Research Papers:

Structural basis of a novel heterodimeric Fc for bispecific antibody production

Hudie Wei, Haiyan Cai, Yuhao Jin, Pilin Wang, Qingqing Zhang, Yihui Lin, Weixiao Wang, Jinke Cheng, Naiyan Zeng, Ting Xu and Aiwu Zhou _

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Oncotarget. 2017; 8:51037-51049. https://doi.org/10.18632/oncotarget.17558

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Hudie Wei1,*, Haiyan Cai1,*, Yuhao Jin2,*, Pilin Wang2,*, Qingqing Zhang2, Yihui Lin3, Weixiao Wang4, Jinke Cheng5, Naiyan Zeng1, Ting Xu2 and Aiwu Zhou1

1Hongqiao International Institute of Medicine, Shanghai Tongren Hospital/Faculty of Basic Medicine, Key Laboratory of Cell Differentiation and Apoptosis of The Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China

2The Therapeutic Antibody Research Center of SEU-Alphamab, Southeast University, Nanjing, China

3Division of Translational Medicine, 3D Medicines Corporation, Shanghai, China

4Department of Pharmaceutical Engineering, College of Humanities-Information, Changchun University of Technology, Changchun, China

5Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China

*These authors contributed equally to this work

Correspondence to:

Aiwu Zhou email: [email protected]

Ting Xu email: [email protected]

Naiyan Zeng email: [email protected]

Keywords: bispecific antibodies, heterodimeric Fc engineering, crystal structure, trastuzumab, pertuzumab

Received: March 14, 2017     Accepted: April 19, 2017     Published: May 02, 2017


Bispecific antibodies provide an efficient tool for combinational clinical therapy. Here we have engineered a heterodimeric Fc for bispecific antibodies production by combining the knob-into-hole and electrostatic steering strategies where a bulky hydrophobic residue Phe405 of the IgG CH3 interface is mutated to a charged residue Lys and Lys409 of the corresponding CH3 domain is mutated to Ala. The crystal structure of this Fc heterodimer solved here at 2.7Å resolution revealed how these two mutations resulted a complementary binding interface and explained why F405K mutation could effectively inhibit Fc homodimer formation during protein expression. An anti-HER2 bispecific antibody derived from trastuzumab and pertuzumab was generated by this heterodimeric Fc. It showed comparable or improved efficacy than the combination of trastuzumab and pertuzumab in inhibiting proliferation of cancer cells in vitro and in vivo. Overall this study shows that the heterodimeric Fc engineered here provides an efficient platform for generating active bispecific antibody for cancer treatment.

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