| Literature DB >> 33649166 |
Emily Han-Chung Hsiue1,2,3, Katharine M Wright2,4,5, Jacqueline Douglass1,2,3, Michael S Hwang1,2,3, Brian J Mog1,2,3,6, Alexander H Pearlman1,2,3, Suman Paul1,2,3,7, Sarah R DiNapoli1,2,3, Maximilian F Konig1,2,3,8, Qing Wang1,2,9, Annika Schaefer1,2,3, Michelle S Miller2,4,5, Andrew D Skora1,2, P Aitana Azurmendi2,4,5, Michael B Murphy10, Qiang Liu1,2,3, Evangeline Watson1,2,3, Yana Li4, Drew M Pardoll5,7, Chetan Bettegowda1,3,11, Nickolas Papadopoulos1,3,5,12, Kenneth W Kinzler1,3,5, Bert Vogelstein13,2,3,5,12, Sandra B Gabelli14,7,15, Shibin Zhou13,3,5.
Abstract
TP53 (tumor protein p53) is the most commonly mutated cancer driver gene, but drugs that target mutant tumor suppressor genes, such as TP53, are not yet available. Here, we describe the identification of an antibody highly specific to the most common TP53 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.Entities:
Mesh：
Substances：
Year: 2021 PMID： 33649166 PMCID： PMC8208645 DOI： 10.1126/science.abc8697
Source DB: PubMed Journal: Science ISSN： 0036-8075 Impact factor: 47.728