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      Preparation of a Novel One-Armed Anti-c-Met Antibody with Antitumor Activity Against Hepatocellular Carcinoma

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          Abstract

          Introduction

          Antibody-based c-mesenchymal–epithelial transition factor (c-Met) inhibition is a promising strategy for hepatocellular carcinoma (HCC) treatment, but the intrinsic agonistic activity of the anti-c-Met antibody limits its application in drug development. Constructing a monovalent one-armed antibody has been reported to be an effective way to create an inhibitory anti-c-Met antibody.

          Materials and methods

          In the present study, a novel monovalent one-armed anti-c-Met antibody was constructed using the knobs-into-holes technology, and its inhibitory effects against HCC and the underlying mechanisms were explored.

          Results

          The one-armed anti-c-Met antibody blocked the hepatocyte growth factor (HGF)/c-Met interaction and the subsequent signal transduction, including phosphorylation of c-Met, Grb2-associated binding protein 1(Gab-1), extracellular regulated protein kinases 1/2(Erk1/2), and Akt, also referred to as protein kinase B (PKB) in HCC cell line HepG2. Furthermore, the autocrine stimulation of HepG2 cell proliferation and HGF-induced HCC cell migration were strongly inhibited by the one-armed anti-c-Met antibody. In addition, the antibody also reduced the HGF-induced proliferation and tube formation of human umbilical vein endothelial cells (HUVECs). Treating HepG2-bearing mice with the one-armed anti-c-Met antibody significantly inhibited the tumor growth in the xenograft nude mouse model.

          Conclusion

          The one-armed anti-c-Met antibody derived from the full-length bivalent anti-c-Met antibody might serve as a potential antitumor agent against HCC.

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          Most cited references 18

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          Molecular cloning and expression of human hepatocyte growth factor.

          Hepatocyte growth factor (HGF) is the most potent mitogen for mature parenchymal hepatocytes in primary culture, and seems to be a hepatotrophic factor that acts as a trigger for liver regeneration after partial hepatectomy and liver injury. The partial purification and characterization of HGF have been reported. We have demonstrated that pure HGF from rat platelets is a new growth factor effective at concentrations as low as 1 ng ml-1. The effects of HGF and epidermal growth factor (EGF) are additive. The activity of HGF is not species-specific, although it does not stimulate growth in Swiss 3T3 fibroblasts. HGF has a relative molecular mass (Mr) of 82,000 and is a heterodimer composed of a large alpha-subunit of Mr 69,000 and a small beta-subunit of Mr 34,000. Here we report the amino-acid sequence of human HGF determined by complementary DNA cloning and the expression of biologically active human HGF from COS-1 cells transfected with cloned cDNA. The nucleotide sequence of the human HGF cDNA reveals that both alpha- and beta-chains are contained in a single open reading frame coding for a pre-pro precursor protein of 728 amino acids.
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            Targeting the c-Met signaling pathway in cancer.

            On binding to the cell surface receptor tyrosine kinase (TK) known as c-Met, hepatocyte growth factor (HGF) stimulates mitogenesis, motogenesis, and morphogenesis in a wide range of cellular targets including, epithelial and endothelial cells, hematopoietic cells, neurons, melanocytes, and hepatocytes. These pleiotropic actions are fundamentally important during development, homeostasis, and tissue regeneration. HGF signaling also contributes to oncogenesis and tumor progression in several human cancers and promotes aggressive cellular invasiveness that is strongly linked to tumor metastasis. Our present understanding of c-Met oncogenic signaling supports at least three avenues of pathway selective anticancer drug development: antagonism of ligand/receptor interaction, inhibition of TK catalytic activity, and blockade of intracellular receptor/effector interactions. Potent and selective preclinical drug candidates have been developed using all three strategies, and human clinical trials in two of the three areas are now under way.
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              Fully human monoclonal antibodies to hepatocyte growth factor with therapeutic potential against hepatocyte growth factor/c-Met-dependent human tumors.

              c-Met is a well-characterized receptor tyrosine kinase for hepatocyte growth factor (HGF). Compelling evidence from studies in human tumors and both cellular and animal tumor models indicates that signaling through the HGF/c-Met pathway mediates a plethora of normal cellular activities, including proliferation, survival, migration, and invasion, that are at the root of cancer cell dysregulation, tumorigenesis, and tumor metastasis. Inhibiting HGF-mediated signaling may provide a novel therapeutic approach for treating patients with a broad spectrum of human tumors. Toward this goal, we generated and characterized five different fully human monoclonal antibodies that bound to and neutralized human HGF. Antibodies with subnanomolar affinities for HGF blocked binding of human HGF to c-Met and inhibited HGF-mediated c-Met phosphorylation, cell proliferation, survival, and invasion. Using a series of human-mouse chimeric HGF proteins, we showed that the neutralizing antibodies bind to a unique epitope in the beta-chain of human HGF. Importantly, these antibodies inhibited HGF-dependent autocrine-driven tumor growth and caused significant regression of established U-87 MG tumor xenografts. Treatment with anti-HGF antibody rapidly inhibited tumor cell proliferation and significantly increased the proportion of apoptotic U-87 MG tumor cells in vivo. These results suggest that an antibody to an epitope in the beta-chain of HGF has potential as a novel therapeutic agent for treating patients with HGF-dependent tumors.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                DDDT
                dddt
                Drug Design, Development and Therapy
                Dove
                1177-8881
                10 December 2019
                2019
                : 13
                : 4173-4184
                Affiliations
                [1 ]Department of Neurology, Shanghai Tongji Hospital, Tongji University School of Medicine , Shanghai 200065, People’s Republic of China
                [2 ]Biomedical Research Center, Tongji University Suzhou Institute , Suzhou, Jiangsu 215101, People’s Republic of China
                [3 ]School of Life Science and Technology, Tongji University , Shanghai 200092, People’s Republic of China
                Author notes
                Correspondence: Ming Jiang Biomedical Research Center, Tongji University Suzhou Institute , Building 2,198 Jinfeng Road, Wuzhong District, Suzhou, Jiangsu215101, People’s Republic of ChinaTel +86 512 6601 6586 Email jiangm@tongji.edu.cn
                Jianmin Fang School of Life Science and Technology, Tongji University , 1239 Siping Road, Shanghai200092, People’s Republic of ChinaTel +86 21 6598 2878 Email jfang@tongji.edu.cn
                [*]

                These authors contributed equally to this work

                Article
                224491
                10.2147/DDDT.S224491
                6911325
                © 2019 Yin et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                Page count
                Figures: 7, References: 25, Pages: 12
                Categories
                Original Research

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