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

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, Parastoo Azadi, Jeffrey J. Gray, Michael C. Jewett, Lai-Xi Wang and Matthew P. DeLisa ()
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Belen Sotomayor: Cornell University
Thomas C. Donahue: Cornell University
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
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

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-61440-7

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