期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：4
DOI：10.1073/pnas.2114478119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
Staphylococcus aureus invariably acquires resistance mechanisms against new antibiotics. The persistent colonization with
S. aureus is the key risk factor for invasive disease and a driver for the evolution of antibiotic resistant isolates. Anti-
S. aureus antibodies that could promote decolonization, prevent infection, or treat disease would alleviate the selection for drug resistance. The successful development of such antibodies is complicated by Staphylococcal protein A (SpA) in the envelope of
S. aureus. SpA captures immunoglobulins via their constant region, preventing antibodies from initiating anti-staphylococcal activities. Here, we demonstrate that therapeutic anti-
S. aureus antibodies can be engineered to avoid sequestration by SpA. Such antibodies display extended half-lives and improve bacterial uptake and killing by immune cells.
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 (Fcγ) is key for complement recruitment. The cell surface of
S. aureus is coated with Staphylococcal protein A (SpA). SpA captures the Fcγ domain of IgG and interferes with opsonization by anti-
S. aureus antibodies. In principle, the Fcγ domain of therapeutic antibodies could be engineered to avoid the inhibitory activity of SpA. However, the SpA-binding site on Fcγ 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 Fcγ mutants that can both weaken SpA–IgG interactions and retain stability. Here, we use both wild-type 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 Fcγ. 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.
