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Monovalent antibody design and mechanism of action of onartuzumab, a MET antagonist with anti-tumor activity as a therapeutic agent

2013; National Academy of Sciences; Volume: 110; Issue: 32 Linguagem: Inglês

10.1073/pnas.1302725110

1091-6490

Mark Merchant, Xiaolei Ma, Henry R. Maun, Zhong Zheng, Jing Peng, Mally Romero, Arthur Huang, Nai-ying Yang, Merry Nishimura, Joan Greve, Lydia Santell, Yu-Wen Zhang, Yanli Su, Dafna Kaufman, Karen L. Billeci, Elaine Mai, Barbara Moffat, Amy Lim, Eileen Duenas, Heidi Phillips, Hong Xiang, Judy Young, George F. Vande Woude, Mark S. Dennis, Dorothea Reilly, Ralph Schwall, Melissa A. Starovasnik, Robert A. Lazarus, Daniel G. Yansura,

Phagocytosis and Immune Regulation

Significance Therapeutic antibodies have revolutionized the treatment of human disease. Despite these advances, antibody bivalency limits their utility against some targets. Here, we describe the development of a one-armed (monovalent) antibody, onartuzumab, targeting the receptor tyrosine kinase MET. While initial screening of bivalent antibodies produced agonists of MET, engineering them into monovalent antibodies produced antagonists instead. We explain the structural basis of the mechanism of action with the crystal structure of onartuzumab antigen-binding fragment in complex with MET and HGF-β. These discoveries have led to an additional antibody-based therapeutic option and shed light on the underpinnings of HGF/MET signaling.