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

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

doi:10.18632/oncotarget.16173

Zu-Jun Sun, Yu-Xiong Wang + Show 5 more

Open Access

https://doi.org/10.18632/oncotarget.16173

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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.

Highlights

Cellular-mesenchymal to epithelial transition factor (c-MET) is confirmed as the only high affinity receptor that binds hepatocyte growth factor (HGF) [1], which mediates cell morphogenesis, mitogenesis, angiogenesis, and cytoprotection in vitro [2, 3]. c-MET is overexpressed in a broad spectrum of human solid tumors [2, 4], and once activated, promotes tumor progression, invasion, metastasis, and angiogenesis [5]. c-MET is overexpressed in human glioblastomas, and expression levels correlate with glioma malignancy grade and vascularity, promoting glioma growth and angiogenesis in vivo [5,6,7,8,9,10]
The results showed that all eight cancer cell lines expressed c-MET protein at a relative high levels (Figure 1B)
We found that HGF-mediated upregulation of p-c-MET in MKN45 and A549 cells was completely inhibited with bispecific antibody (BsAb) treatment, even more profoundly efficiency than JNJ treatment (Figure 3)

Summary

INTRODUCTION

Cellular-mesenchymal to epithelial transition factor (c-MET) is confirmed as the only high affinity receptor that binds hepatocyte growth factor (HGF) [1], which mediates cell morphogenesis, mitogenesis, angiogenesis, and cytoprotection in vitro [2, 3]. c-MET is overexpressed in a broad spectrum of human solid tumors [2, 4], and once activated, promotes tumor progression, invasion, metastasis, and angiogenesis [5]. c-MET is overexpressed in human glioblastomas, and expression levels correlate with glioma malignancy grade and vascularity, promoting glioma growth and angiogenesis in vivo [5,6,7,8,9,10]. C-MET is overexpressed in a broad spectrum of human solid tumors [2, 4], and once activated, promotes tumor progression, invasion, metastasis, and angiogenesis [5]. Monoclonal antibodies against growth factors or their receptors have been approved for cancer therapy. Ipilimumab, a monoclonal antibody that works to activate the immune system by targeting CTLA-4, combined with nivolumab attained intense and synergistic therapeutic effects in the treatment of a deadly form of skin cancer [33,34]. We have further identified that our BsAb could potently inhibit tumor growth and inflammatory factor secretion in vivo, implicating its immunotherapeutic potential in human solid tumor treatment

RESULTS

DISCUSSION

MATERIALS AND METHODS