Engineering the Fc region of immunoglobulin G to modulate in vivo antibody levels.
We have engineered the Fc region of a human immunoglobulin G (IgG) to generate a mutated antibody that modulates the concentrations of endogenous IgGs in vivo. This has been achieved by targeting the activity of the Fc receptor, FcRn, which serves through its IgG salvage function to maintain and regulate IgG concentrations in the body. We show that an IgG whose Fc region was engineered to bind with higher affinity and reduced pH dependence to FcRn potently inhibits FcRn-IgG interactions and induces a rapid decrease of IgG levels in mice. Such FcRn blockers (or 'Abdegs,' for antibodies that enhance IgG degradation) may have uses in reducing IgG levels in antibody-mediated diseases and in inducing the rapid clearance of IgG-toxin or IgG-drug complexes.
Vaccaro
Carlos
C
Center for Immunology, University of Texas Southwestern Medical Center, 6000 Harry Hines Blvd., Dallas, Texas 75390-9093, USA.
Zhou
Jinchun
J
Ober
Raimund J
RJ
Ward
E Sally
ES
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use; D001327:Autoimmune Diseases / Q000276:immunology* / Q000628:therapy*; D005260:Female; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000235:genetics / Q000276:immunology*; D007074:Immunoglobulin G / Q000235:genetics / Q000276:immunology* / Q000627:therapeutic use*; D007167:Immunotherapy / Q000379:methods; D051379:Mice; D015202:Protein Engineering / Q000379:methods*; D011961:Receptors, Fc / Q000276:immunology*; D011994:Recombinant Proteins / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use
D000911:Antibodies, Monoclonal; D015395:Histocompatibility Antigens Class I; D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G; D011961:Receptors, Fc; D011994:Recombinant Proteins; C100688:Fc receptor, neonatal