Importance of the Side Chain at Position 296 of Antibody Fc in Interactions with FcγRIIIa and Other Fcγ Receptors.

Antibody-dependent cellular cytotoxicity (ADCC) is an important effector function determining the clinical efficacy of therapeutic antibodies. Core fucose removal from N-glycans on the Fc portion of immunoglobulin G (IgG) improves the binding affinity for Fcγ receptor IIIa (FcγRIIIa) and dramatically enhances ADCC. Our previous structural analyses revealed that Tyr-296 of IgG1-Fc plays a critical role in the interaction with FcγRIIIa, particularly in the enhanced FcγRIIIa binding of nonfucosylated IgG1.

A nonfucosylated variant of the anti-HIV-1 monoclonal antibody b12 has enhanced FcγRIIIa-mediated antiviral activity in vitro but does not improve protection against mucosal SHIV challenge in macaques.

Eliciting neutralizing antibodies is thought to be a key activity of a vaccine against human immunodeficiency virus (HIV). However, a number of studies have suggested that in addition to neutralization, interaction of IgG with Fc gamma receptors (FcγR) may play an important role in antibody-mediated protection. We have previously obtained evidence that the protective activity of the broadly neutralizing human IgG1 anti-HIV monoclonal antibody (MAb) b12 in macaques is diminished in the absence of FcγR binding capacity.

Structural basis for improved efficacy of therapeutic antibodies on defucosylation of their Fc glycans.

Removal of the fucose residue from the N-glycans of the Fc portion of immunoglobulin G (IgG) results in a dramatic enhancement of antibody-dependent cellular cytotoxicity (ADCC) through improved affinity for Fcγ receptor IIIa (FcγRIIIa). Here, we present the 2.2-Å structure of the complex formed between nonfucosylated IgG1-Fc and a soluble form of FcγRIIIa (sFcγRIIIa) with two N-glycosylation sites.

Nonfucosylated rituximab potentiates human neutrophil phagocytosis through its high binding for FcgammaRIIIb and MHC class II expression on the phagocytotic neutrophils.

Objective: Antibody-dependent cellular cytotoxicity mediated by natural killer cells via leukocyte receptor IIIa (FcgammaRIIIa) is greatly enhanced by the absence of the core fucose of Fc oligosaccharides, and is closely related to the clinical efficacy of anticancer processes in humans in vivo. Here, we focused on the physiological functions of nonfucosylated anti-CD20 IgG1 rituximab, in particular those functions mediated by human neutrophils, which highly express FcgammaRIIIb, a highly homologous FcgammaR to FcgammaRIIIa.

Materials And Methods: After treatment with anti-CD20, the response of neutrophils to fluorescently labeled CD20(+) B-cell lymphoma in human whole blood was quantitatively analyzed by measuring their activities of antibody-dependent phagocytosis and major histocompatibility complex (MHC) class II expression on the phagocytotic neutrophils using flow cytometry.

The N-linked oligosaccharide at Fc gamma RIIIa Asn-45: an inhibitory element for high Fc gamma RIIIa binding affinity to IgG glycoforms lacking core fucosylation.

Human leukocyte receptor IIIa (Fc gamma RIIIa) plays an important role in mediating therapeutic antibodies' antibody-dependent cellular cytotoxicity (ADCC), which is closely related to the clinical efficacy of anticancer processes in humans in vivo. The removal of the core fucose from oligosaccharides attached to the Fc region of antibodies improves Fc gamma RIIIa binding, allowing the antibodies to enhance dramatically the antibody effector functions of ADCC. In this study, the contribution of Fc gamma RIIIa oligosaccharides to the strength of the Fc gamma RIIIa/antibody complex was analyzed using a serial set of soluble human recombinant Fc gamma RIIIa lacking the oligosaccharides.