Remodeling of anti-tumor immunity with antibodies targeting a p53 mutant
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ABSTRACT:
PROVIDER: PRJNA1083988 | ENA |
REPOSITORIES: ENA
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Project description: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.
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2021-12-12 | GSE184009 | GEO
Project description:Proteomic identification and characterization of antibodies comprising the serological response to antigen can provide unique insight into the functional dynamics of adaptive immunity. We have developed a novel method to overcome the technical challenges which previously limited the direct analysis of immunoglobulin proteins in serum, as demonstrated by the identification of human anti-tetanus toxoid (TT) immunoglobulin G (IgG) proteins following booster vaccination. We analyzed the serum IgG repertoire across four time-points corresponding to pre-vaccination, 7 days, 3 months, and 9 months post vaccination. Antigen-specific antibodies were affinity purified against immobilized TT protein and sequenced by bottom-up nanoLC-MS/MS. Interpretation of mass spectra required a custom reference database of IgG heavy and light chain variable sequences determined by NextGen RNA sequencing of the donor's circulating plasmablasts and memory B cells following booster vaccination.
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