Modulating IgG effector function by Fc glycan engineering.

Area of Science:

• Immunology
• Glycobiology
• Biochemistry

Background:

• Antibody N-glycans on the Fc domain modulate effector functions by altering Fc receptor binding.
• Core fucosylation reduces antibody-dependent cellular cytotoxicity (ADCC), while sialylation is linked to anti-inflammatory effects.

Purpose of the Study:

• To investigate the combined effects of fucosylation and sialylation on IgG antibody effector functions.
• To elucidate the impact of specific glycan structures on FcγR binding, ADCC, and in vivo cellular depletion.

Main Methods:

• Synthesis of homogeneous IgG glycoforms with defined fucosylation and sialylation patterns.
• In vitro FcγR-binding assays and cell-based ADCC assays.
• In vivo studies of IgG-mediated cellular depletion.

Main Results:

• Core fucosylation significantly reduced FcγRIIIA binding, in vitro ADCC, and in vivo cellular depletion, irrespective of sialylation.
• Sialylation's impact on ADCC was dependent on fucosylation status.
• Sialylation decreased ADCC in the presence of core fucosylation but not in its absence.

Conclusions:

• Core fucosylation is a major negative regulator of IgG effector functions.
• Sialylation's effect on ADCC is context-dependent, being detrimental only when core fucosylation is present.
• Understanding these glycan-antibody interactions is crucial for optimizing antibody-based therapies.