Human leukocyte antigen class I-peptide complex (pHLA-I)

Human leukocyte antigen class I (HLA-I) molecules presenting specific peptides are essential for immune surveillance, acting as the primary mechanism by which the immune system identifies and eliminates infected or malignant cells (StatPearls, 2023). These complexes are formed by a polymorphic alpha heavy chain, a beta-2 microglobulin subunit, and an 8-11 amino acid peptide derived from the intracellular degradation of proteins (NIH, 2024). In oncology, these complexes present tumor-associated antigens or neoantigens, serving as highly specific targets for T-cell receptor (TCR) based therapies like Tebentafusp and Afamitresgene autoleucel (Nature Reviews Drug Discovery, 2022). Unlike traditional CAR-T therapies that target surface proteins, pHLA-targeting agents can access the entire intracellular proteome, significantly expanding the range of druggable targets (PubMed, 2021). However, therapeutic application is limited by the requirement for specific HLA genotypes (e.g., HLA-A*02:01) and the risk of off-target cross-reactivity with similar peptides in healthy tissues (Journal of Hematology & Oncology, 2023). Additionally, tumors often evade these therapies through HLA downregulation or loss of heterozygosity, necessitating the development of multi-HLA targeting strategies.

Other names

MHC class I-peptide complexpMHC-IPeptide-HLA complexAntigen-HLA complexpHLA-I

Drugs targeting these complexes typically utilize engineered T-cell receptors (TCRs) or TCR-mimetic antibodies to recognize the specific peptide-HLA interface, thereby recruiting and activating cytotoxic T-cells to destroy the target cell (Nature Reviews Drug Discovery, 2022).