Identification of human IgG1 variant with enhanced FcRn binding and without increased binding to rheumatoid factor autoantibody |
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Authors: | Atsuhiko Maeda Yuki Iwayanagi Kenta Haraya Tatsuhiko Tachibana Genki Nakamura Takeru Nambu |
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Institution: | 1. Chugai Pharmaceutical Co. Ltd., Pharmaceutical Technology Division, Ukima Research Labs., Ukima, Kita-ku, Tokyo, Japan;2. Chugai Pharmaceutical Co. Ltd., Research Division, Kamakura Research Labs, Kajiwara, Kamakura, Kanagawa, Japan;3. Chugai Pharmabody Research Pte. Ltd., Synapse, Singapore;4. Chugai Pharmaceutical Co. Ltd., Research Division, Fuji Gotemba Research Labs, Komakado, Gotemba, Shizuoka, Japan |
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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. |
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Keywords: | Antibody therapeutics CH2-CH3 interface Fc engineering FcRn pharmacokinetics pre-existing ADA RF rheumatoid factor sweeping antibody |
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