Biomolecular Structure Studies Advance an Antibody Approach to Cancer Therapy

Crystal structures obtained at the Advanced Light Source helped inform Genentech about the binding mechanism of a unique antibody that targets multiple cancer types.

The one-armed antibody, onartuzumab (pink) binds to the receptor tyrosine kinase, MET (green and blue) found on the surface of cells preventing the binding of hepatocyte growth factor (HGF) (red) disrupting the development and growth of tumors.
Image courtesy of David Wolf, Viscira, LLC
The one-armed antibody, onartuzumab (pink) binds to the receptor tyrosine kinase, MET (green and blue) found on the surface of cells preventing the binding of hepatocyte growth factor (HGF) (red) disrupting the development and growth of tumors.

The Science

Using crystal structures obtained at the Advanced Light Source (ALS), researchers demonstrated the mechanism of action of a unique potential therapeutic antibody against the receptor tyrosine kinase MET, a protein that plays a key role in some cancers. In cancerous cells, the overactivity of MET leads to tumor survival, growth, and metastasis, making disruption of this interaction a promising therapeutic strategy.

The Impact

Seeing how a particular antibody called onartuzumab interacts with the receptor tyrosine kinase MET provides researchers evidence of how MET normally activates to control cell growth. This information will help Genentech assess the effectiveness of onartuzumab in clinical trials as well as potentially develop additional antibody-based therapeutic options.

Summary

Therapeutic antibodies have revolutionized the treatment of human disease, however antibody bivalency (an antibody’s capability to bind to two molecules of an antigen) can limit their utility against some targets due to receptor crosslinking and activation. Genentech has developed a unique one-armed antibody, onartuzumab, which is now in late-stage clinical trials for multiple cancer types. Crystal structures obtained at the Advanced Light Source allowed Genentech to demonstrate the mechanism of action of onartuzumab against its target, the receptor tyrosine kinase MET. MET is activated by binding its only ligand, the hepatocyte growth factor (HGF), resulting in receptor activation and downstream signaling. HGF/MET signaling plays important roles during embryonic development and in wound healing in adults; however, in malignant cells, overactive MET leads to tumor development, so disrupting this interaction is key. MET is activated by dimerization – the binding together of two MET molecules – so any process that enhances dimerization risks enhancing malignant growth rather than inhibiting it. Some traditional bivalent antibodies unfortunately do exactly that: they bind two copies of their target. Therefore, targeting MET with bivalent antibodies may mimic HGF agonism, spurring instead of halting tumor growth.

Contact

Mark Merchant
Genentech
merchant.mark@gene.com

Funding

Genentech

Publications

M. Merchant, X. Mab, H.R. Maunc, Z. Zhenga, J. Penga, M. Romeroa, A. Huangd, N. Yanga, M. Nishimuraa, J. Grevee, L. Santellc, Y. Zhangf, Y. Suf, D. Kaufmanf, K. Billecig, E. Maih, B. Moffatg, A. Limi, E. Duenasi, H. Phillipsa, H. Xiangi, J. Youngh, G. Vande Woudef, M. Dennisd, D. Reillyk, R. Schwalla, M. Starovasnikb, R. Lazarusc, D. Yansurad, “Monovalent antibody design and mechanism of action of onartuzumab, a MET antagonist with anti-tumor activity as a therapeutic agent.” PNAS 110, E2987-96 (2103). [DOI: 10.1073/pnas.1302725110]

Highlight Categories

Program: BES , SUF

Performer: Industry , SC User Facilities , BES User Facilities , ALS