Publication Date
6-18-2024
Journal
Journal of Hematology & Oncology
DOI
10.1186/s13045-024-01566-1
PMID
38886748
PMCID
PMC11184848
PubMedCentral® Posted Date
6-18-2024
PubMedCentral® Full Text Version
Post-Print
Published Open-Access
yes
Keywords
Tumor Suppressor Protein p53, Animals, Humans, Mice, Mutation, Antibodies, Monoclonal, Neoplasms, CD8-Positive T-Lymphocytes, Nanoparticles, Cell Line, Tumor, Mutant p53, E285K, Monoclonal antibody, IgG1, dIgA
Abstract
BACKGROUND: p53, the most frequently mutated gene in cancer, lacks effective targeted drugs.
METHODS: We developed monoclonal antibodies (mAbs) that target a p53 hotspot mutation E285K without cross-reactivity with wild-type p53. They were delivered using lipid nanoparticles (LNPs) that encapsulate DNA plasmids. Western blot, BLI, flow cytometry, single-cell sequencing (scRNA-seq), and other methods were employed to assess the function of mAbs in vitro and in vivo.
RESULTS: These LNP-pE285K-mAbs in the IgG1 format exhibited a robust anti-tumor effect, facilitating the infiltration of immune cells, including CD8+ T, B, and NK cells. scRNA-seq revealed that IgG1 reduces immune inhibitory signaling, increases MHC signaling from B cells to CD8+ T cells, and enriches anti-tumor T cell and B cell receptor profiles. The E285K-mAbs were also produced in the dimeric IgA (dIgA) format, whose anti-tumor activity depended on the polymeric immunoglobulin receptor (PIGR), a membrane Ig receptor, whereas that of IgG1 relied on TRIM21, an intracellular IgG receptor.
CONCLUSIONS: Targeting specific mutant epitopes using DNA-encoded and LNP-delivered mAbs represents a potential precision medicine strategy against p53 mutants in TRIM21- or PIGR-positive cancers.
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