title: PK/PD analysis of a novel pH-dependent antigen-binding antibody using a dynamic antibody-antigen binding model.
abstract: Previously, we have reported novel engineered antibody with pH-dependent antigen-binding (recycling antibody), and with both pH-dependent antigen-binding and increased FcRn-binding at neutral pH (sweeping antibody). The purpose of this study is to perform PK/PD predictions to better understand the potential applications of the antibodies as therapeutics. To demonstrate the applicability of recycling and sweeping antibodies over conventional antibodies, PK/PD analyses were performed. PK/PD parameters for antibody and antigen dynamics were estimated from the results of a pharmacokinetic study in human FcRn transgenic mice. A simulation study was performed using the estimated PK/PD parameters with various target antigen profiles. In comparison to conventional antibody, recycling antibody enhanced antibody-antigen complex clearance by 3 folds, while sweeping antibody accelerated antigen clearance by 10 folds in a pharmacokinetic study. Simulation results showed that recycling and sweeping antibodies can improve dosage frequency and reduce the required dose for target antigens with various clearances, plasma concentrations or binding kinetics. Moreover, importance of the association rate constant to enhance the beneficial effect of antibodies was shown. These results support the conclusion that recycling and sweeping antibodies can be applied to various target antigens with different profiles, and expand the number of antigens that antibodies can target.
authors.affiliation: Chugai Pharmabody Research Pte. Ltd., 3 Biopolis Drive, #04-11 to 17 Synapse, 138623, Singapore. Electronic address: haraya.kenta@chugai-pharm.co.jp.
authors.forename: Kenta
authors.initials: K
authors.lastname: Haraya
authors.affiliation: Chugai Pharmabody Research Pte. Ltd., 3 Biopolis Drive, #04-11 to 17 Synapse, 138623, Singapore.
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Tachibana
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd., Gotemba, Shizuoka, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Iwayanagi
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd., Gotemba, Shizuoka, Japan.
authors.forename: Atsuhiko
authors.initials: A
authors.lastname: Maeda
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd., Gotemba, Shizuoka, Japan.
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Ozeki
authors.affiliation: Chugai Pharmabody Research Pte. Ltd., 3 Biopolis Drive, #04-11 to 17 Synapse, 138623, Singapore.
authors.forename: Junichi
authors.initials: J
authors.lastname: Nezu
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd., Gotemba, Shizuoka, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Ishigai
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd., Gotemba, Shizuoka, Japan.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Igawa
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry* / Q000276:immunology*; D000918:Antibody Specificity; D000937:Antigen-Antibody Reactions; D000941:Antigens / Q000737:chemistry* / Q000276:immunology*; D001666:Binding Sites, Antibody; D006801:Humans; D006863:Hydrogen-Ion Concentration; D051379:Mice; D008822:Mice, Transgenic; D023421:Models, Animal; D011485:Protein Binding
chemical_list: D000911:Antibodies, Monoclonal; D000941:Antigens
keywords: FcRn; Monoclonal antibody; PK/PD; TMDD; pH-dependent antigen-binding