A multivalent binding model infers antibody Fc species from systems serology

Systems serology aims to broadly profile the antigen binding, Fc biophysical features, immune receptor engagement, and effector functions of antibodies. This experimental approach excels at identifying antibody functional features that are relevant to a particular disease. However, a crucial limitation of this approach is its incomplete description of what structural features of the antibodies are responsible for the observed immune receptor engagement and effector functions. Knowing these antibody features is important for both understanding how effector responses are naturally controlled through antibody Fc structure and designing antibody therapies with specific effector profiles. Here, we address this limitation by modeling the molecular interactions occurring in these assays and using this model to infer quantities of specific antibody Fc species among the antibodies being profiled. We used several validation strategies to show that the model accurately infers antibody properties and then applied the model to infer previously unavailable antibody fucosylation information from existing systems serology data. Using this capability, we find that COVID-19 vaccine efficacy is associated with the induction of afucosylated spike protein-targeting IgG. Our results also question an existing assumption that controllers of HIV exhibit gp120-targeting IgG that are less fucosylated than those of progressors. Additionally, we confirm that afucosylated IgG is associated with membrane-associated antigens for COVID-19 and HIV, and present new evidence indicating that this relationship is specific to the host cell membrane. Finally, we use the model to identify redundant assay measurements and subsets of information-rich measurements from which Fc properties can be inferred. In total, our modeling approach provides a quantitative framework for the reasoning typically applied in these studies, improving the ability to draw mechanistic conclusions from these data.