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An Fc variant with two mutations confers prolonged serum half-life and enhanced effector functions on IgG antibodies
Experimental & Molecular Medicine ( IF 9.5 ) Pub Date : 2022-11-01 , DOI: 10.1038/s12276-022-00870-5
Sanghwan Ko 1, 2 , Sora Park 3 , Myung Ho Sohn 3 , Migyeong Jo 1, 4 , Byoung Joon Ko 3, 5 , Jung-Hyun Na 6 , Hojin Yoo 3 , Ae Lee Jeong 3 , Kyungsoo Ha 3 , Ju Rang Woo 3 , Chungsu Lim 3 , Jung Hyu Shin 3 , Dohyun Lee 3 , So-Young Choi 3 , Sang Taek Jung 1, 2, 4, 7
Affiliation  

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.



中文翻译:

具有两个突变的 Fc 变体可延长血清半衰期并增强 IgG 抗体的效应功能

免疫球蛋白 G (IgG) 片段可结晶区域(Fc 区域)与新生儿 Fc 受体 (FcRn) 之间的 pH 选择性相互作用对于通过细胞内运输和再循环延长 IgG 分子的循环半衰期至关重要。通过使用定向进化,我们成功地鉴定了 Fc 突变,这些突变改善了人 FcRn 的 pH 依赖性结合并延长了模型 IgG 抗体和 Fc 融合蛋白的血清持久性。引人注目的是,trastuzumab-PFc29 和 aflibercept-PFc29,分别是模型治疗性 IgG 抗体和 Fc 融合蛋白,当与我们的工程 Fc (Q311R/M428L) 结合使用时,两者在人 FcRn 转基因小鼠中的血清半衰期均显着高于他们与野生型 Fc 的对应物。此外,在食蟹猴模型中,trastuzumab-PFc29 显示出优于 trastuzumab-YTE 和 trastuzumab-LS 的药代动力学特征,后者分别包含经过充分验证的血清半衰期延长 Fcs YTE (M252Y/S254T/T256E) 和 LS (M428L/N434S)。此外,将两个已鉴定的 PFc29 (Q311R/M428L) 突变引入模型抗体增强了补体依赖性细胞毒性和抗体依赖性细胞介导的细胞毒性活性,这些活性由 IgG Fc 和 Fc 结合配体之间的结合触发,并且是对清除癌细胞至关重要。此外,可以通过将 PFc29 的两个突变与效应子功能沉默突变相结合来关闭效应子功能,但抗体仍保持其出色的 pH 依赖性人 FcRn 结合特征。

更新日期:2022-11-02
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