We seek to understand how certain bacteria evade the host immune response by modifying the structure of IgG antibodies to defeat functional Fc-Fcgammareceptor interactions.Streptococcus pyogenessecretes an endoglycosidase, EndoS, that specifically cleaves biantennarary complex carbohydrates linked to the IgG Fc domain residue Asn297. The resulting aglycosylated antibodies no longer bind to Fc gamma receptors and, thus, are functionally inactive. Having determined the crystal structure of EndoS, we are now focusing on further defining its mechanism of action and to engineer new EndoS variants with unique glycan and protein specificities that could be used as therapeutics to treat autoimmune diseases and in the chemoenzymatic synthesis of homogeneously glycosylated antibodies. In a related project, we are rationally manipulating the IgG Fc domain structure by targeted hyper-glycosylation in order to control the ratio of binding affinities to activating versus inhibitory Fc gamma receptors. These novel Fc variants could improve the efficacies of a wide range of tumor immunotherapy antibodies currently used clinically.
Beatriz Trastoy¶, Erik H. Klontz¶, Jared Orwenyo, Alberto Marina, Lai-Xi Wang,Eric J. Sundberg*and Marcelo E. Guerin*(2018).Structural basis for the recognition of complex-type N-glycans by Endoglycosidase S. Nature Communications, 9, 1874 | PDF |Article Link
Beatriz Trastoy, Joseph V. Lomino, Brian Pierce, Lester G. Carter, Sebastian Günther, John P. Giddens, Greg A. Snyder, Thomas M. Weiss, Zhiping Weng, Lai-Xi Wang, and Eric J. Sundberg*(2014). Crystal structure of Streptococcus pyogenes EndoS, an immunomodulatory bacterial endoglycosidase specific for human IgG antibodies. Proceedings of the National Academy of Sciences of the United States of America, 111(8), 6714-6719.
