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Structural basis of a novel heterodimeric Fc for bispecific antibody production

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...

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Autores principales: Wei, Hudie, Cai, Haiyan, Jin, Yuhao, Wang, Pilin, Zhang, Qingqing, Lin, Yihui, Wang, Weixiao, Cheng, Jinke, Zeng, Naiyan, Xu, Ting, Zhou, Aiwu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5584228/
https://www.ncbi.nlm.nih.gov/pubmed/28881627
http://dx.doi.org/10.18632/oncotarget.17558
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author Wei, Hudie
Cai, Haiyan
Jin, Yuhao
Wang, Pilin
Zhang, Qingqing
Lin, Yihui
Wang, Weixiao
Cheng, Jinke
Zeng, Naiyan
Xu, Ting
Zhou, Aiwu
author_facet Wei, Hudie
Cai, Haiyan
Jin, Yuhao
Wang, Pilin
Zhang, Qingqing
Lin, Yihui
Wang, Weixiao
Cheng, Jinke
Zeng, Naiyan
Xu, Ting
Zhou, Aiwu
author_sort Wei, Hudie
collection PubMed
description 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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spelling pubmed-55842282017-09-06 Structural basis of a novel heterodimeric Fc for bispecific antibody production Wei, Hudie Cai, Haiyan Jin, Yuhao Wang, Pilin Zhang, Qingqing Lin, Yihui Wang, Weixiao Cheng, Jinke Zeng, Naiyan Xu, Ting Zhou, Aiwu Oncotarget Research Paper 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. Impact Journals LLC 2017-05-02 /pmc/articles/PMC5584228/ /pubmed/28881627 http://dx.doi.org/10.18632/oncotarget.17558 Text en Copyright: © 2017 Wei et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (http://creativecommons.org/licenses/by/3.0/) (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Wei, Hudie
Cai, Haiyan
Jin, Yuhao
Wang, Pilin
Zhang, Qingqing
Lin, Yihui
Wang, Weixiao
Cheng, Jinke
Zeng, Naiyan
Xu, Ting
Zhou, Aiwu
Structural basis of a novel heterodimeric Fc for bispecific antibody production
title Structural basis of a novel heterodimeric Fc for bispecific antibody production
title_full Structural basis of a novel heterodimeric Fc for bispecific antibody production
title_fullStr Structural basis of a novel heterodimeric Fc for bispecific antibody production
title_full_unstemmed Structural basis of a novel heterodimeric Fc for bispecific antibody production
title_short Structural basis of a novel heterodimeric Fc for bispecific antibody production
title_sort structural basis of a novel heterodimeric fc for bispecific antibody production
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5584228/
https://www.ncbi.nlm.nih.gov/pubmed/28881627
http://dx.doi.org/10.18632/oncotarget.17558
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