Complement activation by IgG subclasses is governed by their ability to oligomerize upon antigen binding

Author:

Frischauf Nikolaus,Strasser Jürgen,Borg Ellen G.F.,Labrijn Aran F.,Beurskens Frank J.,Preiner JohannesORCID

Abstract

AbstractComplement activation through antibody-antigen complexes is crucial in various pathophysiological processes such as infections, inflammation, and autoimmunity, but is also utilized in immunotherapies to eliminate infectious agents, regulatory immune cells, or cancer cells. Although the tertiary structures of the four IgG antibody subclasses are largely identical, complement recruitment and further activation depend strongly on subclass, which is commonly explained by the respective affinity for C1, the first component of the classical complement pathway. Contradicting this established view, we here demonstrate that complement activation by different IgG subclasses is determined by their varying ability to form IgG oligomers on antigenic surfaces large enough to multivalently bind and activate C1. We directly visualize the resulting IgG oligomer structures and characterize their distribution by means of high-speed atomic force microscopy (HS-AFM), quantify their complement recruitment efficiency from quartz crystal microbalance (QCM) experiments, and characterize their ability to activate complement on tumor cell lines as well as in vesicle-based complement lysis assays. We present a mechanistic model of the multivalent interactions that govern C1 binding to IgG oligomers and use this model to extract affinities and kinetic rate constants from real-time interaction QCM data. Together, our detailed characterization yields a comprehensive view on the parameters that govern complement activation by the different IgG subclasses, which may inform the design of future antibody therapies.

Publisher

Cold Spring Harbor Laboratory

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