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Acta Crystallogr D Struct Biol. 2019 Jun 1;75(Pt 6):554-563. doi: 10.1107/S2059798319006995. Epub 2019 May 31.

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

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Hefei National Laboratory for Physical Sciences at the Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230026, People's Republic of China.
Hanke Mab Biotechnologies Inc., Hefei, Anhui 230026, People's Republic of China.
Department of Biology, Southern University of Science and Technology, Shenzhen, Guangdong 518000, People's Republic of China.


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.


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


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