A Kinetic Model of Antigen‐Dependent IgG Oligomerization and Complement Binding

TL;DR

This paper develops a model to predict how IgG antibodies form clusters, which is important for triggering immune responses and could improve antibody-based treatments.

Contribution

A novel kinetic model is introduced to predict IgG oligomerization and its impact on complement pathway activation.

Findings

The model incorporates IgG subclass, concentration, and antigen density to predict oligomerization.

Rate constants and thermodynamic parameters were quantified using high-speed atomic force microscopy data.

The model successfully predicts complement-mediated lysis in liposomal vesicle assays.

Abstract

The classical complement pathway (CCP) is an essential part of the immune system, activated when complement protein C1 binds to IgG antibody oligomers on the surface of pathogens, infected or malignant cells, culminating in the formation of the membrane attack complex and subsequent cell lysis. IgG oligomers also engage immune effector cells through Fcγ receptors or complement receptors, facilitating antibody‐dependent cellular cytotoxicity and phagocytosis. Understanding the factors that drive IgG oligomerization is thus crucial for improving IgG‐based therapies. Herein, a kinetic model to predict oligomer formation based on IgG concentration, antigen density, IgG subclass, Fc mutants, and oligomerization inhibitors like staphylococcal protein A is developed. The underlying molecular interactions in single molecule force spectroscopy and grating coupled interferometry experiments are characterized. By fitting experimental data from high‐speed atomic force microscopy experiments, key rate constants and thermodynamic parameters, including free energy changes associated with oligomerization and apply the model to predict complement‐mediated lysis in liposomal vesicle‐based assays, are further quantified. The presented mechanistic framework may serve as a basis for optimizing antibody engineering and pharmacokinetic/pharmacodynamic modeling in the context of immunotherapies exploiting the CCP.

A kinetic model capable of predicting IgG oligomerization, a key step in activating the classical complement pathway (CCP) of the immune system, is presented. The impacts of IgG subclass, concentration, and antigen density are analyzed using advanced biophysical techniques. The model quantifies rate constants and predicts complement‐mediated vesicle lysis, thereby offering insights for optimizing antibody‐based immunotherapies targeting CCP mechanisms.© 2025 WILEY‐VCH GmbH

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