Inhibitory FcγRIIb-Mediated Soluble Antigen Clearance from Plasma by a pH-Dependent Antigen-Binding Antibody and Its Enhancement by Fc Engineering

The Journal of Immunology : Official Journal of the American Association of Immunologists
Yuki IwayanagiKunihiro Hattori

Abstract

Fc engineering can modulate the Fc-FcγR interaction and thus enhance the potency of Abs that target membrane-bound Ags, but it has not been applied to Abs that target soluble Ags. In this study, we revealed a previously unknown function of inhibitory FcγRII in vivo and, using an Ab that binds to Ag pH dependently, demonstrated that the function can be exploited to target soluble Ag. Because pH-dependent Ab dissociates Ag in acidic endosome, its Ag clearance from circulation reflects the cellular uptake rate of Ag/Ab complexes. In vivo studies showed that FcγR but not neonatal FcR contributes to Ag clearance by the pH-dependent Ab, and when Fc binding to mouse FcγRII and III was increased, Ag clearance was markedly accelerated in wild-type mice and FcR γ-chain knockout mice, but the effect was diminished in FcγRII knockout mice. This demonstrates that mouse FcγRII efficiently promotes Ab uptake into the cell and its subsequent recycling back to the cell surface. Furthermore, when a human IgG1 Fc variant with selectively increased binding to human FcγRIIb was tested in human FcγRIIb transgenic mice, Ag clearance was accelerated without compromising the Ab half-life. Taken together, inhibitory FcγRIIb was found to play a prominent...Continue Reading

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Citations

Apr 4, 2017·Scientific Reports·Otoya UedaKou-Ichi Jishage
Oct 8, 2017·Seminars in Immunopathology·Claire L Harris
Nov 11, 2018·Clinical and Translational Science·Douglas Leipold, Saileta Prabhu
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Jan 20, 2017·The Journal of Biological Chemistry·Srinath KasturiranganChangshou Gao
Jan 27, 2021·Scientific Reports·Hiroyasu MuramatsuJunichi Nezu
Jan 24, 2021·Journal of Biomedical Science·Tomasz Klaus, Sameer Deshmukh

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