Targeting a neoantigen derived from a common TP53 mutation

著者: Emily Han-Chung Hsiue, Katharine M. Wright, Jacqueline Douglass, Michael S. Hwang, Brian J. Mog, Alexander H. Pearlman, Suman Paul, Sarah R. DiNapoli, Maximilian F. Konig, Qing Wang, A. Schaefer, Michelle S. Miller, Andrew D. Skora, P. Aitana Azurmendi, Michael Murphy, Qiang Liu, Evangeline Watson, Yana Li, Drew M. Pardoll, Chetan Bettegowda, Nickolas Papadopoulos, Kenneth W. Kinzler, Bert Vogelstein, Sandra B. Gabelli, Shibin Zhou - Science 2021 被引用: 347

mutation (R175H, in which arginine at position 175 is replaced with histidine) in complex with a common human leukocyte antigen-A (HLA-A) allele on the cell surface. We describe the structural basis of this specificity and its conversion into an immunotherapeutic agent: a bispecific single-chain diabody. Despite the extremely low p53 peptide-HLA complex density on the cancer cell surface, the bispecific antibody effectively activated T cells to lyse cancer cells that presented the neoantigen in vitro and in mice. This approach could in theory be used to target cancers containing mutations that are difficult to target in conventional ways.