Abstract
The neonatal Fc receptor FcRn plays a critical role in the trafficking of IgGs across tissue barriers and in retaining high circulating concentrations of both IgG and albumin. Although generally beneficial from an immunological perspective in maintaining IgG populations, FcRn can contribute to the pathogenesis of autoimmune disorders when an abnormal immune response targets normal biological components. We previously described a monoclonal antibody (DX-2507) that binds to FcRn with high affinity at both neutral and acidic pH, prevents the simultaneous binding of IgG, and reduces circulating IgG levels in preclinical animal models. Here, we report a 2.5 Å resolution X-ray crystal structure of an FcRn-DX-2507 Fab complex, revealing a nearly complete overlap of the IgG-Fc binding site in FcRn by complementarity-determining regions in DX-2507. This overlap explains how DX-2507 blocks IgG binding to FcRn and thereby shortens IgG half-life by preventing IgGs from recycling back into circulation. Moreover, the complex structure explains how the DX-2507 interaction is pH-insensitive unlike normal Fc interactions and how serum albumin levels are unaffected by DX-2507 binding. These structural studies could inform antibody-based therapeutic approaches for limiting the effects of IgG-mediated autoimmune disease.
Highlights
The neonatal Fc receptor FcRn plays a critical role in the trafficking of IgGs across tissue barriers and in retaining high circulating concentrations of both IgG and albumin
We previously isolated and developed a fully human antibody (DX-2507) that binds to the FcRn receptor with high affinity and in a pH-independent manner [3]
Given the role FcRn plays in maintaining elevated IgG levels, there is increasing interest in FcRn as a target for therapeutic intervention in diseases propagated by pathogenic IgG autoantibodies
Summary
Fragment crystallizable region of an antibody; FcRn, neonatal Fc receptor; 2M, 2-microglobulin; CDR, complementarity-determining region; Fab, fragment antigen-binding domain; HSA, human serum albumin; HV, antibody heavy chain variable domain; IvIg, intravenous IgG; LV, antibody light chain variable domain; SEC, sizeexclusion chromatography; shFcRn, soluble human FcRn; SPR, surface plasmon resonance; EDC, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride; RMSD, root mean square deviation; PDB, Protein Data Bank; cyno, cynomolgus; ITP, idiopathic thrombocytopenia purpura; RU, resonance units. Immunomodulatory therapies are used to deplete serum antibodies (immunoabsorption and plasmapheresis procedures) or effectively dilute serum levels by treatment with a large quantity of IgG supplied intravenously (IvIg). Such procedures are considered cumbersome and invasive, can result in severe treatment-related complications [11], and, in the case of IvIg, may rely on a limited supply of plasma from healthy blood donors and carry the risks associated with human-derived products [12, 13]. The complex structure can be used to mechanistically rationalize our in vitro and in vivo findings that DX-2507 inhibits IgG binding to FcRn, provides a template for future protein engineering efforts, and supports the use of DX-2507 for the therapeutic treatment of disease driven by pathologic IgGs
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
