Proteomics

Dataset Information

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Dimeric IgA specifically disables intracellular mutated oncodrivers


ABSTRACT: Despite their long half-life, therapeutic antibodies are considered ineffective against intracellular antigens due to their perceived inability to penetrate epithelial cells. Using recombinant antibodies targeting common mutations in oncogenes, we show that dimeric IgA, but not the same antibody on an IgG backbone, penetrates human epithelial cancer cells through PIGR-dependent directional transcytosis, specifically neutralizing mutated oncodrivers and expelling antigens outside the cell, bound to secretory IgA. Accordingly, targeting of KRasG12D or IDH1R132H with antigen-specific dimeric IgA abrogated the growth of different carcinomas in a mutation-specific manner, including in syngeneic tumor-bearing immunocompetent mice. Our results provide a rationale for developing PIGR-targeting tumor cell-penetrating antibodies to effectively target common mutations in intracellular oncogenes that drive many aggressive and frequent human cancers.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

DISEASE(S): Non-small Cell Lung Carcinoma

SUBMITTER: John Koomen  

LAB HEAD: José Conejo-Garcia

PROVIDER: PXD042914 | Pride | 2025-05-06

REPOSITORIES: Pride

Dataset's files

Source:
Action DRS
20230119_Conejo-Garcia_2_JChain-Check.raw Raw
F003736.dat Other
F003740.dat Other
IgA_Antibody_Dimer_DDA_HFX.raw Raw
checksum.txt Txt
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Publications


Dimeric IgA (dIgA) can move through cells via the IgA/IgM polymeric immunoglobulin receptor (PIGR), which is expressed mainly on mucosal epithelia. Here, we studied the ability of dIgA to target commonly mutated cytoplasmic oncodrivers. Mutation-specific dIgA, but not IgG, neutralized KRAS<sup>G12D</sup> within ovarian carcinoma cells and expelled this oncodriver from tumor cells. dIgA binding changed endosomal trafficking of KRAS<sup>G12D</sup> from accumulation in recycling endosomes to aggreg  ...[more]

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