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

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

  • Immunity. 2023 Oct 26:S1074-7613(23)00418-1. doi: 10.1016/j.immuni.2023.09.013.
Subir Biswas 1,  Gunjan Mandal 2,  Carmen M Anadon 3,  Ricardo A Chaurio 3,  Luis U Lopez-Bailon 4,  Mate Z Nagy 5,  Jessica A Mine 3,  Kay Hänggi 5,  Kimberly B Sprenger 5,  Patrick Innamarato 5,  Carly M Harro 5,  John J Powers 5,  Joseph Johnson 6,  Bin Fang 7,  Mostafa Eysha 8,  Xiaolin Nan 9,  Roger Li 10,  Bradford A Perez 11,  Tyler J Curiel 12,  Xiaoqing Yu 13,  Paulo C Rodriguez 5,  Jose R Conejo-Garcia 14
Affiliations

Affiliations

  • 1 Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Tumor Immunology and Immunotherapy, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Kharghar, Navi Mumbai 410210, India.
  • 2 Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Division of Cancer Biology, DBT-Institute of Life Sciences, Bhubaneswar 751023, India.
  • 3 Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Department of Integrated Immunobiology, Duke School of Medicine, Durham, NC 27710, USA; Duke Cancer Institute, Duke School of Medicine, Durham, NC 27710, USA.
  • 4 Department of Integrated Immunobiology, Duke School of Medicine, Durham, NC 27710, USA; Duke Cancer Institute, Duke School of Medicine, Durham, NC 27710, USA.
  • 5 Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
  • 6 Analytic Microscopy Core, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
  • 7 Proteomics and Metabolomics Core, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
  • 8 Department of Medicine, Duke School of Medicine, Durham, NC 27710, USA.
  • 9 Department of Biomedical Engineering, Knight Cancer Institute, and OHSU Center for Spatial Systems Biomedicine (OCSSB), Oregon Health and Science University, Portland, OR 97239, USA.
  • 10 Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
  • 11 Department of Radiation Therapy, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
  • 12 Departments of Medicine and Microbiology and Immunology, Dartmouth Geisel School of Medicine, Hanover, NH 03755, USA.
  • 13 Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
  • 14 Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Department of Integrated Immunobiology, Duke School of Medicine, Durham, NC 27710, USA; Duke Cancer Institute, Duke School of Medicine, Durham, NC 27710, USA. Electronic address: jose.conejo-garcia@duke.edu.
PMID: 37909039 DOI: 10.1016/j.immuni.2023.09.013
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 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.

Keywords

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

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-134813
    99.42%, KRAS G12D抑制剂
    Ras
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