Cochran Lab
Cochran Lab
RESEARCH

Engineering Proteins that Bind to and Inhibit Multiple Receptors

There is great therapeutic potential for multi-specific proteins that can modulate more than one disease target. For a perspectives piece on bi-specific proteins see: Cochran, J.R., 2010 Science Translational Medicine, 2, 17ps5.

multireceptors diagramOur lab has a strong focus and interest in developing multi-specific proteins for therapeutic applications. As an example of one project, we developed a novel platform for engineering dual-specific protein ligands that can bind to and antagonize two different receptors involved in angiogenesis (Papo et al., 2011, Proceedings of the National Academy of Science, 108, 14067-72). Significant crosstalk exists between receptors that regulate angiogenesis, such as vascular endothelial growth factor receptor-2 (VEGFR2) and αvβ3 integrin. Here, we developed a dual-specific agent that antagonizes both of these receptors and effectively inhibits angiogenic processes in vitro and in vivo. We used an antagonistic VEGF ligand as a molecular scaffold to engineer dual-specific proteins that simultaneously bind to VEGFR2 and αvβ3 integrin with antibody-like affinities. Compared to mono-specific variants that bind only VEGFR2 or αvβ3 integrin, dual-specific proteins more strongly inhibited VEGF-mediated receptor phosphorylation, sprout formation, and proliferation of endothelial cells cultured on Matrigel or vitronectin-coated surfaces. Moreover, dual-specificity conferred nearly complete inhibition of VEGF-mediated blood vessel formation in vivo, whereas mono-specific variants that bind VEGFR2 or αvβ3 integrin were only marginally effective. The vast majority of bi-specific therapeutics are antibodies or proteins that are assembled through associating domains or a flexible tether. Our work is the first example of a dual-specific protein where additional functionality was introduced into a natural protein ligand to complement its existing biological properties. This work was featured in a recent press release: http://med.stanford.edu/ism/2011/august/cochran.html. We are currently evaluating the promise of these engineered proteins as cancer therapeutics and diagnostics. In addition, we are extending this platform to engineer dual-specific proteins against other important receptor combinations.