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Reducing the Complexity of Fc Glycan Enables the Construction of Antibody Conjugates with Unexpected High Efficiency and Payload Capacity via Glycoengineering

Yang, Y.; Song, Z. t.; Tian, T.; Zhao, Z.; Chen, J.; Hu, J. p.; Jiang, X.; Yang, G. l.; Xue, Q.; Zhao, X. l.; Sha, W. x.; Yang, Y.; Li, J. P.

2022-09-05 biochemistry
10.1101/2022.09.04.506510 bioRxiv
Show abstract

Glycoengineering has been demonstrated to be a powerful tool to construct site-specific antibody conjugates. However, with most glycoengineering strategies, several hours to days are needed to complete the reaction, and the payloads are limited to small molecules. Herein, we show that reducing the complexity of Fc glycan could dramatically boost the enzymatic glycoengineering of IgG molecules to achieve unexpectedly high efficiency and payload capacity. Notably, antibodies with the modified Fc glycan were successfully conjugated with biomacromolecules, e.g., oligonucleotides and nanobodies, in one step by an engineered fucosyltransferase. Moreover, the conversion of this chemoenzymatic engineering could be finished in minutes, or up to hours, affording homogeneous products. The trisaccharide linker of these antibody conjugates exhibits excellent hydrophilicity and stability and reduced ADCC activity. Using this platform, we successfully synthesized an antibody-conjugate-based HER2/CD3 bispecific antibody and applied it to selectively destroy patient-derived cancer organoids by reactivating endogenous T cells inside the organoid. These results suggest that this bispecific antibody format has a high translational value.

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