Comprehensive elucidation of the structural and functional roles of engineered disulfide bonds in antibody fc fragment
文献类型：期刊论文
| 作者 | Zeng, Fang1,2; Yang, Chunpeng1,2; Gao, Xinyu1,2; Li, Xuan1; Zhang, Zhe1; Gong, Rui1 |
| 刊名 | Journal of biological chemistry
 |
| 出版日期 | 2018-12-07 |
| 卷号 | 293期号:49页码:19127-19135 |
| ISSN号 | 0021-9258 |
| DOI | 10.1074/jbc.ra118.005367 |
| 通讯作者 | Gong, rui(gongr@wh.iov.cn) |
| 英文摘要 | Therapeutic monoclonal antibodies and fc-fusion proteins containing antibody fc fragment may tend to destabilize (e.g. unfold and aggregate), which leads to loss of functions and increase of adverse risks. although engineering of an additional disulfide bond has been performed in fc or fc domains for optimization, the relationships between introduced disulfide bond and alteration of the stability, aggregation propensity and function were still unclear and should be addressed for achievement of better therapeutic outcome. here, we constructed three human igg1 fc mutants including fc(ch2-s-s-) (one engineered disulfide bond in ch2 domain), fc(ch3-s-s-) (one engineered disulfide bond in ch3 domain), and fc(ch3-s-s-)(ch2-s-s-) (two engineered disulfide bonds in ch2 and ch3 domains, respectively) for evaluation. as expected, each mutated domain shows obviously increased stability during thermo-induced unfolding, and fc(ch3-s-s-)(ch2-s-s-) is most thermo-stable among wildtype fc (wtfc) and three mutants. the order of overall stability against denaturant is fc(ch3-s-s-)(ch2-s-s-) > fc(ch2-s-s-) > fc(ch3-s-s-) > wtfc. then the aggregation propensity was compared among these four proteins. under conditions of incubation at 60 degrees c, their aggregation resistance is in the order of fc(ch3-s-s-)(ch2-s-s-) > fc(ch2-s-s-) > fc(ch3-s-s-) approximate to wtfc. in contrast, the order is fc(ch3-s-s-)(ch2-s-s-) > fc(ch3-s-s-) > fc(ch2-s-s-) approximate to wtfc under acidic conditions. in addition, the fc-mediated functions are not obviously affected by engineered disulfide bond. our results give a comprehensive elucidation of structural and functional effects caused by additional disulfide bonds in the fc fragment, which is important for fc engineering toward the desired clinical performance. |
| WOS关键词 | HUMAN-IMMUNOGLOBULIN G ; HUMAN IGG1 ; COLLOIDAL STABILITIES ; CONSTANT DOMAINS ; AGGREGATION ; RECEPTOR ; BINDING ; DESIGN |
| WOS研究方向 | Biochemistry & Molecular Biology |
| WOS类目 | Biochemistry & Molecular Biology |
| 语种 | 英语 |
| 出版者 | AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC |
| WOS记录号 | WOS:000458467400024 |
| URI标识 | http://www.irgrid.ac.cn/handle/1471x/2373189 |
| 专题 | 武汉病毒研究所 |
| 通讯作者 | Gong, Rui |
| 作者单位 | 1.Chinese Acad Sci, Key Lab Special Pathogens & Biosafety, Wuhan Inst Virol, Wuhan 430071, Hubei, Peoples R China 2.Univ Chinese Acad Sci, Beijing 100049, Peoples R China |
| 推荐引用方式 GB/T 7714 | Zeng, Fang,Yang, Chunpeng,Gao, Xinyu,et al. Comprehensive elucidation of the structural and functional roles of engineered disulfide bonds in antibody fc fragment[J]. Journal of biological chemistry,2018,293(49):19127-19135. |
| APA | Zeng, Fang,Yang, Chunpeng,Gao, Xinyu,Li, Xuan,Zhang, Zhe,&Gong, Rui.(2018).Comprehensive elucidation of the structural and functional roles of engineered disulfide bonds in antibody fc fragment.Journal of biological chemistry,293(49),19127-19135. |
| MLA | Zeng, Fang,et al."Comprehensive elucidation of the structural and functional roles of engineered disulfide bonds in antibody fc fragment".Journal of biological chemistry 293.49(2018):19127-19135. |
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来源：武汉病毒研究所
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