title: Engineered monoclonal antibody with novel antigen-sweeping activity in vivo.
abstract: Monoclonal antibodies are widely used to target disease-related antigens. However, because conventional antibody binds to the antigen but cannot eliminate the antigen from plasma, and rather increases the plasma antigen concentration by reducing the clearance of the antigen, some clinically important antigens are still difficult to target with monoclonal antibodies because of the huge dosages required. While conventional antibody can only bind to the antigen, some natural endocytic receptors not only bind to the ligands but also continuously eliminate them from plasma by pH-dependent dissociation of the ligands within the acidic endosome and subsequent receptor recycling to the cell surface. Here, we demonstrate that an engineered antibody, named sweeping antibody, having both pH-dependent antigen binding (to mimic the receptor-ligand interaction) and increased binding to cell surface neonatal Fc receptor (FcRn) at neutral pH (to mimic the cell-bound form of the receptor), selectively eliminated the antigen from plasma. With this novel antigen-sweeping activity, antibody without in vitro neutralizing activity exerted in vivo efficacy by directly eliminating the antigen from plasma. Moreover, conversion of conventional antibody with in vitro neutralizing activity into sweeping antibody further potentiated the in vivo efficacy. Depending on the binding affinity to FcRn at neutral pH, sweeping antibody reduced antigen concentration 50- to 1000-fold compared to conventional antibody. Thereby, sweeping antibody antagonized excess amounts of antigen in plasma against which conventional antibody was completely ineffective, and could afford marked reduction of dosage to a level that conventional antibody can never achieve. Thus, the novel mode of action of sweeping antibody provides potential advantages over conventional antibody and may allow access to the target antigens which were previously undruggable by conventional antibody.
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd., Gotemba, Shizuoka, Japan. igawatmy@chugai-pharm.co.jp
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Igawa
authors.forename: Atsuhiko
authors.initials: A
authors.lastname: Maeda
authors.forename: Kenta
authors.initials: K
authors.lastname: Haraya
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Tachibana
authors.forename: Yuki
authors.initials: Y
authors.lastname: Iwayanagi
authors.forename: Futa
authors.initials: F
authors.lastname: Mimoto
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Higuchi
authors.forename: Shinya
authors.initials: S
authors.lastname: Ishii
authors.forename: Shigero
authors.initials: S
authors.lastname: Tamba
authors.forename: Naoka
authors.initials: N
authors.lastname: Hironiwa
authors.forename: Kozue
authors.initials: K
authors.lastname: Nagano
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Wakabayashi
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Tsunoda
authors.forename: Kunihiro
authors.initials: K
authors.lastname: Hattori
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism*; D000941:Antigens / Q000097:blood / Q000378:metabolism*; D015395:Histocompatibility Antigens Class I / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007074:Immunoglobulin G / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D011485:Protein Binding / Q000276:immunology; D015202:Protein Engineering / Q000379:methods*; D011961:Receptors, Fc / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D000941:Antigens; D015395:Histocompatibility Antigens Class I; D007074:Immunoglobulin G; D011961:Receptors, Fc; C100688:Fc receptor, neonatal