Team:CU-Boulder

Abstract

Biologic based therapies have become a promising field in cancer medicine due to their ability to harness the immune system to attack cancer cells. However, a potential side-effect of these therapies is an overactive immune system which can lead to severe reactions and possibly death. A solution to this overactive autoimmune attack would be to engineer and implement a safety switch into the system. This would allow for more aggressive monoclonal antibody therapies to be used while limiting the hazards of potential severe side-effects of current therapies. Biologics are typically antibody-based macromolecules that are injected into the bloodstream and are cleared from the body on the order of weeks. Due to these reasons, if a problem arose from immunotherapy treatment it is not currently possible to quickly remove the antibody. We propose to engineer an antibody with an allosteric on/off switch using specific protein domains that are responsive to the small molecule rapamycin as a solution to this problem. Rapamycin is orally available, fast acting and is cleared from the body within hours. When rapamycin binds to the domains, there would be a conformational change to the active site of the antibody resulting in the dangerous autoimmune response to be shut down, protecting the body. We are currently modeling our protein designs using molecular dynamics simulations to predict conformational changes in the antibody active site upon the binding of rapamycin. We will produce our protein designs in a bacterial system, purify the components with chromatography and test their responsiveness to rapamycin with ELISA assays. The application of our antibody “switches” could improve the safety of future biologic based therapies.