Engineered human antibodies for the opsonization and killing of Staphylococcus aureus

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 119; no. 4; p. 1
• Main Authors: Chen, Xinhai, Schneewind, Olaf, Missiakas, Dominique
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 25.01.2022
• Subjects: Amino Acid Sequence; Antibodies; Antibodies, Bacterial - genetics; Antibodies, Bacterial - immunology; Antibodies, Monoclonal - genetics; Antibodies, Monoclonal - immunology; Antibody-Dependent Cell Cytotoxicity - immunology; Asthma; Binding sites; Biological Sciences; Cell surface; Complement; Complement Activation; Domains; Dose-Response Relationship, Drug; Dose-Response Relationship, Immunologic; Fc receptors; Half-life; Humans; Immunoglobulin G; Immunoglobulins; Immunotherapy; Infections; Monoclonal antibodies; Neonates; Opsonization; Opsonization - immunology; Opsonophagocytosis; Phagocytes; Phagocytosis - immunology; Protein A; Protein Binding; Protein Engineering - methods; Protein Interaction Domains and Motifs - genetics; Protein Interaction Domains and Motifs - immunology; Receptors, Fc - genetics; Staphylococcal Protein A - immunology; Staphylococcus aureus; Staphylococcus aureus - immunology; Transgenic mice; FcRn; C1q; immune evasion; Staphylococcus aureus; engineered antibody
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2114478119

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 is coated with Staphylococcal protein A (SpA). SpA captures the Fcγ domain of IgG and interferes with opsonization by anti- 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 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 and undergoing monoclonal antibody treatment.