title: Inhibitory FcγRIIb-Mediated Soluble Antigen Clearance from Plasma by a pH-Dependent Antigen-Binding Antibody and Its Enhancement by Fc Engineering.
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 role in the cellular uptake of monomeric Ag/Ab immune complexes in vivo, and when the Fc of a pH-dependent Ab was engineered to selectively enhance human FcγRIIb binding, the Ab could accelerate soluble Ag clearance from circulation. We assume such a function would enhance the therapeutic potency of Abs that target soluble Ags.
authors: Research Division, Chugai Pharmaceutical Co. Ltd., Tokyo 103-8324, Japan.
authors: Yuki
authors: Y
authors: Iwayanagi
authors: Research Division, Chugai Pharmaceutical Co. Ltd., Tokyo 103-8324, Japan igawatmy@chugai-pharm.co.jp.
authors: Tomoyuki
authors: T
authors: Igawa
authors: Research Division, Chugai Pharmaceutical Co. Ltd., Tokyo 103-8324, Japan.
authors: Atsuhiko
authors: A
authors: Maeda
authors: Research Division, Chugai Pharmaceutical Co. Ltd., Tokyo 103-8324, Japan.
authors: Kenta
authors: K
authors: Haraya
authors: Research Division, Chugai Pharmaceutical Co. Ltd., Tokyo 103-8324, Japan.
authors: Naoko A
authors: NA
authors: Wada
authors: Research Division, Chugai Pharmaceutical Co. Ltd., Tokyo 103-8324, Japan.
authors: Norihito
authors: N
authors: Shibahara
authors: Research Division, Chugai Pharmaceutical Co. Ltd., Tokyo 103-8324, Japan.
authors: Ken
authors: K
authors: Ohmine
authors: Research Division, Chugai Pharmaceutical Co. Ltd., Tokyo 103-8324, Japan.
authors: Takeru
authors: T
authors: Nambu
authors: Research Division, Chugai Pharmaceutical Co. Ltd., Tokyo 103-8324, Japan.
authors: Genki
authors: G
authors: Nakamura
authors: Research Division, Chugai Pharmaceutical Co. Ltd., Tokyo 103-8324, Japan.
authors: Futa
authors: F
authors: Mimoto
authors: Research Division, Chugai Pharmaceutical Co. Ltd., Tokyo 103-8324, Japan.
authors: Hitoshi
authors: H
authors: Katada
authors: Research Division, Chugai Pharmaceutical Co. Ltd., Tokyo 103-8324, Japan.
authors: Shunsuke
authors: S
authors: Ito
authors: Research Division, Chugai Pharmaceutical Co. Ltd., Tokyo 103-8324, Japan.
authors: Tatsuhiko
authors: T
authors: Tachibana
authors: Research Division, Chugai Pharmaceutical Co. Ltd., Tokyo 103-8324, Japan.
authors: Kou-ichi
authors: K
authors: Jishage
authors: Research Division, Chugai Pharmaceutical Co. Ltd., Tokyo 103-8324, Japan.
authors: Kunihiro
authors: K
authors: Hattori
mesh_terms: D000818:Animals; D000906:Antibodies / Q000097:blood / Q000276:immunology; D000936:Antigen-Antibody Complex / Q000097:blood* / Q000276:immunology; D000937:Antigen-Antibody Reactions / Q000276:immunology*; D000941:Antigens / Q000097:blood* / Q000276:immunology; D006801:Humans; D007074:Immunoglobulin G / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017452:Receptors, IgG / Q000235:genetics / Q000276:immunology*
chemical_list: D000906:Antibodies; D000936:Antigen-Antibody Complex; D000941:Antigens; C499172:Fcgr2b protein, mouse; D007074:Immunoglobulin G; D017452:Receptors, IgG