Beschreibung
Complement activation through antibody-antigen complexes is crucial in various pathophysiological processes such as infections, inflammation, and autoimmunity, and is also utilized in immunotherapies to eliminate infectious agents, regulatory immune cells, or cancer cells. The tertiary structures of the four IgG antibody subclasses are largely comparable with the most prominent difference being the hinge regions that connect the Fab- and Fc-domains and which provide the respective subclass with unique structural flexibility. Complement recruitment and further activation depend strongly on IgG subclass, which is commonly rationalized by subclass-specific differences in hinge flexibility and the respective affinities for C1, the first component of the classical complement pathway. However, a unifying mechanism how these different IgG subclass properties combine to modulate C1 activation has not yet been proposed. 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 characterize the involved molecular interactions in single molecule force spectroscopy (SMFS) experiments and quartz crystal microbalance (QCM) experiments, directly visualize the resulting IgG oligomer structures and distributions by means of high-speed atomic force microscopy (HS-AFM) and characterize their ability to activate complement on tumor cell lines as well as in vesicle-based complement lysis assays. Based on these experiments we developed a mechanistic model of the multivalent interactions that govern antigen-dependent IgG oligomerization and C1 binding that leads to complement activation and CDC. Together, we provide a comprehensive view on the parameters that govern complement activation by the different IgG subclasses, which may inform the design of future antibody therapies.
Zeitraum | 4 Sep. 2024 |
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Ereignistitel | The Antibody Series 2024 |
Veranstaltungstyp | Konferenz |
Ort | Madeira, PortugalAuf Karte anzeigen |
Bekanntheitsgrad | International |