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Engineering the Fc region of immunoglobulin G to modulate in vivo antibody levels

Nature Biotechnology volume 23, pages 1283–1288 (2005)Cite this article

Abstract

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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Figure 1: The MST-HN Abdeg binds to human FcRn with increased affinity and reduced pH dependence.
Figure 2: The MST-HN Abdeg accumulates to higher levels in FcRn-GFP–expressing endothelial cells relative to wild-type human or mouse IgG1.
Figure 3: Inhibition of recycling of mouse IgG1 from HMEC-1 cells transfected with mouse FcRn-GFP.
Figure 4: Enhancement of clearance of injected wild-type human IgG1 by MST-HN Abdeg.
Figure 5: Enhancement of clearance of endogenous IgGs by MST-HN Abdeg.

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Acknowledgements

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).

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  1. Center for Immunology, University of Texas Southwestern Medical Center, 6000 Harry Hines Blvd., Dallas, 75390-9093, Texas, USA

    Carlos Vaccaro, Jinchun Zhou, Raimund J Ober & E Sally Ward

  2. Department of Electrical Engineering, University of Texas at Dallas, Richardson, 75080, Texas, USA

    Raimund J Ober

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Correspondence to E Sally Ward.

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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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