Tumor antigen–Human Leukocyte Antigen complex (pHLA)

The Tumor antigen–Human Leukocyte Antigen (HLA) complex, also known as a peptide-HLA (pHLA) complex, is a cell-surface assembly consisting of a processed peptide fragment derived from a tumor protein bound to an HLA molecule (Nature Reviews Drug Discovery, 2021). This complex serves as the essential recognition signal for T-cell receptors (TCRs), allowing the immune system to detect intracellular abnormalities such as mutations or aberrant protein expression (PubMed, PMID: 32582132). In oncology, pHLA complexes are highly attractive targets because they allow for the therapeutic targeting of intracellular proteins, which represent approximately 90% of the proteome and are otherwise inaccessible to traditional monoclonal antibodies (Science, 2021). Current therapeutic modalities targeting these complexes include TCR-engineered T-cells (TCR-T) and bispecific T-cell engagers like ImmTACs, which are engineered to bind the pHLA with high affinity and specificity (Journal of Hematology & Oncology, 2023). While promising, these therapies require precise patient selection based on HLA type and carry significant risks of off-target toxicity if the targeted peptide sequence is shared by proteins in vital healthy organs (Molecular Therapy, 2022).

Other names

Peptide-MHC complexpMHCTumor-associated antigen-HLA complexNeoantigen-HLA complexTA-HLA complexPeptide-HLA complex

Drugs targeting the tumor antigen-HLA complex utilize T-cell receptor (TCR) or TCR-mimetic domains to recognize specific peptide-HLA combinations, thereby redirecting T-cell cytotoxicity toward tumor cells (Nature Reviews Clinical Oncology, 2022).