Paired-like homeobox 2B-derived peptide–Human Leukocyte Antigen complex (PHOX2B-HLA)

The PHOX2B-derived peptide–HLA complex is a tumor-specific antigen consisting of a fragment of the Paired-like homeobox 2B (PHOX2B) protein presented on the cell surface by Human Leukocyte Antigen (HLA) molecules, specifically HLA-A*24:02. PHOX2B is a master regulator of autonomic nervous system development and is highly and specifically expressed in neuroblastoma, an aggressive childhood cancer, while remaining largely absent in normal postnatal tissues (UniProt Q99453). Because PHOX2B is an intracellular transcription factor, it is traditionally considered undruggable by monoclonal antibodies; however, its degradation products are presented as peptides on the cell surface, making them accessible to engineered T-cell therapies. Research has demonstrated that peptide-centric chimeric antigen receptor (PC-CAR) T cells can be engineered to bind this pMHC complex with high affinity and specificity (Yarmarkovich et al., Nature 2021). This targeting strategy allows for the potent elimination of neuroblastoma cells in a lineage-specific manner. Clinical application of this target is currently focused on high-risk neuroblastoma patients who carry the HLA-A*24:02 allele (Children's Hospital of Philadelphia, 2021).

Other names

PHOX2B-HLA-A*24:02PHOX2B peptide-MHC complexPHOX2B-derived pMHCQRPQDPAASL-HLA-A*24:02

The therapeutic approach utilizes peptide-centric chimeric antigen receptor (PC-CAR) T cells designed to recognize the specific PHOX2B-derived peptide (QRPQDPAASL) presented by the HLA-A*24:02 molecule. Upon binding to this peptide-MHC complex, the CAR T cells are activated, leading to the targeted lysis of neuroblastoma cells through the release of cytotoxic molecules like perforin and granzymes (Yarmarkovich et al., Nature 2021).