Peptide-Human Leukocyte Antigen complex (pHLA complex) (pHLA)

Peptide-Human Leukocyte Antigen (pHLA) complexes are molecular assemblies consisting of a short peptide fragment, typically 8-15 amino acids long, nestled within the binding groove of an HLA molecule on the cell surface [1]. These complexes serve as the primary mechanism by which the immune system surveys the internal health of a cell, as the presented peptides are derived from the degradation of intracellular proteins [2]. In the context of oncology, pHLA complexes on tumor cells display neoantigens or overexpressed proteins, making them highly specific targets for T-cell-based therapies [3]. Unlike traditional monoclonal antibodies that target surface proteins, pHLA-targeting agents can access the vast intracellular proteome, which accounts for approximately 90% of potential cancer targets [4]. Current therapeutic strategies include TCR-engineered T-cells (TCR-T) and soluble bispecific T-cell engagers, such as Tebentafusp, which are designed to recognize these complexes with high affinity to induce potent anti-tumor immune responses [5]. However, the high polymorphism of HLA alleles and the risk of lethal cross-reactivity with self-peptides in vital organs remain significant challenges in drug development [6]. Sources: [1] UniProt (HLA-A/B/C); [2] Janeway's Immunobiology; [3] Nature Reviews Drug Discovery (2021, 20:437-458); [4] Journal of Hematology & Oncology (2023, 16:102); [5] FDA Label for Kimmtrak (Tebentafusp); [6] PubMed (PMID: 23852344).

Other names

pMHC complexPeptide-Major Histocompatibility ComplexTumor-specific pHLAHLA-peptide complexAntigen-HLA complexMHC-peptide complex

Binding of therapeutic T-cell receptors (TCRs), TCR-engineered T-cells, or TCR-like antibodies to the specific peptide-HLA complex on the cell surface to trigger T-cell mediated cytotoxicity and targeted cell lysis.