Human leukocyte antigen A*02:01-presented tumor-associated antigen epitopes (HLA-A*02:01/TAA pMHC)

Human leukocyte antigen A*02:01 (HLA-A*02:01)-presented tumor-associated antigen (TAA) epitopes are molecular complexes consisting of the Major Histocompatibility Complex (MHC) Class I allele HLA-A*02:01 and specific peptide fragments derived from intracellular proteins (UniProt: P01892). These epitopes are displayed on the surface of cancer cells, where they serve as targets for the adaptive immune system, specifically CD8+ cytotoxic T-cells. HLA-A*02:01 is the most common HLA-A allele in many populations, making it a high-priority scaffold for developing immunotherapies like T-cell receptor (TCR)-engineered T-cells and bispecific T-cell engagers (PMID: 31043417). Therapeutic agents such as Tebentafusp and Afamitresgene autoleucel are designed to recognize these specific pMHC complexes with high affinity to induce tumor cell lysis (FDA: Kimmtrak, Tecelra). Because these targets represent processed internal proteins, they allow for the targeting of "undruggable" intracellular oncogenes that are not accessible to traditional antibody therapies. However, the primary challenge in targeting these epitopes is ensuring high specificity to avoid cross-reactivity with similar peptides presented on healthy tissues, which can lead to severe off-target toxicity (PMID: 23846757). Patient selection for these therapies requires screening for both the HLA-A*02:01 genotype and the expression of the specific tumor antigen being targeted.

Other names

HLA-A*02:01-restricted tumor antigensHLA-A2-presented peptidesPeptide-MHC class I complexespMHCMHC-I-restricted tumor epitopesHLA-A*02:01-peptide complex

Recognition of the specific peptide-MHC complex by engineered T-cell receptors (TCRs) or TCR-mimetic antibodies, leading to T-cell activation and directed lysis of the tumor cell.