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

Abstract

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 G12D within ovarian carcinoma cells and expelled this oncodriver from tumor cells. dIgA binding changed endosomal trafficking of KRAS G12D from accumulation in recycling endosomes to aggregation in the early/late endosomes through which dIgA transcytoses. dIgA targeting of KRAS G12D abrogated tumor cell proliferation in cell culture assays. In vivo , KRAS G12D -specific dIgA1 limited the growth of KRAS G12D -mutated ovarian and lung carcinomas in a manner dependent on CD8 + T cells. dIgA specific for IDH1 R132H reduced colon cancer growth, demonstrating effective targeting of a cytoplasmic oncodriver not associated with surface receptors. dIgA targeting of KRAS G12D restricted tumor growth more effectively than small-molecule KRAS G12D inhibitors, supporting the potential of this approach for the treatment of human cancers.