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

Abstract

IntroductionAntibody-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 methodsIn 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.ResultsThe 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.ConclusionThe 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.