6W51

Structure of the antibody fragment H2 in complex with HLA-A*02:01/p53R175H

Summary for 6W51

• Entry DOI: 10.2210/pdb6w51/pdb
• Descriptor: MHC class I antigen, Beta-2-microglobulin, Cellular tumor antigen p53 peptide, ... (7 entities in total)
• Functional Keywords: immunotherapy, mhc-i, hla-a2, p53, immune system
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 20
• Total formula weight: 386132.70

Authors

Wright, K.M.,Gabelli, S.B. (deposition date: 2020-03-12, release date: 2021-03-17, Last modification date: 2024-11-20)

Primary citation

Hsiue, E.H.,Wright, K.M.,Douglass, J.,Hwang, M.S.,Mog, B.J.,Pearlman, A.H.,Paul, S.,DiNapoli, S.R.,Konig, M.F.,Wang, Q.,Schaefer, A.,Miller, M.S.,Skora, A.D.,Azurmendi, P.A.,Murphy, M.B.,Liu, Q.,Watson, E.,Li, Y.,Pardoll, D.M.,Bettegowda, C.,Papadopoulos, N.,Kinzler, K.W.,Vogelstein, B.,Gabelli, S.B.,Zhou, S.
Targeting a neoantigen derived from a common TP53 mutation.
Science, 371:-, 2021

PubMed Abstract: (tumor protein p53) is the most commonly mutated cancer driver gene, but drugs that target mutant tumor suppressor genes, such as , are not yet available. Here, we describe the identification of an antibody highly specific to the most common 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.

PubMed: 33649166
DOI: 10.1126/science.abc8697

Experimental method

X-RAY DIFFRACTION (3.53 Å)