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Discovery of a single-subunit oligosaccharyltransferase that enables glycosylation of full-length IgG antibodies in bacteria

Author

Listed:
  • Belen Sotomayor

    (Cornell University)

  • Thomas C. Donahue

    (Cornell University
    University of Maryland)

  • Sai Pooja Mahajan

    (Johns Hopkins University)

  • May N. Taw

    (Cornell University)

  • Sophia W. Hulbert

    (Cornell University)

  • Erik J. Bidstrup

    (Cornell University)

  • D. Natasha Owitipana

    (University of Maryland)

  • Alexandra Pang

    (Cornell University)

  • Xu Yang

    (315 Riverbend Road)

  • Souvik Ghosal

    (Cornell University)

  • Christopher A. Alabi

    (Cornell University
    Cornell University)

  • Parastoo Azadi

    (315 Riverbend Road)

  • Jeffrey J. Gray

    (Johns Hopkins University)

  • Michael C. Jewett

    (Stanford University)

  • Lai-Xi Wang

    (University of Maryland)

  • Matthew P. DeLisa

    (Cornell University
    Cornell University
    Cornell University
    130 Biotechnology Building)

Abstract

Human immunoglobulin G (IgG) antibodies are a major class of biotherapeutics and undergo N-linked glycosylation in their Fc domain, which is critical for immune functions and therapeutic activity. Hence, technologies for producing authentically glycosylated IgGs are in high demand. Previous attempts to engineer Escherichia coli for this purpose have met limited success due in part to the lack of oligosaccharyltransferase (OST) enzymes that can install N-glycans at the conserved N297 site in the Fc region. Here, we identify a single-subunit OST from Desulfovibrio marinus with relaxed substrate specificity that catalyzes glycosylation of native Fc acceptor sites. By chemoenzymatic remodeling the attached bacterial glycans to homogeneous, asialo complex-type G2 N-glycans, the E. coli-derived Fc binds human FcγRIIIa/CD16a, a key receptor for antibody-dependent cellular cytotoxicity (ADCC). Overall, the discovery of D. marinus OST provides previously unavailable biocatalytic capabilities and sets the stage for using E. coli to produce fully human antibodies.

Suggested Citation

  • Belen Sotomayor & Thomas C. Donahue & Sai Pooja Mahajan & May N. Taw & Sophia W. Hulbert & Erik J. Bidstrup & D. Natasha Owitipana & Alexandra Pang & Xu Yang & Souvik Ghosal & Christopher A. Alabi & P, 2025. "Discovery of a single-subunit oligosaccharyltransferase that enables glycosylation of full-length IgG antibodies in bacteria," Nature Communications, Nature, vol. 16(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-61440-7
    DOI: 10.1038/s41467-025-61440-7
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