About The Speaker
Leoni Abendstein
Predoctoral Visiting Scientist, Institute of Science and Technology Austria
Leoni Abendstein
Leoni studied Microbiology at the University of Innsbruck, Austria, where she completed her master’s thesis under the supervision of Susanne Zeilinger-Migsich. For her PhD, she moved to the Leiden University Medical Center (LUMC) in the Netherlands, joining the research group of Thom Sharp. In the Sharp lab, her research focused on gaining a deeper understanding of the complement system, a crucial component of the innate immune system, with the aim of achieving greater control over its functions. To accomplish this, she developed DNA nanostructures to pattern antigens, which could be used to bind IgG1 antibodies and study the classical complement pathway.
Leoni also investigated the activation of IgG3 in a native state without pre-patterned antigen platforms. Her studies specialised in the use of cryo-electron tomography. Earlier this year, Leoni joined Florian Praetorius’ group at the Institute of Science and Technology Austria (ISTA), where she will apply molecular design to create de novo proteins with novel and optimised functions.
Using cryo-electron tomography to study the activation of complement by elevated IgG3 hexameric platforms on liposomal surfaces
IgG3 is unique among the IgG subclasses due to its extended hinge, allotypic diversity and enhanced effector functions, including highly efficient pathogen neutralization and complement activation. It is also underrepresented as an immunotherapeutic candidate, partly due to a lack of structural information.
Here, we use cryoEM to solve structures of antigen-bound IgG3 alone and in complex with complement components. These structures reveal a propensity for IgG3-Fab clustering, which is possible due to the IgG3-specific flexible upper hinge region and may maximize pathogen neutralization by forming high-density antibody arrays. IgG3 forms elevated hexameric Fc platforms that extend above the protein corona to maximize binding to receptors and the complement C1 complex, which here adopts a unique protease conformation that may precede C1 activation. Mass spectrometry revealed that C1 deposits C4b directly onto specific IgG3 residues proximal to the Fab domains. Structural analysis shows this to be caused by the height of the C1-IgG3 complex.
Together, these data provide the first structural insights into the role of the unique IgG3 extended hinge, which will aid the development and design of upcoming immunotherapeutics based on IgG3