title: Identification of human IgG1 variant with enhanced FcRn binding and without increased binding to rheumatoid factor autoantibody.
abstract: Various studies have demonstrated that Fc engineering to enhance neonatal Fc receptor (FcRn) binding is effective for elongating half-life or increasing cellular uptake of IgG. A previous study has shown that a N434H mutation to enhance FcRn binding resulted in increased binding to rheumatoid factor (RF) autoantibody, which is not desirable for therapeutic use in autoimmune disease. In this study, we first showed that all the existing Fc variants with enhanced FcRn binding also show increased RF binding, and then identified specific mutations that could be introduced to those Fc variants to reduce the RF binding. Furthermore, we generated novel Fc variants that do not increase RF binding and show half-lives of 45 d in cynomolgus monkey, which is longer than those of previously reported Fc variants. In addition, we generated novel Fc variants with antigen sweeping activity that do not increase RF binding. We expect that these novel Fc variants will be useful as antibody therapeutics against autoimmune diseases.
authors.affiliation: a Chugai Pharmaceutical Co. Ltd., Pharmaceutical Technology Division, Ukima Research Labs. , Ukima, Kita-ku , Tokyo , Japan.
authors.forename: Atsuhiko
authors.initials: A
authors.lastname: Maeda
authors.affiliation: b Chugai Pharmaceutical Co. Ltd., Research Division, Kamakura Research Labs , Kajiwara, Kamakura , Kanagawa , Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Iwayanagi
authors.affiliation: c Chugai Pharmabody Research Pte. Ltd. , Synapse , Singapore.
authors.forename: Kenta
authors.initials: K
authors.lastname: Haraya
authors.affiliation: b Chugai Pharmaceutical Co. Ltd., Research Division, Kamakura Research Labs , Kajiwara, Kamakura , Kanagawa , Japan.
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Tachibana
authors.affiliation: d Chugai Pharmaceutical Co. Ltd., Research Division, Fuji Gotemba Research Labs , Komakado, Gotemba , Shizuoka , Japan.
authors.forename: Genki
authors.initials: G
authors.lastname: Nakamura
authors.affiliation: d Chugai Pharmaceutical Co. Ltd., Research Division, Fuji Gotemba Research Labs , Komakado, Gotemba , Shizuoka , Japan.
authors.forename: Takeru
authors.initials: T
authors.lastname: Nambu
authors.affiliation: d Chugai Pharmaceutical Co. Ltd., Research Division, Fuji Gotemba Research Labs , Komakado, Gotemba , Shizuoka , Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Esaki
authors.affiliation: b Chugai Pharmaceutical Co. Ltd., Research Division, Kamakura Research Labs , Kajiwara, Kamakura , Kanagawa , Japan.
authors.forename: Kunihiro
authors.initials: K
authors.lastname: Hattori
authors.affiliation: d Chugai Pharmaceutical Co. Ltd., Research Division, Fuji Gotemba Research Labs , Komakado, Gotemba , Shizuoka , Japan.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Igawa
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D015395:Histocompatibility Antigens Class I / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D007074:Immunoglobulin G / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D008252:Macaca fascicularis; D051379:Mice; D011961:Receptors, Fc / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D012217:Rheumatoid Factor / Q000737:chemistry / Q000276:immunology*
chemical_list: D015395:Histocompatibility Antigens Class I; D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G; D011961:Receptors, Fc; D012217:Rheumatoid Factor; C100688:Fc receptor, neonatal
keywords: Antibody therapeutics; CH2-CH3 interface; Fc engineering; FcRn; RF; pharmacokinetics; pre-existing ADA; rheumatoid factor; sweeping antibody