Structural insight into a matured humanized monoclonal antibody HuA21 against HER2-overexpressing cancer cells

Wang, Zhenyi1,2,3,4; Cheng, Liansheng5; Guo, Gongrui1,2,3; Cheng, Baoyun1,2,3; Hu, Siyi5; Zhang, Hongmin4; Zhu, Zhongliang1,2,3; Niu, Liwen1,2,3

2019-06

10.1107/S2059798319006995

ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY   影响因子和分区

2059-7983

HER2, a member of the epidermal growth factor receptor (EGFR) family, has been associated with human breast, ovarian and gastric cancers. Anti-HER2 monoclonal antibodies (mAbs) have demonstrated clinical efficacy for HER2-overexpressing breast cancer. A chimeric antibody chA21 that specifically inhibits the growth of HER2-overexpressing cancer cells both in vitro and in vivo has previously been developed. To reduce a potential human anti-mouse immune response, the humanized antibody HuA21 was developed and was further subjected to affinity maturation by phage display on the basis of chA21. Here, the crystal structure of HuA21-scFv in complex with the extracellular domain of HER2 is reported, which demonstrates that HuA21 binds almost the same epitope as chA21 and also provides insight into how substitutions in HuA21 improve the binding affinity compared with chA21, which could facilitate structure-based optimization in the future. Furthermore, the effects of HuA21 variants with constant domains of different lengths were explored and it was noticed that the deletion of constant domain 1 could improve the inhibition efficacy in a cell-proliferation assay, possibly functioning via increased internalization, which might guide the design of other monoclonal antibodies.

HER2-overexpressing cancer humanized antibody EGFR family cell signaling crystal structure

SCI

英语

通讯

Ministry of Science and Technology of the People's Republic of China[2017YFA0503600] ; Ministry of Science and Technology of the People's Republic of China[2017YFA0504903] ; Ministry of Science and Technology of the People's Republic of China[2012CB917200]

Biochemistry & Molecular Biology ; Biophysics ; Crystallography

Biochemical Research Methods ; Biochemistry & Molecular Biology ; Biophysics ; Crystallography

WOS:000471848800005

INT UNION CRYSTALLOGRAPHY

Web of Science

1.Univ Sci & Technol China, Hefei Natl Lab Phys Sci Microscale, Hefei 230026, Anhui, Peoples R China
2.Univ Sci & Technol China, Sch Life Sci, Hefei 230026, Anhui, Peoples R China
3.Chinese Acad Sci, Key Lab Struct Biol, Hefei 230026, Anhui, Peoples R China
4.Southern Univ Sci & Technol, Dept Biol, Shenzhen 518000, Guangdong, Peoples R China
5.Hanke Mab Biotechnol Inc, Hefei 230026, Anhui, Peoples R China

Wang, Zhenyi,Cheng, Liansheng,Guo, Gongrui,et al. Structural insight into a matured humanized monoclonal antibody HuA21 against HER2-overexpressing cancer cells[J]. ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY,2019,75:554-563.

Wang, Zhenyi.,Cheng, Liansheng.,Guo, Gongrui.,Cheng, Baoyun.,Hu, Siyi.,...&Niu, Liwen.(2019).Structural insight into a matured humanized monoclonal antibody HuA21 against HER2-overexpressing cancer cells.ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY,75,554-563.

Wang, Zhenyi,et al."Structural insight into a matured humanized monoclonal antibody HuA21 against HER2-overexpressing cancer cells".ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY 75(2019):554-563.