Engineering non-antibody proteins to modulate cancer cells and tumor microenvironment interactions
- Tumor cell proliferation, migration, and survival and the formation of stromal blood vessel networks are all directed by aberrant signaling from protein ligands and their cognate receptors in the tumor microenvironment. These molecules play a central role in a wide range of biological systems by allowing intercellular communication. Thus, therapeutics that can effectively modulate these processes have been developed and highlighted as important drugs. Traditionally, tumor targeting of cell surface receptors and ligands is accomplished using neutralizing antibodies. However, this approach is limited by the high affinity of ligand-receptor interactions that often cannot be effectively inhibited by monoclonal antibodies, which typically have affinities in the low nanomolar range. To overcome this challenge, we have taken two approaches to developing new cancer therapeutics: 1) Creating a high affinity (pM) dimeric tumor targeting protein scaffold using site-specific chemical conjugation; 2) Engineering high affinity (pM) inhibitors of a natural ligand, and its cognate receptor, to block crosstalk between tumor cells and cancer-associated fibroblasts. In this work, we developed a strategy for incorporating a non-natural amino acid for site-specific chemical conjugation to create dimeric integrin-targeting cystine knot (knottin) miniproteins that bound tumor cells with pM affinity and more effectively inhibited tumor cell migration and proliferation compared to the knottin monomers or the small molecule drug cilengitide. Additionally, based on a novel mode of crosstalk between tumor cells and cancer-associated fibroblast discovered by our collaborator, professor Alejandro Sweet-Cordero (University of California, San Francisco), we developed inhibitors of ciliary neurotrophic factor receptor (CNTFR) and its ligand, cardiotrophin-like cytokine factor 1 (CLCF1), by engineering the molecules themselves to function as a high affinity 'decoy receptor' and an antagonistic ligand, respectively. In the process of engineering the antagonistic ligand we also identified potent receptor agonists, which may have beneficial effects in neuroregeneration.
|Type of resource
|electronic; electronic resource; remote
|1 online resource.
|Kim, Jun Woo
|Stanford University, Department of Bioengineering.
|Cochran, Jennifer R
|Cochran, Jennifer R
|Statement of responsibility
|Jun Woo Kim.
|Submitted to the Department of Bioengineering.
|Thesis (Ph.D.)--Stanford University, 2017.
- © 2017 by Jun Woo Kim
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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