title: Aglycosylated immunoglobulin G1 variants productively engage activating Fc receptors.
abstract: Immunoglobulin G plays a vital role in adaptive immunity and antibody-based therapy through engagement of its Fc region by the Fc gamma receptors (Fc gammaRs) on immune cells. In addition to specific protein-protein contacts, N-linked glycosylation of the IgG Fc has been thought to be essential for the recognition of Fc by Fc gammaR. This requirement for the N-linked glycan has limited biomanufacture of therapeutic antibodies by restricting it to mammalian expression systems. We report here aglycosylated Fc domain variants that maintain engagement to Fc gammaRs, both in vitro and in vivo, demonstrating that Fc glycosylation is not strictly required for the activation of immune cells by IgG. These variants provide insight into how the N-linked glycan is used biologically in the recognition of Fc by Fc gammaRs, as well as represent a step toward the production in alternative expression systems of antibody-based therapeutics capable of eliciting immune effector functions.
authors.affiliation: Department of Biological Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Sazinsky
authors.forename: René G
authors.initials: RG
authors.lastname: Ott
authors.forename: Nathaniel W
authors.initials: NW
authors.lastname: Silver
authors.forename: Bruce
authors.initials: B
authors.lastname: Tidor
authors.forename: Jeffrey V
authors.initials: JV
authors.lastname: Ravetch
authors.forename: K Dane
authors.initials: KD
authors.lastname: Wittrup
mesh_terms: D014644:Genetic Variation; D006031:Glycosylation; D007074:Immunoglobulin G / Q000235:genetics* / Q000276:immunology; D011485:Protein Binding / Q000235:genetics / Q000276:immunology; D011961:Receptors, Fc / Q000276:immunology*; D017452:Receptors, IgG / Q000276:immunology
chemical_list: D007074:Immunoglobulin G; D011961:Receptors, Fc; D017452:Receptors, IgG