Aglycosylated immunoglobulin G1 variants productively engage activating Fc receptors. Proc. Natl. Acad. Sci. USA. 105: 20167-20172

Department of Biological Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 01/2009; 105(51):20167-72. DOI: 10.1073/pnas.0809257105
Source: PubMed


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.

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    • "In addition, HuMAb with the Fc region mutation, D23-1G7C2-IgG1-N297A, showed the least ADE activity (Fig. 2), without losing neutralizing activity (Fig. 1B). A single mutation at N297 residue of IgG has been shown to impair the binding to FcgR (Arnold et al., 2007;Sazinsky et al., 2008;Lux et al., 2013). D23-1G7C2-IgG1-N297A is an ideal therapeutic antibody ; however, D23-1G7C2-IgG1-N297A partially lost its protective activity (Fig. 3A). "
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