碎片结晶区
新生儿Fc受体
抗体
抗体依赖性细胞介导的细胞毒性
免疫球蛋白G
效应器
分子生物学
曲妥珠单抗
细胞毒性
免疫球蛋白Fc片段
化学
单克隆抗体
生物
免疫学
癌症研究
生物化学
癌症
体外
遗传学
乳腺癌
作者
Sanghwan Ko,Sora Park,Myung Ho Sohn,Migyeong Jo,Byoung Joon Ko,Jung-Hyun Na,Hojin Yoo,Ae Lee Jeong,Kyungsoo Ha,Ju Rang Woo,Chungsu Lim,Jung Hyu Shin,Dohyun Lee,Soyoung Choi,Sang Taek Jung
标识
DOI:10.1038/s12276-022-00870-5
摘要
The pH-selective interaction between the immunoglobulin G (IgG) fragment crystallizable region (Fc region) and the neonatal Fc receptor (FcRn) is critical for prolonging the circulating half-lives of IgG molecules through intracellular trafficking and recycling. By using directed evolution, we successfully identified Fc mutations that improve the pH-dependent binding of human FcRn and prolong the serum persistence of a model IgG antibody and an Fc-fusion protein. Strikingly, trastuzumab-PFc29 and aflibercept-PFc29, a model therapeutic IgG antibody and an Fc-fusion protein, respectively, when combined with our engineered Fc (Q311R/M428L), both exhibited significantly higher serum half-lives in human FcRn transgenic mice than their counterparts with wild-type Fc. Moreover, in a cynomolgus monkey model, trastuzumab-PFc29 displayed a superior pharmacokinetic profile to that of both trastuzumab-YTE and trastuzumab-LS, which contain the well-validated serum half-life extension Fcs YTE (M252Y/S254T/T256E) and LS (M428L/N434S), respectively. Furthermore, the introduction of two identified mutations of PFc29 (Q311R/M428L) into the model antibodies enhanced both complement-dependent cytotoxicity and antibody-dependent cell-mediated cytotoxicity activity, which are triggered by the association between IgG Fc and Fc binding ligands and are critical for clearing cancer cells. In addition, the effector functions could be turned off by combining the two mutations of PFc29 with effector function-silencing mutations, but the antibodies maintained their excellent pH-dependent human FcRn binding profile. We expect our Fc variants to be an excellent tool for enhancing the pharmacokinetic profiles and potencies of various therapeutic antibodies and Fc-fusion proteins.
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