What is it about?
The classical complement pathway is an important effector mechanism for clearance of infections, which is also employed in immunotherapies to eliminate tumor cells. Its initiation is governed by the binding and activation of C1 to multiple IgG antibody Fc domains. The ability to activate complement differs strongly between the four IgG subclasses; however, a unifying mechanism rationalizing the respective potencies to activate complement has not been established. We here show that complement activation is determined by the respective ability of IgG1-4 to form large oligomers on antigenic surfaces that can multivalently bind C1.
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Why is it important?
We provide a comprehensive mechanistic framework of how C1 binding to large IgG oligomers is linked to target cell clearance and how the latter is related to differences in oligomerization propensity among IgG subclasses. We believe that these insights will allow IgG subclass-specific differences to be specifically adapted and exploited in future immunotherapies.
Perspectives
I believe that our work makes an important contribution to our understanding of how multiple weak interactions combine to initiate biological functions - a perspective that needs to be considered when optimizing antibodies and other biologics for specific applications.
Johannes Preiner
University of Applied Sciences Upper Austria
Read the Original
This page is a summary of: Complement activation by IgG subclasses is governed by their ability to oligomerize upon antigen binding, Proceedings of the National Academy of Sciences, October 2024, Proceedings of the National Academy of Sciences,
DOI: 10.1073/pnas.2406192121.
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