Human leukocyte antigen A (HLA-A) major histocompatibility complex class I molecule (HLA-A)

HLA-A2 and HLA-A3 are specific serotypes of the Human Leukocyte Antigen A (HLA-A) gene, which encodes the alpha chain of the Major Histocompatibility Complex (MHC) class I molecule. These molecules are expressed on the surface of nearly all nucleated cells, including antigen-presenting cells, where they present short endogenous peptides (typically 8-10 amino acids) to CD8+ cytotoxic T lymphocytes. This presentation is essential for the immune system to monitor for intracellular pathogens and malignant transformations. HLA-A2, particularly the HLA-A*02:01 allele, is one of the most common HLA alleles in Western populations and serves as a primary restriction element for a wide range of T-cell receptor (TCR)-based immunotherapies. In the context of drug development, HLA-A2 and HLA-A3 are not targeted as naked proteins but rather as part of a peptide-HLA (pHLA) complex. Modern biotherapeutics, such as tebentafusp and various TCR-T cell therapies, are engineered to recognize specific tumor-associated antigens (e.g., gp100, MAGE-A4) only when they are presented by these specific HLA alleles. This 'HLA restriction' means that patients must be screened for their HLA genotype (e.g., HLA-A*02 positive) to be eligible for treatment. While highly effective at directing the immune system toward intracellular targets, these therapies face challenges such as tumor immune escape through HLA downregulation and the risk of severe inflammatory responses like cytokine release syndrome.

Other names

MHC class I antigen AHLA-A2HLA-A3Major histocompatibility complex, class I, AHLA-A*02HLA-A*03Human leukocyte antigen A2Human leukocyte antigen A3

Drugs targeting these molecules typically function as TCR-mimetic antibodies, bispecific T-cell engagers (BiTEs), or TCR-T cell therapies that recognize specific intracellular peptides presented by the HLA-A2 or HLA-A3 groove. These therapies bridge the target cell with T-cells to induce directed cytotoxicity.