6J71

HuA21-scFv in complex with the extracellular domain(ECD) of HER2

Summary for 6J71

• Entry DOI: 10.2210/pdb6j71/pdb
• Descriptor: Receptor tyrosine-protein kinase erbB-2, anti-HER2 humanized antibody HuA21, beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (4 entities in total)
• Functional Keywords: tyrosine-protein kinase, antibody, transcription regulation, signaling protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 95889.77

Authors

Wang, Z.,Guo, G.,Cheng, B.,Zhu, Z.,Niu, L.,Zhang, H. (deposition date: 2019-01-16, release date: 2019-02-27, Last modification date: 2023-11-22)

Primary citation

Wang, Z.,Cheng, L.,Guo, G.,Cheng, B.,Hu, S.,Zhang, H.,Zhu, Z.,Niu, L.
Structural insight into a matured humanized monoclonal antibody HuA21 against HER2-overexpressing cancer cells.
Acta Crystallogr D Struct Biol, 75:554-563, 2019

PubMed Abstract: 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.

PubMed: 31205018
DOI: 10.1107/S2059798319006995

Experimental method

X-RAY DIFFRACTION (2.918 Å)