Mixed IgG Fc immune complexes exhibit blended binding profiles and refine FcR affinity estimates

Area of Science:

• Immunology
• Structural Biology
• Biophysics

Background:

• Immunoglobulin G (IgG) antibodies mediate immune responses via Fcγ receptors.
• IgG Fc domain variations (subclass, glycosylation) influence effector functions.
• Immune responses typically involve mixtures of IgG Fc variants, but their combined effects are poorly understood.

Purpose of the Study:

• To investigate Fcγ receptor binding to mixed IgG Fc immune complexes.
• To develop a quantitative model for predicting effector cell regulation by mixed IgG Fc variants.
• To re-evaluate the role of IgG2 in effector functions.

Main Methods:

• Measurement of Fcγ receptor binding to various mixtures of IgG Fc immune complexes.
• Development and application of a mechanistic binding model.
• Validation of the model using platelet depletion assays in humanized mice.

Main Results:

• Binding of mixed IgG Fc immune complexes follows a continuum predictable by a mechanistic model.
• The model provides refined affinity estimates, particularly for low-affinity interactions involving IgG2.
• IgG2 demonstrates binding through avidity, though insufficient for effector response induction.

Conclusions:

• A quantitative framework for modeling mixed IgG Fc-effector cell regulation has been established.
• The model accurately predicts effector cell-mediated responses, including platelet depletion.
• This work refines understanding of IgG subclass function and immune complex interactions.