Human leukocyte antigen A*02:01-restricted peptide-major histocompatibility complex (HLA-A*02:01-pMHC)

HLA-A*02:01-restricted peptide-major histocompatibility complex (pMHC) molecules are essential mediators of the adaptive immune response, responsible for presenting intracellularly derived peptides to CD8+ T cells (UniProt: P01892). These complexes consist of a polymorphic heavy chain (HLA-A*02:01), a non-polymorphic beta-2 microglobulin (B2M), and a short peptide (typically 8-11 amino acids) derived from proteasomal degradation of cellular proteins (PubMed: 32165630). Because HLA-A*02:01 is the most prevalent HLA-A allele in many populations, it serves as a primary scaffold for developing immunotherapies targeting tumor-associated antigens like MAGE-A4, NY-ESO-1, and gp100 (FDA: Tecelra, Kimmtrak). Drugs targeting these complexes, such as TCR-engineered T-cells (TCR-T) and bispecific T-cell engagers, are designed to recognize the unique structural interface formed by both the peptide and the HLA molecule. This specificity allows for the targeted destruction of malignant or infected cells that present non-self or overexpressed self peptides. However, therapeutic challenges include the potential for off-target toxicity due to cross-reactivity with similar peptides presented by the same HLA allele and the risk of immune evasion through HLA downregulation (PubMed: 31515461).

Other names

HLA-A*02:01-peptide complexHLA-A2-restricted antigenpMHC complexMHC class I-peptide complex

Targeted recognition by engineered T-cell receptors (TCRs) or bispecific molecules that bind the specific peptide-HLA interface to induce T-cell mediated cytotoxicity.