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Antibodies target intracellular oncodrivers through PIGR-mediated transcytosis

Genes & Immunity volume 25, pages 85–86 (2024)Cite this article

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Monoclonal antibodies have revolutionized the landscape of cancer and autoimmunity patient care and are at the forefront of contemporary drug development. However, antibodies have been traditionally considered ineffective for targeting intracellular antigens, due to their large size, which hinders effective penetration into the cytoplasm. However, it has been known for a long time that IgG crosses the placenta through binding to FcRn and endosomal intracellular trafficking, a phenomenon known as transcytosis. In addition, dimeric IgA and pentameric IgM also undergo directional transcytosis through mucosal cells in a Polymeric Immunoglobulin Receptor (PIGR)-dependent manner. This intricate process not only enables the transport of these immunoglobulins to the luminal side of mucosal locations, but neutralizes viruses that have already infected epithelial cells [1].

Neutralization of KRASG12D was not restricted to in vitro experiments, because KRASG12D-specifc dimeric IgA abrogated the progression of multiple carcinomas spontaneously or ectopically carrying the mutation in vivo, both in immunodeficient and immunocompetent mice. Equally important, transcytosing dIgA can also target cytosolic proteins that are not located close to the cell membrane, where interactions between early and recycling endosomes could be less frequent. Thus, we demonstrated that IDH1R132H-specific dIgA can also abrogate the growth of IDH1R132H-mutant tumors, in a mutation- and PIGR-dependent manner. Our study therefore opens new avenues for targeting virtually any cytosolic protein using antibodies that are internalized through PIGR-mediated transcytosis, including hotspots in other oncodrivers or other tumor-promoting molecules, such as the cytosolic fraction of survivin or Myc. In addition, the range of proteins that could be intracellularly neutralized could be extended to other diseases. For instance, one could envision the cGAS–STING pathway as a therapeutic target in inflammatory mucosal diseases.

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Fig. 1: Antigen-specific dIgA and intracellular target interact in early and late endosomes inside tumor cells.

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Acknowledgements

This study was supported by the National Institutes of Health R01CA157664, R01CA124515, R01CA178687, and R01CA278907 to JRCG.

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Authors and Affiliations

  1. Tumor Immunology and Immunotherapy, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Kharghar, Navi Mumbai, 410210, India

    Subir Biswas

  2. Homi Bhabha National Institute, Anushaktinagar, Mumbai, 400 094, Maharashtra, India

    Subir Biswas

  3. Department of Integrative Immunobiology, Durham, NC, 27710, USA

    Carmen M. Anadon & Jose R. Conejo-Garcia

  4. Duke Cancer Institute, Duke School of Medicine, Durham, NC, 27710, USA

    Carmen M. Anadon & Jose R. Conejo-Garcia

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  1. Subir Biswas
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  2. Carmen M. Anadon
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  3. Jose R. Conejo-Garcia
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Contributions

The 3 authors worked on developing the text, based on a consensus on the interpretation of existing results and future refinements of this technology. JRCG elaborated the Figure.

Corresponding author

Correspondence to Jose R. Conejo-Garcia.

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Competing interests

JRCG has stock options in Compass Therapeutics, Anixa Biosciences and Alloy Therapeutics; has sponsored research with Anixa Biosciences; receives an honorarium from Alloy Therapeutics; and intellectual property with Compass Therapeutics and Anixa Biosciences; and is co-founder of Cellepus Therapeutics; all outside the submitted work. JRCG, SB and CMA have filed a patent application for intracellular targeting of oncodrivers using modified IgG.

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Biswas, S., Anadon, C.M. & Conejo-Garcia, J.R. Antibodies target intracellular oncodrivers through PIGR-mediated transcytosis. Genes Immun 25, 85–86 (2024). https://doi.org/10.1038/s41435-023-00239-2

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