Chemically Self-Assembling Nanorings (CSANs) can be functionalized with groups such as protein binding domains for cancer targeting or peptide sequences with the potential to be farnesylated. Farnesylation is a post-translational protein modification where a farnesyl is added to the cysteine of a C-terminal CaaX box motif, such as CVIA. Farnesylation, by adding a hydrophobic isoprenoid, encourages association with cell membranes, enabling the farnesylated CSANs to modify T cells’ surface for cancer immunotherapy. We have designed two constructs for CSAN formation, both of which target Epithelial Cell Adhesion Molecule (EpCAM), which is overexpressed on the cell surface of several cancers. One construct consists of a fibronectin-based EpCAM targeting domain fused to DHFR2 and has a terminal CVIA sequence for farnesylation. The other construct utilizes the promiscuity of PFTase to introduce an azido-farnesyl analog to a prenylatable EpCAM-binding DARPin protein. Through a DBCO-PEG5-DBCO linker, the EpCAM-binding DARPin protein can be linked to the general CSAN construct, offering an alternative way to construct cancer-targeting CSANs without the need for new fusion proteins. Both constructs could be used for CSAN formation and subsequent anti-cancer applications.

Constructing farnesylated anti-EpCAM CSANs for cancer immunotherapy

2019 Spring National Meeting

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