mRNA-LNP vaccines targeting mutation-derived BRCA2 and p53 elicit antigen-specific immune responses in beagles

Messenger RNA (mRNA) vaccines are next-generation platforms capable of eliciting potent cellular and humoral immunity through intracellular expression of tumor-associated or mutation-specific antigens. Canine mammary gland tumor (CMT), commonly encountered in female dogs, frequently harbors mutations in the BRCA2 and p53 genes, which are also relevant to human breast cancers. We aimed to design mutation-targeted mRNA-lipid nanoparticle (LNP) vaccines encoding canine BRCA2 and p53 variants using in silico epitope prediction and evaluate their immunogenicity and safety. Three mRNA constructs encoding BRCA2 and p53 mutations were synthesized and encapsulated in ionizable-lipid-based LNPs. The resulting mRNA-LNP formulations, namely canine BRCA2-10204ins candidates (cBR2-Cand), canine BRCA2-p53 28-mer epitopes (cBR2-p53), and canine BRCA2-partial (cBR2-Part), were then admixed to prepare the cBR2-cocktail, a mixed mRNA-LNP vaccine designed to enhance mutation-specific immune responses. In vitro expression was confirmed in HeLa cells. In vivo immunization in mice induced strong interferon (IFN)-γ secretion, particularly against BRCA2 H143R, K801R, and T1425P mutations. Beagles immunized with cBR2-cocktail mRNA-LNPs exhibited increased IFN-γ production in peripheral blood mononuclear cells after repeated dosing, without significant hematological or biochemical abnormalities. Mutation-derived mRNA-LNP vaccines safely induced mutation-specific T-cell responses in vivo. Although anticancer efficacy was not assessed, we established a preclinical foundation for developing mutation-targeted mRNA immunotherapies for CMT and underscored the translational relevance of the canine model for human BRCA2/p53-related cancers.

Abstract from PubMed (PMID 43019901). This entry was added automatically by our daily literature monitor because it matches the topics we follow; read the full paper at the original source.