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.

Keywords: IDH1; IgA transcytosis; KRAS; PIGR; dimeric IgA; epithelial malignancies; immunotherapy; intracellular targeting; mutation-specific antibodies; therapeutic antibody.