Full synthesis of enzymatically cleavable linker between 929-designed ankyrin repeat protein and 17-dimethlyamino geldanamycin

Targeted cancer therapeutics are an important and promising field of cancer research due to their ability to reduce the off target effects produced in other therapies such as chemotherapy. Antibody Drug Conjugates (ADC) are one such therapeutic that specifically target cancer cells through antibody-antigen interactions. The ADC Trastuzumab-DM1 (TDM-1) is used to treat Human Epidermal Growth Factor Receptor 2 (HER-2) positive ovarian cancer, but based on previous work has been shown to be met with resistance, specifically through endosomal recycling of the drug. To combat resistance, an enzymatically cleavable linker was synthesized to conjugate 17-Dimethylamino Geldanamycin (DMAG) and 929 designed ankyrin repeat protein (929-DARPin) where DMAG was used to inhibit the route of endosomal recycling, and 929-DARPin used as the ligand to bind to HER-2. Following the synthesis and conjugation of the linker to 929-DARPin, we will be able to co-dose 929DARPin-DMAG and TDM-1 in order to see the changes in efficacy of TDM-1 as well as explore other linker applications to overcome drug resistance.