Project abstract for group wagnercr

Development of Anti-Cancer Nanorings

Recent advances with bispecific antibodies have demonstrated that T-cells can be targeted to cancer cells, resulting in selective cell destruction. An alternative approach is adoptive T-cell therapy, which relies on gene transfer technologies for the expression of tumor targeting single chain antibodies (scFvs), referred to as chimeric antigen receptors (CARs). Although promising, the efficiency of gene transfer, cell-to-cell CAR gene expression variability, and a dependence on time consuming plasmid re-engineering in order to alter the targeting receptor pose significant hurdles. To address these concerns, these researchers have developed a new modular approach for the rapid engineering of cell surfaces. The approach relies on their discovery that when scFV-DHFR-DHFR fusion proteins are combined with bivalent methotrexate (bisMTX), chemically self-assembled antibody nanorings (CSANS) are formed with tunable valencies of 2, 4 and 8 scFv’s. Recently, the researchers have prepared bisMTX-phospholipid conjugates, which when treated with DHFR-DHFR-anti-EpCam scFv fusion proteins, containing either a 13 or 1 amino acid linker between the DHFRs, form bivalent and octavalent anti-EpCam lipid-CSANS (L-CSANS), respectively. The anti-EpCam L-CSANS were shown to rapidly incorporate into the membranes of cells, including activated T-cells. The cell surface modified cells were shown to selectively bind to EpCam+ cells, such as the breast cancer cell line, MDA-MD-231 cells. Upon treatment with a non-toxic DHFR inhibitor, trimethoprim, which leads to CSANS disassembly, the cells were shown to quickly disengage from each other. In addition, activated T-cells that had been modified by anti-EpCam L-CSANS, demonstrated selective cytotoxicity to the target cells, MDA-MB-231. Thus, the researchers have shown that targeting L-CSANS have the potential to be a flexible and modular approach for the rapid engineering of T-cell surfaces for T-cell immunotherapy. 

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