Engineered human antibodies for the opsonization and killing of Staphylococcus aureus

Gram-positive organisms with their thick envelope cannot be lysed by complement alone. Nonetheless, antibody-binding on the surface can recruit complement and mark these invaders for uptake and killing by phagocytes, a process known as opsonophagocytosis. The crystallizable fragment of immunoglobulins (Fc gamma) is key for complement recruitment. The cell surface of S. aureus is coated with Staphylococcal protein A (SpA). SpA captures the Fc gamma domain of IgG and interferes with opsonization by anti-S. aureus antibodies. In principle, the Fc gamma domain of therapeutic antibodies could be engineered to avoid the inhibitory activity of SpA. However, the SpA-binding site on Fc. overlaps with that of the neonatal Fc receptor (FcRn), an interaction that is critical for prolonging the half-life of serum IgG. This evolutionary adaptation poses a challenge for the exploration of Fc gamma mutants that can both weaken SpA-IgG interactions and retain stability. Here, we use both wildtype and transgenic human FcRn mice to identify antibodies with enhanced half-life and increased opsonophagocytic killing in models of S. aureus infection and demonstrate that antibody-based immunotherapy can be improved by modifying Fc gamma. Our experiments also show that by competing for FcRn-binding, staphylococci effectively reduce the half-life of antibodies during infection. These observations may have profound impact in treating cancer, autoimmune, and asthma patients colonized or infected with S. aureus and undergoing monoclonal antibody treatment.

Automated summary

This study demonstrates that modifying the Fc gamma domain of therapeutic antibodies can enhance their half-life and opsonophagocytic killing, leading to improved antibody-based immunotherapy. Additionally, staphylococci are able to reduce antibody half-life by competing for FcRn binding.