Mutant tumor protein p53 peptide-HLA-A*02 complex (mutp53-HLA-A*02)

The mutant p53 peptide-HLA-A*02 complex is a highly specific tumor neoantigen formed when mutated tumor protein p53 (TP53) is degraded by the proteasome and its resulting peptide fragments are presented on the cell surface by the Human Leukocyte Antigen A*02 (HLA-A*02) molecule (Hsiue et al., 2021, Science). TP53 is the most frequently mutated gene in human cancers, and specific 'hotspot' mutations, such as R175H or R273H, create unique amino acid sequences that are absent in normal tissues (Lo et al., 2020, JCI). Because p53 is an intracellular protein, it was historically considered inaccessible to antibody-based therapies; however, the presentation of these mutant fragments on MHC Class I molecules provides a targetable 'window' for the immune system. Current therapeutic approaches include T-cell receptor (TCR)-engineered T cells and bispecific T-cell engagers (BiTEs) designed to recognize the extremely low density of these complexes on the tumor cell surface (Hsiue et al., 2021, Science). Targeting this complex allows for the selective destruction of malignant cells while minimizing damage to healthy cells that express only wild-type p53. This target is particularly relevant for solid tumors where p53 mutations are a primary driver of oncogenesis and chemoresistance.

Other names

p53 neoantigen-HLA complexMutant p53-MHC class I complexp53 mutant peptide-HLA-A*02:01mutp53/HLA-A2

Redirection of T-cell cytotoxicity toward tumor cells via T-cell receptor (TCR) or TCR-mimetic binding to the mutant peptide-HLA complex, leading to granzyme/perforin-mediated apoptosis.