Remodeling of anti-tumor immunity with antibodies targeting a p53 mutant

p53 is the most mutated gene in cancer, yet there are no effective drugs targeting p53 mutants. Here, we report the development of monoclonal antibodies targeting a p53 hotspot mutation E285K (E285K-mAbs). These mAbs recognize the mutant E285K epitope without cross-reactivity against wild-type p53. They are delivered by lipid nanoparticles (LNPs) that encapsulate DNA plasmids. The LNP-pE285K-mAbs in the IgG1 formats exhibit a robust anti-tumor effect, facilitating the infiltration of immune cells, including CD8+ T cells, B cells, and NK cells. Single-cell sequencing reveals that the therapeutic effects of IgG1 are associated with reduced immune inhibitory signaling, increased MHC signaling from B cells to CD8+ T cells, and enriched anti-tumor T cell and B cell receptor profiles. The E285K-mAbs can also be made in the dimeric IgA (dIgA) format. The anti-tumor activity of IgA is dependent on PIGR, whereas that of IgG1 is dependent on TRIM21. These findings indicate that targeting specific mutant epitopes through DNA-encoded and LNP-delivered mAbs represents a novel approach for precision medicine against p53 mutants in PIGR- or TRIM21-positive cancers.