Maeda Atsuhiko, Iwayanagi Yuki, Haraya Kenta, Tachibana Tatsuhiko, Nakamura Genki, Nambu Takeru, Esaki Keiko, Hattori Kunihiro, Igawa Tomoyuki
a Chugai Pharmaceutical Co. Ltd., Pharmaceutical Technology Division, Ukima Research Labs. , Ukima, Kita-ku , Tokyo , Japan.
b Chugai Pharmaceutical Co. Ltd., Research Division, Kamakura Research Labs , Kajiwara, Kamakura , Kanagawa , Japan.
MAbs. 2017 Jul;9(5):844-853. doi: 10.1080/19420862.2017.1314873. Epub 2017 Apr 7.
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.
多项研究表明，通过Fc工程改造增强新生儿Fc受体（FcRn）结合能力，对于延长IgG的半衰期或增加其细胞摄取是有效的。先前的一项研究表明，增强FcRn结合能力的N434H突变导致与类风湿因子（RF）自身抗体的结合增加，这对于自身免疫性疾病的治疗应用而言并非理想情况。在本研究中，我们首先表明，所有现有的增强FcRn结合能力的Fc变体也显示出RF结合增加，然后确定了可以引入这些Fc变体以降低RF结合的特定突变。此外，我们生成了不增加RF结合且在食蟹猴中半衰期为45天的新型Fc变体，这比先前报道的Fc变体的半衰期更长。另外，我们生成了具有抗原清除活性且不增加RF结合的新型Fc变体。我们期望这些新型Fc变体将作为针对自身免疫性疾病的抗体疗法发挥作用。
