Structural basis for pH-insensitive inhibition of immunoglobulin G recycling by an anti-neonatal Fc receptor antibody [Immunology]

The neonatal Fc receptor FcRn plays a critical role in the trafficking of immunoglobulins (IgGs) across tissue barriers and in retaining high circulating concentrations of both IgG and albumin. Although generally beneficial in maintaining IgG populations from an immunological perspective, 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 neutral and acidic pH, prevents the simultaneous binding of IgG, and reduces circulating IgG levels in preclinical animal models. Here, we show the a 2.5 Å x-ray crystal structure of an FcRn:DX-2507 Fab complex, revealing a near complete overlap of the IgG Fc-binding site in FcRn by DX-2507 Fab CDR regions. This overlap explains how DX-2507 blocks IgG binding to FcRn and consequently shortens IgG half-life by preventing them from recycling back into circulation. Additionally, 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 studies support a novel therapeutic approach for limiting the effects of antibody-mediated autoimmune disease.

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