| Autor: |
Sun ZJ; Key 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., Wu Y; Key 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., Hou WH; Key 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., Wang YX; Key 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., Yuan QY; Key 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., Wang HJ; Department of Medical Oncology, Shanghai Cancer Center and Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China., Yu M; Key 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. |
| Abstrakt: |
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. |
