Peptide-human leukocyte antigen complex (pHLA)

Peptide-human leukocyte antigen (pHLA) complexes are molecular assemblies consisting of a peptide fragment bound to a Human Leukocyte Antigen (HLA) molecule, which is the human version of the Major Histocompatibility Complex (MHC). These complexes are expressed on the cell surface and serve as the primary signal for T-cell recognition, with HLA class I presenting intracellularly derived peptides to CD8+ cytotoxic T cells and HLA class II presenting extracellularly derived peptides to CD4+ helper T cells [16, 17, 18]. In healthy states, pHLA complexes display self-peptides to maintain tolerance; however, in cancer or infection, they present neoantigens or viral peptides that trigger an immune response [2, 6, 9]. Because pHLA complexes can present fragments of intracellular proteins that are otherwise inaccessible to traditional antibodies, they are highly attractive targets for precision immunotherapies [2, 5]. Current therapeutic approaches include TCR-engineered T cells (TCR-T), TCR-mimic (TCRm) antibodies, and bispecific T-cell engagers (BiTEs) that specifically bind to disease-associated pHLA targets [2, 4, 9]. Challenges in targeting these complexes include the extreme polymorphism of HLA alleles and the risk of off-target toxicity due to cross-reactivity with similar self-peptides [3, 4, 15].

Other names

pMHCPeptide-MHC complexAntigen-HLA complexHLA-peptide complexPeptide-major histocompatibility complex

Drugs targeting peptide-HLA complexes typically function by utilizing a T-cell receptor (TCR) or a TCR-mimic (TCRm) binding domain to recognize a specific peptide-HLA combination on the target cell surface. This recognition event facilitates the recruitment and activation of cytotoxic T cells, often through a bispecific engager or by direct engineering of the T cell (TCR-T), leading to the selective lysis of the target cell [2, 4, 9].