Dataset Information

Targeting a neoantigen derived from a common TP53 mutation.

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.

SUBMITTER: Hsiue EH

PROVIDER: S-EPMC8208645 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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Targeting a neoantigen derived from a common TP53 mutation.

Hsiue Emily Han-Chung EH Wright Katharine M KM Douglass Jacqueline J Hwang Michael S MS Mog Brian J BJ Pearlman Alexander H AH Paul Suman S DiNapoli Sarah R SR Konig Maximilian F MF Wang Qing Q Schaefer Annika A Miller Michelle S MS Skora Andrew D AD Azurmendi P Aitana PA Murphy Michael B MB Liu Qiang Q Watson Evangeline E Li Yana Y Pardoll Drew M DM Bettegowda Chetan C Papadopoulos Nickolas N Kinzler Kenneth W KW Vogelstein Bert B Gabelli Sandra B SB Zhou Shibin S

Science (New York, N.Y.) 20210301 6533

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 ...[more]

PMID: 33649166

Dataset Information

Targeting a neoantigen derived from a common TP53 mutation.

Publications

Targeting a neoantigen derived from a common <i>TP53</i> mutation.

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