Remodeling of anti-tumor immunity with antibodies targeting a p53 mutant.
J Hematol Oncol
; 17(1): 45, 2024 Jun 18.
Article
en En
| MEDLINE
| ID: mdl-38886748
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.Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Proteína p53 Supresora de Tumor
/
Anticuerpos Monoclonales
/
Mutación
Límite:
Animals
/
Humans
Idioma:
En
Revista:
J Hematol Oncol
Asunto de la revista:
HEMATOLOGIA
/
NEOPLASIAS
Año:
2024
Tipo del documento:
Article
País de afiliación:
Estados Unidos
Pais de publicación:
Reino Unido