Antibody-derived therapeutics have proved to be very effective in several disease conditions where conventional therapies have failed and several therapeutic antibodies have gained clinical use for major diseases including cancers, chronic inflammatory diseases, and autoimmune diseases. However, therapeutic antibodies are typically administered in the blood circulation at high doses, and their intended protein targets can have additional functions unrelated to the disease. For this reason, systemic inhibition of the target can produce undesirable adverse effects.As many therapeutic antibodies currently show dose-limiting on-target toxicity, improved spatial and temporal control of antibody activity is needed to reduce unwanted side effects.
Summary of the Invention
The use of chemical biology to modulate protein activity is a powerful strategy that can be used to engineer small molecule-dependent protein activity into specific proteins of interest. By tethering protein activity to the presence of a small molecule, one can “switch on” the protein using that small molecule. By engineering a new allosteric site into therapeutic antibodies such as checkpoint inhibitors, the antibody can be produced in an “off state” by default, such that administering this inactive form of the antibody does not engage antigen. Upon introduction of the activating small molecule into the intended (tumor) site, the antibody will be activated and thus elicit toxicity only in the proximity of the injection site. Thus, applying this scheme to therapeutic antibodies in cancer can reduce adverse side effects caused by antibody activity outside the tumor microenvironment. Scientists at Fox Chase Cancer Center and University of Kansas have successfully designed and introduced mutations that inactivate an antibody, with a partner small molecule that 'rescues' the antibody activity. The inactive form of the antibody and the small molecule are envisioned administered in parallel and delivered locally to the tumor environment. Thus, the antibody is active at the target site, and not elsewhere in the body.
- Novel immuno-oncology therapy employing "switchable" antibody by a small molecule.
- Targeted, effective, precision treatment of tumors.
- Novel technology to modulate activity of therapeutic antibodies.IP StatusPatent application has been filed.
For Licensing/Partnering information, please contact:
Inna Khartchenko, MSc, MBADirector,
Technology Transfer and New Ventures
Fox Chase Cancer Center