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

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.

Keywords:

• antitumor
• c-Met
• hepatocellular carcinoma
• knobs into holes
• monovalent antibody
• targeted therapy

Acknowledgment

This study was financially supported by the National Major Scientic and Technological Special Project for Significant New Drugs Development (2019ZX09732002-12), the Natural Science Foundation of Jiangsu Province of China (BK20150278) and the Shanghai Science and Technology Commission (19431903200).

Disclosure

Jianmin Fang reports personal fees from RemeGen Ltd., outside the submitted work. The authors report no other conflicts of interest in this work.