (e.g., MMWDRGLGMM), which can trigger activation of high-affinity TCRs like DMF5 through unanticipated structural rearrangements and register shifts (Riley et al., 2018; NIH). While MART-1 therapies primarily target melanoma, the presence of these cross-reactive peptides on healthy tissues can lead to off-target toxicities, including damage to melanocytes in the eye and ear (Journal of Immunology, 2011). Understanding and predicting these interactions is critical for ensuring the safety and specificity of adoptive T-cell immunotherapies, particularly when using affinity-enhanced TCRs that may have a broader recognition profile than natural receptors (Blood, 2013). These complexes serve as critical safety benchmarks during the preclinical screening of therapeutic TCR candidates to avoid lethal autoimmune reactions (Frontiers in Immunology, 2013).

Other names

Cross-reactive MART-1 mimicsDRG-class peptidesOff-target HLA-A*02:01 ligandsNon-cognate MART-1 TCR ligandsMART-1 cross-reactive peptide-MHC complexes

Off-target T-cell activation and cytotoxicity mediated by TCR cross-recognition of non-cognate peptide-MHC complexes.