Targeting intracellular oncoproteins with dimeric IgA promotes expulsion from the cytoplasm and immune-mediated control of epithelial cancers.

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 KRASG12D within ovarian carcinoma cells and expelled this oncodriver from tumor cells. dIgA binding changed endosomal trafficking of KRASG12D from accumulation in recycling endosomes to aggregation in the early/late endosomes through which dIgA transcytoses. dIgA targeting of KRASG12D abrogated tumor cell proliferation in cell culture assays. In vivo , KRASG12D-specific dIgA1 limited the growth of KRASG12D-mutated ovarian and lung carcinomas in a manner dependent on CD8+ T cells. dIgA specific for IDH1R132H reduced colon cancer growth, demonstrating effective targeting of a cytoplasmic oncodriver not associated with surface receptors. dIgA targeting of KRASG12D restricted tumor growth more effectively than small-molecule KRASG12D inhibitors, supporting the potential of this approach for the treatment of human cancers. [Display omitted] • Dimeric IgA undergoes bona fide transcytosis through PIGR+ carcinoma cells • Dimeric IgA specifically neutralizes mutated oncogenes inside tumor cells • Oncodrivers are expelled outside tumor cells through altered endosomal trafficking • Mutation-specific dimeric IgA specifically abrogates tumor growth in vivo Despite their long half-life, therapeutic antibodies are considered ineffective against intracellular antigens. Biswas et al. demonstrate that dimeric IgA undergoes transcytosis through PIGR+ epithelial cancer cells and can be engineered for the specific targeting of intracellular mutated oncodrivers. Binding of mutation-specific IgA expels oncodrivers from the cytoplasm and promotes anti-tumor immunity. [ABSTRACT FROM AUTHOR]