Oncotarget

Research Papers:

A novel bispecific c-MET/PD-1 antibody with therapeutic potential in solid cancer

Zu-Jun Sun, Yi Wu, Wei-Hua Hou, Yu-Xiong Wang, Qing-Yun Yuan, Hui-Jie Wang _ and Min Yu

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Oncotarget. 2017; 8:29067-29079. https://doi.org/10.18632/oncotarget.16173

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Abstract

Zu-Jun Sun1,*, Yi Wu1,*, Wei-Hua Hou1, Yu-Xiong Wang1, Qing-Yun Yuan1, Hui-Jie Wang2, Min Yu1

1Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education and Department of Biochemistry and Molecular Biology, School of Basic Medical Science, Fudan University, Shanghai, China

2Department of Medical Oncology, Shanghai Cancer Center and Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China

*These authors have contributed equally to this work

Correspondence to:

Hui-Jie Wang, email: wanghj98@hotmail.com

Min Yu, email: minyu@shmu.edu.cn

Keywords: cellular-mesenchymal to epithelial transition factor, programmed death-1

Received: September 13, 2016     Accepted: January 24, 2017     Published: March 14, 2017

ABSTRACT

The bispecific antibody is a novel antibody, which can target two different antigens and mediate specific killing effects by selectively redirecting effector cells to the target cells. Here, we designed and synthesized a bispecific antibody (BsAb) that can bind cellular-mesenchymal to epithelial transition factor (c-MET, overexpressed in several human solid tumor), and programmed death-1 (PD-1, involved in cancer cell immune evasion) with high affinity and specificity. We found that BsAb can induce the degradation of c-MET protein in cancer cells, including MKN45, a gastric cancer cell line, and A549, a lung cancer cell line. BsAb inhibited hepatocyte growth factor (HGF)-mediated proliferation, migration, and antiapoptosis, and downregulated HGF-stimulated phosphorylation of c-MET, protein kinase B (AKT), and extracellular signal-regulated kinase (ERK1/2). BsAb can also rescue T cell activation. Furthermore, xenograft analysis revealed that BsAb markedly inhibits the growth of subcutaneously implanted tumors and chronic inflammation. On the basis of these results, we have identified a potential bispecific drug, which can effectively target c-MET and PD-1 for the treatment of human solid cancers.


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