期刊
SCIENCE
卷 371, 期 6533, 页码 1009-+出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.abc8697
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资金
- Virginia and D. K. Ludwig Fund for Cancer Research
- Lustgarten Foundation for Pancreatic Cancer Research
- Commonwealth Fund
- Bloomberg-Kimmel Institute for Cancer Immunotherapy
- Bloomberg Philanthropies
- Mark Foundation for Cancer Research
- NIH Cancer Center support grant [P30 CA006973]
- NIH [T32 GM73009, 5T32 CA009071-38, T32 AR048522]
- SITC-Amgen Cancer Immunotherapy in Hematologic Malignancies Fellowship
- NCI [R37 CA230400]
- NIH, the National Institute of General Medical Sciences [P41GM111244]
- U.S. Department of Energy (DOE) Office of Biological and Environmental Research [KP1605010]
- National Synchrotron Light Source II at Brookhaven National Laboratory
- DOE Office of Basic Energy Sciences [DE-SC0012704 (KC0401040)]
An antibody highly specific to the most common TP53 mutation has been identified and converted into an immunotherapeutic agent. Despite low complex density on the cancer cell surface, the bispecific antibody effectively activates T cells to lyse cancer cells expressing the neoantigen. This approach may be used to target cancers with mutations that are difficult to target conventionally.
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.Y
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