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.
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We are grateful to Fernando Mateos, Jerry Chao and Rafael Guevara for excellent technical assistance. We also thank Steven Gibbons and Sripad Ram for assistance with preparation of the figures. This study was supported by grants from the National Institutes of Health R01 AI 39167, RO1 AI 55556 (E.S.W.) and R01 AI 50747 (R.J.O).
The University of Texas Southwestern Medical Center has filed a patent application describing the technology in this paper.
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Vaccaro, C., Zhou, J., Ober, R. et al. Engineering the Fc region of immunoglobulin G to modulate in vivo antibody levels. Nat Biotechnol 23, 1283–1288 (2005). https://doi.org/10.1038/nbt1143
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