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Oncotarget. 2017 May 2;8(31):51037-51049. doi: 10.18632/oncotarget.17558. eCollection 2017 Aug 1.

Structural basis of a novel heterodimeric Fc for bispecific antibody production.

Author information

1
Hongqiao 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.
2
The Therapeutic Antibody Research Center of SEU-Alphamab, Southeast University, Nanjing, China.
3
Division of Translational Medicine, 3D Medicines Corporation, Shanghai, China.
4
Department of Pharmaceutical Engineering, College of Humanities-Information, Changchun University of Technology, Changchun, China.
5
Department 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.
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Contributed equally

Abstract

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.

KEYWORDS:

bispecific antibodies; crystal structure; heterodimeric Fc engineering; pertuzumab; trastuzumab

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